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Acquired immunodeficiency syndrome (AIDS) and its causal agent, the human immunodeficiency virus 1 (HIV-1), remain a global public health concern since they were first identified in the early 1980s. Diligent research and gradual scientific advances have led to innovative strategies in HIV-1/AIDS prevention and treatment, transforming an obscure and deadly disease into a manageable condition with a normal life expectancy. Despite this progress, researchers have yet to develop a safe and effective vaccine against HIV-1. The work presented here describes a structural perspective related to the HIV-1 Envelope (Env) glycoprotein, the sole viral target of vaccines that seek to elicit neutralizing antibodies.
\r\n\r\nEnv is the only viral protein on the surface of HIV-1 virions and is composed of a homotrimer of gp120/gp41 heterodimers. Env mediates entry into target cells by engaging the host receptor, CD4. CD4 triggers conformational changes in gp120, thereby enabling coreceptor recognition. Interactions with the host coreceptor trigger structural rearrangements in gp41 that facilitate fusion of host and viral membranes leading to infection. Our work builds upon our understanding of Env structural plasticity. First, we evaluated the conformational plasticity of soluble Env constructs using double electron-electron resonance (DEER) spectroscopy. This method measured distances between probes in Env subunits, allowing us to interpret the distribution in distances as Env flexibility. Our findings captured previously unseen nuances in static Env structures including gp41 elasticity and conformational heterogeneity associated with CD4-receptor binding. Although our work gave a new perspective on Env flexibility, it largely corroborated observations from static Env structures. Importantly, this suggested that soluble versions of Env, which serve as templates for immunogen design, retain favorable structural properties.
\r\n\r\nInformed with these insights in Env structure, we then sought to address a prevailing question related to receptor engagement: how many CD4 receptors are needed to induce gp120 conformation changes that lead to coreceptor binding followed by fusion? Prior work only characterized CD4-induced Env structural changes in Envs complexed with three soluble CD4 proteins. In our work, we designed and structurally characterized Envs bound to only one or two CD4 receptors. We found that Env engagement of one CD4 resulted in minor changes to the prefusion, closed Env conformation while Env bound to two CD4 molecules led to CD4-induced opening in the CD4-bound gp120s and a partially open conformation in the unliganded gp120.
\r\n\r\nStructural biology has also been leveraged to characterize the mechanism by which broadly neutralizing antibodies (bNAbs) recognize HIV-1 Env. We include an extensive review of how structural observations from antibodies bound to viral proteins contribute to our understanding of antibody-mediated viral neutralization. We also present a technical evaluation of bNAb binding assays that revealed how Env conformations can be unintentionally altered resulting in misleading antibody binding results and identified ideal methods to ensure reliable data.
\r\n\r\nAdditionally, we report on projects related to bNAbs that target the CD4 binding site (CD4bs) epitope of Env. In the first, we characterized the inferred germline (iGL) precursor of BG24, a VRC01-class bNAb with features that make it a promising target for vaccine design. We solved four cryo-EM structures of BG24iGL constructs complexed with different Envs and provided insight on the mode of iGL accommodation. The second project centers around the IOMA-class of CD4bs bNAbs. We characterized features of IOMA-class bNAbs and measured how different features contribute to neutralization breadth and potency. Taken together, the conclusions from our work provide guidance for the next generation of structure-based, CD4bs-targeting immunogen design.
", "date": "2023", "date_type": "degree", "id_number": "CaltechTHESIS:06022023-003659646", "refereed": "FALSE", "official_url": "https://resolver.caltech.edu/CaltechTHESIS:06022023-003659646", "related_url": { "items": [ { "description": "Article adapted for ch. 1", "type": "doi", "url": "https://doi.org/10.1016/j.immuni.2018.06.017" }, { "description": "Article adapted for ch. 2", "type": "doi", "url": "https://doi.org/10.1101/2023.01.27.525985" }, { "description": "Article adapted for ch. 3", "type": "doi", "url": "https://doi.org/10.3390/v13102106" }, { "description": "Article adapted for ch. 4", "type": "doi", "url": "https://doi.org/10.1038/s41598-022-15506-x" }, { "description": "Article adapted for ch. 5", "type": "doi", "url": "https://doi.org/10.1101/2022.03.25.485873" } ] }, "rights": "No commercial reproduction, distribution, display or performance rights in this work are provided.", "funders": { "items": [ { "agency": "National Institute of Health (NIH)", "grant_number": "NIH U54 AI170856" }, { "agency": "National Institute of Allergy and Infectious Diseases (NIAID) Grant HIVRAD", "grant_number": "P01 AI100148" }, { "agency": "Bill and Melinda Gates Foundation Collaboration for AIDS Vaccine Discovery (CAVD)", "grant_number": "INV-002143" } ] }, "collection": "CaltechTHESIS", "reviewer": "Kathy Johnson", "suggestions": "Released 2023-06-09 after 1-week embargo.", "deposited_by": "Kim-Marie Dam", "deposited_on": "2023-06-02 23:43:38", "doi": "10.7907/8pvb-dx31", "divisions": { "items": [ "div_bbe" ] }, "institution": "California Institute of Technology", "thesis_type": "phd", "thesis_advisor": { "items": [ { "email": "bjorkman@caltech.edu", "id": "Bjorkman-P-J", "name": { "family": "Bjorkman", "given": "Pamela J." }, "orcid": "0000-0002-2277-3990", "role": "advisor" } ] }, "thesis_committee": { "items": [ { "email": "sarkis@caltech.edu", "id": "Mazmanian-S-K", "name": { "family": "Mazmanian", "given": "Sarkis K." }, "orcid": "0000-0003-2713-1513", "role": "chair" }, { "email": "dchan@caltech.edu", "id": "Chan-D-C", "name": { "family": "Chan", "given": "David C." }, "orcid": "0000-0002-0191-2154", "role": "member" }, { "email": "voorhees@caltech.edu", "id": "Voorhees-R-M", "name": { "family": "Voorhees", "given": "Rebecca M." }, "orcid": "0000-0003-1640-2293", "role": "member" }, { "email": "bjorkman@caltech.edu", "id": "Bjorkman-P-J", "name": { "family": "Bjorkman", "given": "Pamela J." }, "orcid": "0000-0002-2277-3990", "role": "member" } ] }, "thesis_degree": "PHD", "thesis_degree_grantor": "California Institute of Technology", "thesis_defense_date": "2022-10-25", "gradofc_approval_date": "2023-06-02", "review_status": "approved", "option_major": { "items": [ "biology" ] }, "copyright_statement": "Author's Rights Authorization: I hereby certify that, if appropriate, I have obtained a written permission statement from the owner(s) of each third party copyrighted matter to be included in my thesis, dissertation, or project report, allowing distribution as specified below. I certify that the version I submitted here is the same as that approved by my advisory committee.\n\nI hereby grant to California Institute of Technology or its agents the non-exclusive license to archive and make accessible, under the conditions specified under \"Thesis Availability\" in this submission, my thesis, dissertation, or project report in whole or in part in all forms of media, now or hereafter known. I retain all other ownership rights to the copyright of the thesis, dissertation, or project report. I also retain the right to use in future works (such as articles or books) all or part of this thesis, dissertation, or project report.", "resource_type": "thesis", "pub_year": "2023", "author_list": "Dam, Kim-Marie Anh", "advisor_list": "Bjorkman, Pamela J.", "comittee_list": "Mazmanian, Sarkis K.; Chan, David C.; et el." }, { "id": "https://thesis.library.caltech.edu/id/eprint/14487", "eprint_id": 14487, "rev_number": 25, "documents": [ { "id": "/id/document/135925", "doc_id": 135925, "rev_number": 6, "files": [ { "id": "/id/file/389232", "fileid": 389232, "datasetid": "document", "objectid": 135925, "filename": "Abernathy-Thesis-020121.pdf", "mime_type": "application/pdf", "hash": "dfcfa45e3f3456a5ec3804eee31efe1b", "hash_type": "MD5", "filesize": 26146429, "mtime": "2022-02-01 19:19:17", "url": "/14487/1/Abernathy-Thesis-020121.pdf" } ], "eprint_id": 14487, "pos": 1, "placement": 1, "mime_type": "application/pdf", "format": "application/pdf", "format_desc": "Original deposit. KJ deleted blank pages p.xi-xii, p.[287] (last page) in replacement copy / skj 2022-02-01", "language": "en", "security": "internal", "license": "other", "main": "Abernathy-Thesis-020121.pdf", "media_duration": "0", "media_aspect_ratio": "0", "media_sample_start": "0", "media_sample_stop": "0", "content": "final" }, { "id": "/id/document/135926", "doc_id": 135926, "rev_number": 3, "files": [ { "id": "/id/file/389234", "fileid": 389234, "datasetid": "document", "objectid": 135926, "filename": "Abernathy-Thesis-020121.docx", "mime_type": "application/vnd.openxmlformats-officedocument.wordprocessingml.document", "hash": "63158da4b97c1952974a0e2bbce50204", "hash_type": "MD5", "filesize": 25754483, "mtime": "2022-02-01 19:19:58", "url": "/14487/2/Abernathy-Thesis-020121.docx" } ], "eprint_id": 14487, "pos": 2, "placement": 2, "mime_type": "application/vnd.openxmlformats-officedocument.wordprocessingml.document", "format": "application/msword", "format_desc": "source file", "language": "en", 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"0", "media_sample_start": "0", "media_sample_stop": "0", "content": "final" }, { "id": "/id/document/135930", "doc_id": 135930, "rev_number": 1, "files": [ { "id": "/id/file/389249", "fileid": 389249, "datasetid": "document", "objectid": 135930, "filename": "indexcodes.txt", "mime_type": "text/plain", "hash": "fbc1c7b9678b28549a31aa140b810a47", "hash_type": "MD5", "filesize": 63660, "mtime": "2022-02-01 20:18:04", "url": "/14487/6/indexcodes.txt" } ], "eprint_id": 14487, "pos": 6, "placement": 6, "mime_type": "text/plain", "format": "other", "format_desc": "Generate index codes conversion from application/pdf to indexcodes", "language": "en", "security": "public", "license": "other", "main": "indexcodes.txt", "media_duration": "0", "media_aspect_ratio": "0", "media_sample_start": "0", "media_sample_stop": "0", "relation": { "items": [ { "type": "http://eprints.org/relation/isVersionOf", "uri": "/id/document/135929" }, { "type": "http://eprints.org/relation/isVolatileVersionOf", "uri": "/id/document/135929" }, { "type": "http://eprints.org/relation/isIndexCodesVersionOf", "uri": "/id/document/135929" } ] } } ], "eprint_status": "archive", "userid": 12667, "dir": "disk0/00/01/44/87", "datestamp": "2022-03-11 23:57:53", "lastmod": "2023-11-08 00:16:02", "status_changed": "2022-03-11 23:57:53", "type": "thesis", "metadata_visibility": "show", "creators": { "items": [ { "email": "morgan.abernathy481@gmail.com", "id": "Abernathy-Morgan-Elizabeth", "name": { "family": "Abernathy", "given": "Morgan Elizabeth" }, "orcid": "0000-0001-9959-7713", "show_email": "NO" } ] }, "title": "Antibody Targeting of HIV-1 Env: a Structural Perspective", "ispublished": "unpub", "full_text_status": "public", "keywords": "broadly neutralizing antibody, HIV-1, SARS-CoV-2, cryo-EM", "abstract": "A key component of contemporary efforts toward a human immunodeficiency virus 1 (HIV-1) vaccine is the use of structural biology to understand the structural characteristics of antibodies elicited both from human patients and animals immunized with engineered 'immunogens,' or early vaccine candidates. This thesis will report on projects characterizing both types of antibodies against HIV-1. Chapter 1 will introduce relevant topics, including the reasons HIV-1 is particularly capable of evading the immune system in natural infection and after vaccination, the 20+ year history of unsuccessful HIV-1 vaccine large-scale efficacy trials, an introduction to broadly neutralizing antibodies (bNAbs), and a review of common strategies utilized in HIV-1 immunogen design today. Chapter 2 describes the isolation, high-resolution structural characterization, and in vitro resistance profile of a new bNAb, 1-18, that is both very broad and potent, as well as able to restrict HIV-1 escape in vivo. Chapter 3 reports the results of an epitope-focusing immunogen design and immunization experiment carried out in wild type mice, rabbits, and non-human primates where it was shown that B cells targeting the desired epitope were expanded after a single prime immunization with immunogen RC1 or a variant, RC1-4fill. Chapter 4 describes Ab1245, an off-target non-neutralizing monoclonal antibody isolated in a macaque that had been immunized with a series of sequential immunogens after the prime immunization reported in Chapter 3. The antibody structure describes a specific type of distracting response as it binds in a way that causes a large structural change in Env, resulting in the destruction of the neutralizing fusion peptide epitope. Chapter 5 is adapted from a review about how antibodies differentially recognize the viruses HIV-1, SARS-CoV-2, and Zika virus. This review serves as an introduction to the virus SARS-CoV-2, which is the topic of the final chapter, Chapter 6. In this chapter, structures of many neutralizing antibodies isolated from SARS-CoV-2 patients were used to define potentially therapeutic classes of neutralizing receptor-binding domain (RBD) antibodies based on their epitopes and binding profiles.", "date": "2022", "date_type": "degree", "id_number": "CaltechTHESIS:02012022-191225421", "refereed": "FALSE", "official_url": "https://resolver.caltech.edu/CaltechTHESIS:02012022-191225421", "related_url": { "items": [ { "description": "Article adapted for ch. 2", "type": "doi", "url": "https://doi.org/10.1016/j.cell.2020.01.010" }, { "description": "Article adapted for ch. 3", "type": "doi", "url": "https://doi.org/10.1038/s41586-019-1250-z" }, { "description": "Article adapted for ch. 4", "type": "doi", "url": "https://doi.org/10.1038/s41541-021-00387-4" }, { "description": "Article adapted for ch. 5", "type": "doi", "url": "https://doi.org/10.3390/v13102106" }, { "description": "Article adapted for ch. 6", "type": "doi", "url": "https://doi.org/10.1038/s41586-020-2852-1" } ] }, "rights": "No commercial reproduction, distribution, display or performance rights in this work are provided.", "collection": "CaltechTHESIS", "reviewer": "Kathy Johnson", "local_group": { "items": [ "COVID-19" ] }, "suggestions": "2022-03-18 released after 1-week embargo.", "deposited_by": "Morgan Abernathy", "deposited_on": "2022-03-11 23:57:53", "doi": "10.7907/0p2b-aa45", "divisions": { "items": [ "div_chem" ] }, "institution": "California Institute of Technology", "thesis_type": "phd", "thesis_advisor": { "items": [ { "email": "bjorkman@caltech.edu", "id": "Bjorkman-P-J", "name": { "family": "Bjorkman", "given": "Pamela J." }, "orcid": "0000-0002-2277-3990", "role": "advisor" } ] }, "thesis_committee": { "items": [ { "email": "dcrees@caltech.edu", "id": "Rees-D-C", "name": { "family": "Rees", "given": "Douglas C." }, "orcid": "0000-0003-4073-1185", "role": "chair" }, { "email": "tirrell@caltech.edu", "id": "Tirrell-D-A", "name": { "family": "Tirrell", "given": "David A." }, "orcid": "0000-0003-3175-4596", "role": "member" }, { "email": "clemons@caltech.edu", "id": "Clemons-W-M", "name": { "family": "Clemons", "given": "William M." }, "orcid": "0000-0002-0021-889X", "role": "member" }, { "email": "bjorkman@caltech.edu", "id": "Bjorkman-P-J", "name": { "family": "Bjorkman", "given": "Pamela J." }, "orcid": "0000-0002-2277-3990", "role": "member" } ] }, "thesis_degree": "PHD", "thesis_degree_grantor": "California Institute of Technology", "thesis_defense_date": "2021-12-03", "gradofc_approval_date": "2022-03-11", "review_status": "approved", "option_major": { "items": [ "chemistry" ] }, "copyright_statement": "Author's Rights Authorization: I hereby certify that, if appropriate, I have obtained a written permission statement from the owner(s) of each third party copyrighted matter to be included in my thesis, dissertation, or project report, allowing distribution as specified below. I certify that the version I submitted here is the same as that approved by my advisory committee.\n\nI hereby grant to California Institute of Technology or its agents the non-exclusive license to archive and make accessible, under the conditions specified under \"Thesis Availability\" in this submission, my thesis, dissertation, or project report in whole or in part in all forms of media, now or hereafter known. I retain all other ownership rights to the copyright of the thesis, dissertation, or project report. I also retain the right to use in future works (such as articles or books) all or part of this thesis, dissertation, or project report.", "resource_type": "thesis", "pub_year": "2022", "author_list": "Abernathy, Morgan Elizabeth", "advisor_list": "Bjorkman, Pamela J.", "comittee_list": "Rees, Douglas C.; Tirrell, David A.; et el." }, { "id": "https://thesis.library.caltech.edu/id/eprint/14413", "eprint_id": 14413, "rev_number": 96, "documents": [ { "id": "/id/document/135278", "doc_id": 135278, "rev_number": 6, "files": [ { "id": "/id/file/385500", "fileid": 385500, "datasetid": "document", "objectid": 135278, "filename": "hoffmann-magnus_full-embargo-request.pdf", "mime_type": "application/pdf", "hash": "1d5784c1da8c5eef48a2953eabe5863d", "hash_type": "MD5", "filesize": 87042, "mtime": "2021-11-01 17:53:31", "url": "/14413/3/hoffmann-magnus_full-embargo-request.pdf" } ], "eprint_id": 14413, "pos": 3, "placement": 4, "mime_type": "application/pdf", "format": "application/pdf", 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Anti-retroviral therapy (ART) prolongs the life expectancy of HIV-1-infected individuals but is associated with side effects, and multiple drugs need to be given in combination to prevent the development of viral resistance. In addition, treatment must continue for the lifetime of the individual due to the existence of a long-lived latent proviral reservoir. While a \"sterilizing\" cure remains difficult to achieve due to difficulties associated with identifying and clearing latently-infected cells, recent research has focused on designing a \"functional\" cure, i.e., a therapeutic strategy that enables long-term suppression of HIV-1 replication and remission of symptoms in the absence of ART. The work presented here describes a new therapeutic direction for the development of a functional cure against HIV-1. This approach is based on the hypothesis that HIV-1 is unable to escape from a nanoparticle (NP)-based decoy that presents clusters of the HIV-1 receptor CD4, because CD4-NPs mimic viral target cells more accurately than soluble CD4-based inhibitors and permit high-avidity interactions with trimeric HIV-1 Env proteins. We demonstrate that CD4-NPs are >10,000-fold more potent than soluble CD4 (sCD4) and prevent viral escape in vitro. AAV-mediated delivery of self-assembling CD4-NPs produced stable CD4-NP serum concentrations in mice that were almost 1,000-fold higher than concentrations required to neutralize HIV-1 in vitro, suggesting that these concentrations could be therapeutic. Viral challenge studies in non-human primates are underway to evaluate the potential of this therapeutic strategy.
\r\n\r\nAs an alternative approach to generate decoys against HIV-1, we generated engineered red blood cells (RBCs) that expressed viral receptors and potently inhibited HIV-1 infection of target cells in vitro. Because RBCs do not contain nuclei or functional organelles required for protein translation, infection of engineered RBCs represents a dead-end for a lentivirus such as HIV-1, which must integrate into the host cell genome as part of its lifecycle. We generated stable erythroid progenitor cell lines that continuously produced HIV-1 receptor-expressing RBCs that could be administered to HIV-1-infected individuals. As RBCs vastly outnumber CD4+ T-cells, HIV-1\u2019s main target cells, and have extended lifetimes, only a fraction of an individual\u2019s RBCs would need to be replaced with the engineered RBC viral traps in order to suppress HIV-1 infection in vivo.
\r\n\r\nMy work on CD4-NP therapeutics against HIV-1 also led to the invention and development of the EBR NP technology that is ideally suited for vaccine design applications. This technology can be used to modify any type of membrane protein to self-assemble into enveloped virus-like NPs without the need for additional proteins. EBR NP assembly is induced by inserting a short amino acid sequence into the cytoplasmic tail of the membrane protein, which was designed to recruit host proteins from the endosomal sorting complex required for transport (ESCRT) pathway. We applied this technology to design protein NP-based vaccines against Severe Acute Respiratory Syndrome coronavirus 2 (SARS-CoV-2), which elicited potent serum neutralizing antibody responses in mice. The EBR NP technology is also ideally suited for the development of hybrid vaccine approaches that allow genetic encoding of protein-based NPs, thereby combining attributes of mRNA and protein-based NP vaccines. Pilot studies demonstrated that mRNA and DNA vaccines encoding the self-assembling SARS-CoV-2 spike-EBR construct elicited ~10-fold higher neutralizing antibody responses than mRNA and DNA vaccines encoding the unmodified spike protein. This hybrid approach has the potential to substantially enhance the potency of mRNA vaccines and could become a leading vaccine platform technology. Future applications for the EBR NP technology are discussed, including the development of a universal coronavirus vaccine to prevent future pandemics, and engineering EBR NPs to mRNA vaccines or therapeutic cargoes for efficient and targeted delivery.
", "date": "2022", "date_type": "degree", "id_number": "CaltechTHESIS:10302021-184745797", "refereed": "FALSE", "official_url": "https://resolver.caltech.edu/CaltechTHESIS:10302021-184745797", "related_url": { "items": [ { "description": "Article adapted for ch. 2", "type": "doi", "url": "https://doi.org/10.1073/pnas.2010320117" }, { "description": "Article adapted for ch. 4", "type": "doi", "url": "https://doi.org/10.1016/j.omtm.2021.03.003" } ] }, "rights": "No commercial reproduction, distribution, display or performance rights in this work are provided.", "funders": { "items": [ { "agency": "Bill and Melinda Gates Foundation", "grant_number": "OPP1202246" }, { "agency": "DeLogi Science and Technology Grant" }, { "agency": "Kairos Ventures (Gift)" }, { "agency": "Rothenburg Innovation Initiative" }, { "agency": "Rosen Bioengineering Center (Pilot grant)" }, { "agency": "Center for Environmental Microbiology Interactions (Pilot grant)" } ] }, "collection": "CaltechTHESIS", "reviewer": "Melissa Ray", "local_group": { "items": [ "COVID-19" ] }, "suggestions": "Released 2023-01-03 with author and OTTCP approval.\r\n\r\n// Withheld until 3 January 2023. OTTCP has a patent pending related to this thesis, and have asked that we continue the embargo until end of calendar year - Kathy 2022-08-08. //\r\n\r\n// Fully withheld until will hear officially from OTTCP; email from Hannah to Kathy indicates that Meimei is waiting to hear back from Magnus as of 2021-11-08//\r\n\r\n\r\n// Restriction to campus until 02 May 2022 - author has spoken to OTTCP who advised that restriction to campus would be good enough - SKJ 20211102. Was originally scheduled to be Withheld until 2022-05-02 // From author: My thesis contains details about a technology that I invented as a PhD student in Pamela Bjorkman's laboratory. We have filed a provisional patent application for this technology: Hoffmann MAG, Bjorkman PJ (2021). Self-assembling viral spike-EBR nanoparticles as a vaccine platform technology. US Patent Application No. 63/208,889. US Patent and Trademark Office. We would like to request a full embargo as this technology is subject to ongoing negotiations about licensing agreements with potential industrial partners.", "deposited_by": "Magnus Hoffmann", "deposited_on": "2021-11-12 20:39:38", "doi": "10.7907/g0w1-rc77", "divisions": { "items": [ "div_bbe" ] }, "institution": "California Institute of Technology", "thesis_type": "phd", "thesis_advisor": { "items": [ { "email": "bjorkman@caltech.edu", "id": "Bjorkman-P-J", "name": { "family": "Bjorkman", "given": "Pamela J." }, "orcid": "0000-0002-2277-3990", "role": "advisor" } ] }, "thesis_committee": { "items": [ { "email": "sarkis@caltech.edu", "id": "Mazmanian-S-K", "name": { "family": "Mazmanian", "given": "Sarkis K." }, "orcid": "0000-0003-2713-1513", "role": "chair" }, { "email": "niles@caltech.edu", "id": "Pierce-N-A", "name": { "family": "Pierce", "given": "Niles A." }, "orcid": "0000-0003-2367-4406", "role": "member" }, { "email": "baltimo@caltech.edu", "id": "Baltimore-D-L", "name": { "family": "Baltimore", "given": "David L." }, "orcid": "0000-0001-8723-8190", "role": "member" }, { "email": "bjorkman@caltech.edu", "id": "Bjorkman-P-J", "name": { "family": "Bjorkman", "given": "Pamela J." }, "orcid": "0000-0002-2277-3990", "role": "member" } ] }, "thesis_degree": "PHD", "thesis_degree_grantor": "California Institute of Technology", "thesis_defense_date": "2021-10-26", "gradofc_approval_date": "2021-11-12", "thesis_awards": "Milton and Francis Clauser Doctoral Prize, 2022.\r\nLawrence L. and Audrey W. Ferguson Prize, 2022.", "review_status": "approved", "option_major": { "items": [ "biology" ] }, "copyright_statement": "Author's Rights Authorization: I hereby certify that, if appropriate, I have obtained a written permission statement from the owner(s) of each third party copyrighted matter to be included in my thesis, dissertation, or project report, allowing distribution as specified below. I certify that the version I submitted here is the same as that approved by my advisory committee.\n\nI hereby grant to California Institute of Technology or its agents the non-exclusive license to archive and make accessible, under the conditions specified under \"Thesis Availability\" in this submission, my thesis, dissertation, or project report in whole or in part in all forms of media, now or hereafter known. I retain all other ownership rights to the copyright of the thesis, dissertation, or project report. 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Thesis - source file.zip", "media_duration": "0", "media_aspect_ratio": "0", "media_sample_start": "0", "media_sample_stop": "0", "content": "archival" }, { "id": "/id/document/135876", "doc_id": 135876, "rev_number": 1, "files": [ { "id": "/id/file/388963", "fileid": 388963, "datasetid": "document", "objectid": 135876, "filename": "indexcodes.txt", "mime_type": "text/x-c", "hash": "d17977e0d51bfd6c9968439fb2bf179a", "hash_type": "MD5", "filesize": 25778, "mtime": "2022-01-26 01:09:33", "url": "/14483/11/indexcodes.txt" } ], "eprint_id": 14483, "pos": 11, "placement": 11, "mime_type": "text/x-c", "format": "other", "format_desc": "Generate index codes conversion from application/pdf to indexcodes", "language": "en", "security": "validuser", "license": "other", "main": "indexcodes.txt", "media_duration": "0", "media_aspect_ratio": "0", "media_sample_start": "0", "media_sample_stop": "0", "relation": { "items": [ { "type": "http://eprints.org/relation/isVersionOf", "uri": "/id/document/135871" }, { "type": "http://eprints.org/relation/isVolatileVersionOf", "uri": "/id/document/135871" }, { "type": "http://eprints.org/relation/isIndexCodesVersionOf", "uri": "/id/document/135871" } ] } } ], "eprint_status": "archive", "userid": 10939, "dir": "disk0/00/01/44/83", "datestamp": "2022-05-16 22:50:17", "lastmod": "2023-11-08 00:16:02", "status_changed": "2022-05-16 22:50:17", "type": "thesis", "metadata_visibility": "show", "creators": { "items": [ { "email": "yangzcit@gmail.com", "id": "Yang-Zhi", "name": { "family": "Yang", "given": "Zhi" }, "orcid": "0000-0001-8680-3784", "show_email": "NO" } ] }, "title": "Conformational Plasticity of HIV-1 Env and Implications for Vaccine Design", "ispublished": "unpub", "full_text_status": "public", "keywords": "HIV; HIV-1 Env; anti-HIV antibody; Env conformation; cryo-EM; X-ray crystallography; double electron-electron resonance spectroscopy", "abstract": "The human immunodeficiency virus (HIV) envelope glycoprotein (Env), a (gp120/gp41)\u2083 trimer, is present on the surface of the viral envelope membrane. Env binding to the host cell receptor, CD4, and the co-receptor, CCR5 or CXCR4, triggers a cascade of Env conformational changes and structural rearrangements which ultimately leads to the viral and host cell membrane fusion, marking the initiation of a viral infection. In this work, we present findings of the conformational changes of an Env trimer from a closed, pre-fusion state to an asymmetrically open state when bound to receptor CD4 and a co-receptor mimicking antibody, E51. We showed the importance of tyrosine sulfation in gp120 binding. The EM structures also indicate the existence of Env\u2019s multiple conformational states. Based on the structural information, we modeled the order of conformations on the path to co-receptor binding and viral-host cell membrane fusion.
\r\n\r\nAs the sole viral protein present on the virion surface, the Env acts as the target for anti-HIV antibodies. Using various types of engineered Env as the immunogen, researchers made attempts to elicit anti-HIV neutralizing antibodies in animals. In this work, we identified and analyzed two neutralizing antibodies, Ab1303 and Ab1573, that target the Env CD4 binding site (CD4bs), one of the conserved epitopes on the Env gp120 surface. Using biophysical and structural methods, we described a novel recognition mechanism of these antibodies and proposed a model about the unique behavior of Env under physiological conditions. This study proved that CD4bs Abs that recognize an \"occluded open\" Env can be raised by sequential animal immunizations, thereby guiding the future immunogen design and therapeutic applications.
", "date": "2022", "date_type": "degree", "id_number": "CaltechTHESIS:01222022-001845303", "refereed": "FALSE", "official_url": "https://resolver.caltech.edu/CaltechTHESIS:01222022-001845303", "related_url": { "items": [ { "description": "Article adapted for Chapter 2", "type": "doi", "url": "https://doi.org/10.1038/s41594-019-0344-5" }, { "description": "Article adapted for Chapter 3", "type": "doi", "url": "https://doi.org/10.1038/s41467-022-28424-3" } ] }, "rights": "No commercial reproduction, distribution, display or performance rights in this work are provided.", "collection": "CaltechTHESIS", "reviewer": "Melissa Ray", "suggestions": "Released 2022-05-23.", "deposited_by": "Zhi Yang", "deposited_on": "2022-05-16 22:50:17", "doi": "10.7907/99hp-y284", "divisions": { "items": [ "div_bbe" ] }, "institution": "California Institute of Technology", "thesis_type": "phd", "thesis_advisor": { "items": [ { "email": "bjorkman@caltech.edu", "id": "Bjorkman-P-J", "name": { "family": "Bjorkman", "given": "Pamela J." }, "orcid": "0000-0002-2277-3990", "role": "advisor" } ] }, "thesis_committee": { "items": [ { "email": "dcrees@caltech.edu", "id": "Rees-D-C", "name": { "family": "Rees", "given": "Douglas C." }, "orcid": "0000-0003-4073-1185", "role": "chair" }, { "email": "voorhees@caltech.edu", "id": "Voorhees-R-M", "name": { "family": "Voorhees", "given": "Rebecca M." }, "orcid": "0000-0003-1640-2293", "role": "member" }, { "email": "dchan@caltech.edu", "id": "Chan-D-C", "name": { "family": "Chan", "given": "David C." }, "orcid": "0000-0002-0191-2154", "role": "member" }, { "email": "bjorkman@caltech.edu", "id": "Bjorkman-P-J", "name": { "family": "Bjorkman", "given": "Pamela J." }, "orcid": "0000-0002-2277-3990", "role": "member" } ] }, "thesis_degree": "PHD", "thesis_degree_grantor": "California Institute of Technology", "thesis_defense_date": "2021-12-10", "gradofc_approval_date": "2022-05-16", "review_status": "approved", "option_major": { "items": [ "biochem" ] }, "copyright_statement": "Author's Rights Authorization: I hereby certify that, if appropriate, I have obtained a written permission statement from the owner(s) of each third party copyrighted matter to be included in my thesis, dissertation, or project report, allowing distribution as specified below. I certify that the version I submitted here is the same as that approved by my advisory committee.\n\nI hereby grant to California Institute of Technology or its agents the non-exclusive license to archive and make accessible, under the conditions specified under \"Thesis Availability\" in this submission, my thesis, dissertation, or project report in whole or in part in all forms of media, now or hereafter known. I retain all other ownership rights to the copyright of the thesis, dissertation, or project report. I also retain the right to use in future works (such as articles or books) all or part of this thesis, dissertation, or project report.", "resource_type": "thesis", "pub_year": "2022", "author_list": "Yang, Zhi", "advisor_list": "Bjorkman, Pamela J.", "comittee_list": "Rees, Douglas C.; Voorhees, Rebecca M.; et el." }, { "id": "https://thesis.library.caltech.edu/id/eprint/14592", "eprint_id": 14592, "rev_number": 42, "documents": [ { "id": "/id/document/136441", "doc_id": 136441, "rev_number": 6, "files": [ { "id": "/id/file/392128", "fileid": 392128, "datasetid": "document", "objectid": 136441, "filename": "Esswein_Shannon_PhD_thesis_submitted.pdf", "mime_type": "application/pdf", "hash": "40527fbabbdc02c18d970f492d36657e", "hash_type": "MD5", "filesize": 10577822, "mtime": "2022-05-21 23:00:03", "url": "/14592/6/Esswein_Shannon_PhD_thesis_submitted.pdf" } ], "eprint_id": 14592, "pos": 6, "placement": 2, "mime_type": "application/pdf", "format": "application/pdf", "format_desc": 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"doc_id": 136626, "rev_number": 1, "files": [ { "id": "/id/file/392992", "fileid": 392992, "datasetid": "document", "objectid": 136626, "filename": "indexcodes.txt", "mime_type": "text/plain", "hash": "6dec4c6cb8e5462c69f83ca49377001c", "hash_type": "MD5", "filesize": 91985, "mtime": "2022-05-25 23:54:13", "url": "/14592/11/indexcodes.txt" } ], "eprint_id": 14592, "pos": 11, "placement": 11, "mime_type": "text/plain", "format": "other", "format_desc": "Generate index codes conversion from application/msword to indexcodes", "language": "en", "security": "internal", "license": "other", "main": "indexcodes.txt", "media_duration": "0", "media_aspect_ratio": "0", "media_sample_start": "0", "media_sample_stop": "0", "relation": { "items": [ { "type": "http://eprints.org/relation/isVersionOf", "uri": "/id/document/136619" }, { "type": "http://eprints.org/relation/isVolatileVersionOf", "uri": "/id/document/136619" }, { "type": "http://eprints.org/relation/isIndexCodesVersionOf", "uri": "/id/document/136619" } ] } } ], "eprint_status": "archive", "userid": 12808, "dir": "disk0/00/01/45/92", "datestamp": "2022-05-24 19:11:10", "lastmod": "2023-11-08 00:16:02", "status_changed": "2022-05-24 19:11:10", "type": "thesis", "metadata_visibility": "show", "creators": { "items": [ { "email": "sesswein@g.ucla.edu", "id": "Esswein-Shannon-Rose", "name": { "family": "Esswein", "given": "Shannon Rose" }, "orcid": "0000-0002-5142-0190", "show_email": "NO" } ] }, "title": "Structural Basis of Antibody Recognition of Viruses", "ispublished": "unpub", "full_text_status": "public", "keywords": "Zika; flavivirus; coronavirus; immunology; neutralizing antibodies; structural biology, cryo-electron microscopy, X-ray crystallography", "abstract": "The Zika epidemic in 2015-2016 and COVID-19 pandemic in 2019-2021 are the latest reminders of the enormous impact of viruses on the world. Zika, a flavivirus transmitted by mosquitos, can cause severe neurodevelopmental abnormalities including microcephaly in the newborns of the infected mothers. Vaccine design is complicated by concern that elicited antibodies may also recognize other epidemic-causing flaviviruses that share a similar envelope protein, such as dengue virus, West Nile Virus, and yellow fever virus. This cross-reactivity, if non-neutralizing, may worsen symptoms of a subsequent infection through antibody-dependent enhancement (ADE). To better understand the neutralizing antibody response and risk of ADE, we compared germline and mature antibody binding to Zika and other flaviviruses. We showed that affinity maturation of the light chain variable domain is important for strong binding of VH3-23/VK1-5 neutralizing antibodies to Zika virus envelope domain III (EDIII) and identified interactions that contribute to weak, cross-reactive binding to West Nile Virus EDIII. These findings informed our design of EDIII-conjugated mosaic nanoparticles as a pan-flavivirus vaccine candidate. Sera from immunization trials with nanoparticles displaying EDIIIs of Zika and dengue serotypes 1-4 showed cross-reactive binding to Zika, dengue 1-4, and West Nile Virus, a promising step towards the development of safe and effective flavivirus vaccines.
\r\n\r\nCoronaviruses are another group of viruses responsible for widespread morbidity and mortality, including the severe acute respiratory syndrome coronavirus (SARS-CoV) and Middle East Respiratory Syndrome coronavirus (MERS-CoV) epidemics and current SARS-CoV-2 pandemic. Given concerns regarding new SARS-CoV-2 variants and the possibility for additional zoonotic betacoronaviruses to cause future outbreaks, we investigated how the epitopes on the SARS-CoV-2 receptor binding domain (RBD) targeted by VH3-30-derived antibodies correlate with their neutralization potency and breadth of betacoronavirus recognition. Analyses showed how variations in antibody light chains and CDRH3 lengths facilitate the diverse RBD epitopes, cross-reactivity, and neutralization profiles of VH3-30 Abs, illustrating their importance for vaccine design and therapeutic antibody development.
", "date": "2022", "date_type": "degree", "id_number": "CaltechTHESIS:05202022-005152490", "refereed": "FALSE", "official_url": "https://resolver.caltech.edu/CaltechTHESIS:05202022-005152490", "related_url": { "items": [ { "description": "Article adapted for Chapter 2", "type": "doi", "url": "https://doi.org/10.1073/pnas.1919269117" }, { "description": "Article related to content in Chapter 5.", "type": "doi", "url": "https://doi.org/10.1038/s41586-020-2852-1" }, { "description": "Article related to content in Chapter 2.", "type": "doi", "url": "https://doi.org/10.1073/pnas.2000414117" }, { "description": "Article related to content in Chapters 1-5.", "type": "doi", "url": "https://doi.org/10.3390/v13102106" } ] }, "rights": "No commercial reproduction, distribution, display or performance rights in this work are provided.", "funders": { "items": [ { "agency": "NIH", "grant_number": "P01AI138938" }, { "agency": "NIH", "grant_number": "5-T32-GM007616-40" }, { "agency": "NIH", "grant_number": "F30AI147579" }, { "agency": "NIH", "grant_number": "T32-GM008042" } ] }, "collection": "CaltechTHESIS", "reviewer": "Melissa Ray", "local_group": { "items": [ "COVID-19" ] }, "suggestions": "1-week embargo expires 2022-05-31.", "deposited_by": "Shannon Esswein", "deposited_on": "2022-05-24 19:11:10", "doi": "10.7907/krjp-se81", "divisions": { "items": [ "div_chem" ] }, "institution": "California Institute of Technology", "thesis_type": "phd", "thesis_advisor": { "items": [ { "email": "bjorkman@caltech.edu", "id": "Bjorkman-P-J", "name": { "family": "Bjorkman", "given": "Pamela J." }, "orcid": "0000-0002-2277-3990", "role": "advisor" } ] }, "thesis_committee": { "items": [ { "email": "dcrees@caltech.edu", "id": "Rees-D-C", "name": { "family": "Rees", "given": "Douglas C." }, "orcid": "0000-0003-4073-1185", "role": "chair" }, { "email": "vorphan@gps.caltech.edu", "id": "Orphan-V-J", "name": { "family": "Orphan", "given": "Victoria J." }, "orcid": "0000-0002-5374-6178", "role": "member" }, { "email": "tirrell@caltech.edu", "id": "Tirrell-D-A", "name": { "family": "Tirrell", "given": "David A." }, "orcid": "0000-0003-3175-4596", "role": "member" }, { "email": "bjorkman@caltech.edu", "id": "Bjorkman-P-J", "name": { "family": "Bjorkman", "given": "Pamela J." }, "orcid": "0000-0002-2277-3990", "role": "member" } ] }, "thesis_degree": "PHD", "thesis_degree_grantor": "California Institute of Technology", "thesis_defense_date": "2021-07-14", "gradofc_approval_date": "2022-05-24", "thesis_awards": "NIH NIAID F30 MD-PhD Pre-doctoral Fellowship, Josephine de Karman Dissertation Fellowship, Chen Graduate Innovator Award", "review_status": "approved", "option_major": { "items": [ "biochem" ] }, "copyright_statement": "Author's Rights Authorization: I hereby certify that, if appropriate, I have obtained a written permission statement from the owner(s) of each third party copyrighted matter to be included in my thesis, dissertation, or project report, allowing distribution as specified below. I certify that the version I submitted here is the same as that approved by my advisory committee.\n\nI hereby grant to California Institute of Technology or its agents the non-exclusive license to archive and make accessible, under the conditions specified under \"Thesis Availability\" in this submission, my thesis, dissertation, or project report in whole or in part in all forms of media, now or hereafter known. I retain all other ownership rights to the copyright of the thesis, dissertation, or project report. I also retain the right to use in future works (such as articles or books) all or part of this thesis, dissertation, or project report.", "resource_type": "thesis", "pub_year": "2022", "author_list": "Esswein, Shannon Rose", "advisor_list": "Bjorkman, Pamela J.", "comittee_list": "Rees, Douglas C.; Orphan, Victoria J.; et el." }, { "id": "https://thesis.library.caltech.edu/id/eprint/14565", "eprint_id": 14565, "rev_number": 27, "documents": [ { "id": "/id/document/136248", "doc_id": 136248, "rev_number": 3, "files": [ { "id": "/id/file/391121", "fileid": 391121, "datasetid": "document", "objectid": 136248, "filename": "jette_claudia_2022_thesis.docx", "mime_type": "application/vnd.openxmlformats-officedocument.wordprocessingml.document", "hash": "8ddf2fccc9d14c657f19eaa97d690068", "hash_type": "MD5", "filesize": 99231443, "mtime": "2022-04-28 19:50:30", "url": "/14565/1/jette_claudia_2022_thesis.docx" } ], "eprint_id": 14565, "pos": 1, "placement": 1, "mime_type": "application/vnd.openxmlformats-officedocument.wordprocessingml.document", "format": "application/msword", "format_desc": "source file for .pdf", "language": "en", "security": "internal", "license": "cc_by_nc", "main": "jette_claudia_2022_thesis.docx", "media_duration": "0", "media_aspect_ratio": "0", "media_sample_start": "0", "media_sample_stop": "0", "content": "updated" }, { "id": "/id/document/136250", "doc_id": 136250, "rev_number": 5, "files": [ { "id": "/id/file/391127", "fileid": 391127, "datasetid": "document", "objectid": 136250, "filename": "jette_claudia_2022_thesis.pdf", "mime_type": "application/pdf", "hash": "76289e06fd04a1739443984bd9de5479", "hash_type": "MD5", "filesize": 57758294, "mtime": "2022-04-28 20:26:52", "url": "/14565/2/jette_claudia_2022_thesis.pdf" } ], "eprint_id": 14565, "pos": 2, "placement": 2, "mime_type": "application/pdf", "format": "application/pdf", "language": "en", "security": "public", "license": "other", "main": "jette_claudia_2022_thesis.pdf", "media_duration": "0", "media_aspect_ratio": "0", "media_sample_start": "0", "media_sample_stop": "0", "content": "final" }, { "id": "/id/document/136255", "doc_id": 136255, "rev_number": 1, "files": [ { "id": "/id/file/391138", "fileid": 391138, "datasetid": "document", "objectid": 136255, "filename": "indexcodes.txt", "mime_type": "text/x-c", "hash": "4b92e70ef3162cab284c9bdb3ea88a5a", "hash_type": "MD5", "filesize": 596431, "mtime": "2022-04-28 20:39:07", "url": "/14565/7/indexcodes.txt" } ], "eprint_id": 14565, "pos": 7, "placement": 7, "mime_type": "text/x-c", "format": "other", "format_desc": "Generate index codes conversion from other to indexcodes", "language": "en", "security": "internal", "license": "other", "main": "indexcodes.txt", "media_duration": "0", "media_aspect_ratio": "0", "media_sample_start": "0", "media_sample_stop": "0", "relation": { "items": [ { "type": "http://eprints.org/relation/isVersionOf", "uri": "/id/document/136248" }, { "type": "http://eprints.org/relation/isVolatileVersionOf", "uri": "/id/document/136248" }, { "type": "http://eprints.org/relation/isIndexCodesVersionOf", "uri": "/id/document/136248" } ] } }, { "id": "/id/document/136256", "doc_id": 136256, "rev_number": 1, "files": [ { "id": "/id/file/391139", "fileid": 391139, "datasetid": "document", "objectid": 136256, "filename": "indexcodes.txt", "mime_type": "text/plain", "hash": "846c31a05413c963f9155f2488199bc3", "hash_type": "MD5", "filesize": 51878, "mtime": "2022-04-28 20:39:07", "url": "/14565/8/indexcodes.txt" } ], "eprint_id": 14565, "pos": 8, "placement": 8, "mime_type": "text/plain", "format": "other", "format_desc": "Generate index codes conversion from application/pdf to indexcodes", "language": "en", "security": "public", "license": "other", "main": "indexcodes.txt", "media_duration": "0", "media_aspect_ratio": "0", "media_sample_start": "0", "media_sample_stop": "0", "relation": { "items": [ { "type": "http://eprints.org/relation/isVersionOf", "uri": "/id/document/136250" }, { "type": "http://eprints.org/relation/isVolatileVersionOf", "uri": "/id/document/136250" }, { "type": "http://eprints.org/relation/isIndexCodesVersionOf", "uri": "/id/document/136250" } ] } } ], "eprint_status": "archive", "userid": 12796, "dir": "disk0/00/01/45/65", "datestamp": "2022-05-03 20:35:04", "lastmod": "2023-11-08 00:16:02", "status_changed": "2022-05-03 20:35:04", "type": "thesis", "metadata_visibility": "show", "creators": { "items": [ { "email": "akie.jette@gmail.com", "id": "Jette-Claudia-Angela", "name": { "family": "Jette", "given": "Claudia Angela" }, "orcid": "0000-0002-5085-8027", "show_email": "NO" } ] }, "title": "Targeting Fusion Proteins of HIV-1 and SARS-CoV-2", "ispublished": "unpub", "full_text_status": "public", "keywords": "structural biology, viruses, HIV-1, SARS-CoV-2, COVID-19, antibody, small molecule, peptide, cryo-EM, X-ray crystallography, protein", "abstract": "Viruses are disease-causing pathogenic agents that require host cells to replicate. Fusion of host and viral membranes is critical for the lifecycle of enveloped viruses. Studying viral fusion proteins can allow us to better understand how they shape immune responses and inform the design of therapeutics such as drugs, monoclonal antibodies, and vaccines. This thesis discusses two approaches to targeting two fusion proteins: Env from HIV-1 and S from SARS-CoV-2. The first chapter of this thesis is an introduction to viruses with a specific focus on HIV-1 CD4 mimetic drugs and antibodies against SARS-CoV-2. It discusses the architecture of these viruses and fusion proteins and how small molecules, peptides, and antibodies can target these proteins successfully to treat and prevent disease. In addition, a brief overview is included of the techniques involved in structural biology and how it has informed the study of viruses. For the interested reader, chapter 2 contains a review article that serves as a more in-depth introduction for both viruses as well as how the use of structural biology has informed the study of viral surface proteins and neutralizing antibody responses to them. The subsequent chapters provide a body of work divided into two parts. The first part in chapter 3 involves a study on conformational changes induced in the HIV-1 Env protein by CD4-mimemtic drugs using single particle cryo-EM. The second part encompassing chapters 4 and 5 includes two studies on antibodies isolated from convalescent COVID-19 donors. The former involves classification of antibody responses to the SARS-CoV-2 S receptor-binding domain (RBD). The latter discusses an anti-RBD antibody class that binds to a conserved epitope on the RBD and shows cross-binding and cross-neutralization to other coronaviruses in the sarbecovirus subgenus.
", "date": "2022", "date_type": "degree", "id_number": "CaltechThesis:04282022-192922044", "refereed": "FALSE", "official_url": "https://resolver.caltech.edu/CaltechThesis:04282022-192922044", "related_url": { "items": [ { "description": "Article adapted for Chapter 3", "type": "doi", "url": "http://www.doi.org/10.1038/s41467-021-21816-x" }, { "description": "Article adapted for Chapter 4", "type": "doi", "url": "http://www.doi.org/10.1038/s41586-020-2852-1" }, { "description": "Article adapted for Chapter 5", "type": "doi", "url": "http://www.doi.org/10.1016/j.celrep.2021.109760" }, { "description": "Article adapted for Chapter 2", "type": "doi", "url": "http://www.doi.org/10.3390/v13102106" } ] }, "rights": "No commercial reproduction, distribution, display or performance rights in this work are provided.", "collection": "CaltechTHESIS", "reviewer": "Melissa Ray", "local_group": { "items": [ "COVID-19" ] }, "suggestions": "2022-05-10 released after 1-week embargo expired.", "deposited_by": "Claudia Jette", "deposited_on": "2022-05-03 20:35:04", "doi": "10.7907/pxa2-dy41", "divisions": { "items": [ "div_chem" ] }, "institution": "California Institute of Technology", "thesis_type": "phd", "thesis_advisor": { "items": [ { "email": "bjorkman@caltech.edu", "id": "Bjorkman-P-J", "name": { "family": "Bjorkman", "given": "Pamela J." }, "orcid": "0000-0002-2277-3990", "role": "advisor" } ] }, "thesis_committee": { "items": [ { "email": "clemons@caltech.edu", "id": "Clemons-W-M", "name": { "family": "Clemons", "given": "William M." }, "orcid": "0000-0002-0021-889X", "role": "chair" }, { "email": "voorhees@caltech.edu", "id": "Voorhees-R-M", "name": { "family": "Voorhees", "given": "Rebecca M." }, "orcid": "0000-0003-1640-2293", "role": "member" }, { "email": "baltimore@caltech.edu", "id": "Baltimore-D-L", "name": { "family": "Baltimore", "given": "David L." }, "orcid": "0000-0001-8723-8190", "role": "member" }, { "email": "bjorkman@caltech.edu", "id": "Bjorkman-P-J", "name": { "family": "Bjorkman", "given": "Pamela J." }, "orcid": "0000-0002-2277-3990", "role": "member" } ] }, "thesis_degree": "PHD", "thesis_degree_grantor": "California Institute of Technology", "thesis_defense_date": "2022-04-06", "gradofc_approval_date": "2022-05-03", "review_status": "approved", "option_major": { "items": [ "biochem" ] }, "copyright_statement": "Author's Rights Authorization: I hereby certify that, if appropriate, I have obtained a written permission statement from the owner(s) of each third party copyrighted matter to be included in my thesis, dissertation, or project report, allowing distribution as specified below. I certify that the version I submitted here is the same as that approved by my advisory committee.\n\nI hereby grant to California Institute of Technology or its agents the non-exclusive license to archive and make accessible, under the conditions specified under \"Thesis Availability\" in this submission, my thesis, dissertation, or project report in whole or in part in all forms of media, now or hereafter known. I retain all other ownership rights to the copyright of the thesis, dissertation, or project report. I also retain the right to use in future works (such as articles or books) all or part of this thesis, dissertation, or project report.", "resource_type": "thesis", "pub_year": "2022", "author_list": "Jette, Claudia Angela", "advisor_list": "Bjorkman, Pamela J.", "comittee_list": "Clemons, William M.; Voorhees, Rebecca M.; et el." }, { "id": "https://thesis.library.caltech.edu/id/eprint/14262", "eprint_id": 14262, "rev_number": 62, "documents": [ { "id": "/id/document/119518", "doc_id": 119518, "rev_number": 4, "files": [ { "id": "/id/file/364350", "fileid": 364350, "datasetid": "document", "objectid": 119518, "filename": "Alexander Cohen_Caltech-Thesis Final version .pdf", "mime_type": "application/pdf", "hash": "28d66f545d7782df866847b3aff4993c", "hash_type": "MD5", "filesize": 42649473, "mtime": "2021-06-08 21:36:28", "url": "/14262/1/Alexander Cohen_Caltech-Thesis Final version .pdf" } ], "eprint_id": 14262, "pos": 1, "placement": 1, "mime_type": "application/pdf", "format": 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"media_sample_start": "0", "media_sample_stop": "0", "relation": { "items": [ { "type": "http://eprints.org/relation/isVersionOf", "uri": "/id/document/119518" }, { "type": "http://eprints.org/relation/isVolatileVersionOf", "uri": "/id/document/119518" }, { "type": "http://eprints.org/relation/isIndexCodesVersionOf", "uri": "/id/document/119518" } ] } } ], "eprint_status": "archive", "userid": 12609, "dir": "disk0/00/01/42/62", "datestamp": "2021-06-09 00:20:43", "lastmod": "2023-11-08 00:16:02", "status_changed": "2021-06-09 00:20:43", "type": "thesis", "metadata_visibility": "show", "creators": { "items": [ { "email": "alexanderac92@g.ucla.edu", "id": "Cohen-Alexander-Armand", "name": { "family": "Cohen", "given": "Alexander Armand" }, "orcid": "0000-0002-2818-656X", "show_email": "YES" } ] }, "title": "Developing Multivalent Nanoparticle Vaccines Against Current and Future Viruses", "ispublished": "unpub", "full_text_status": "public", "keywords": "Immunology, Virology, Vaccines, Coronavirus, Influenza", "abstract": "The 1918-1919 flu pandemic resulted in an estimated 50 to 100 million deaths worldwide, making it the deadliest pandemic in modern history. It was caused by a new influenza virus that likely spilled over from birds and reassorted with a human influenza virus. Since the human population was immunologically na\u00efve to this virus, transmission and lethality was much higher than for seasonal influenza outbreaks. Numerous pandemic influenza viruses emerged within the next century, with none causing the same amount of carnage. There is likely to be future influenza pandemics, with wild migratory birds being carriers of a wide swath of different influenza A viruses. Zoonotic transmission of Avian influenza has taken place with limited human to human transmission. There is evidence showing that the barrier of human transmissibility by some of these avian viruses is not very high, and therefore emergence into humans is possible, with most if not all of the population immunologically na\u00efve. The humoral immune response to influenza is defined by the imprinting of the antibody response to immunodominant epitopes. Such responses can impair immunity, providing less adequate protection against seasonal and pandemic infections, as well as poorer immunity induced by seasonal vaccines. There are instances where imprinting can be advantageous and even offer protection against pandemic or avian viruses, particularly when conserved epitopes to the HA stalk are exploited. Manipulating the antibody response to recognizing conserved stalk epitopes on influenza HA is therefore a strategy being used for universal influenza vaccines. In the second Chapter of this thesis, a mosaic nanoparticle immunization strategy for inducing breadth of antibody responses against HA will be described. This strategy involves the co-display of HAs from up to eight different strains on a particle platform. Although the breadth of antibody responses elicited by immunization of these particles was limited, this work provides insight into the antigenicity of such particles, and a possible alternative to current influenza vaccines.
\r\n \r\nApproximately 100 years after the 1918-1919 flu pandemic, a deadly SARS-like coronavirus, known as SARS-CoV-2, emerged in the human population resulting in a currently ongoing pandemic. This came less than two decades after the small but deadly SARS outbreak, essentially a warning call for this class of coronaviruses. Other SARS-like coronavirus strains in bats have been identified and shown to be human tropic, though resulting in an attenuated infection. Some of these viruses can infect via hACE2 but there are others that may use an unknown receptor for entry into VERO cells as well as human cell lines. There is evidence that the major barrier to zoonosis is protease compatibility, which could be gained through recombination events or errors during replication. Therefore, future SARS-like coronaviruses (sarbecovirus) may emerge in humans, seeding future outbreaks. The antibody response to SARS-CoV-2 is robust and protective. Furthermore, there is the presence of conserved epitopes particularly on the RBD that can be targeted by antibodies that are cross-neutralizing against many SARS-like coronaviruses. Exploiting these cross-reactive epitopes is one strategy that can be used for developing a universal coronavirus vaccine. In Chapter 3 of this thesis, a similar mosaic nanoparticle immunization strategy will be described, that attempts to elicit cross-reactive antibodies against the SARS-like coronavirus family. The mosaic nanoparticles co-display the RBDs of eight different sarbecovirus strains including SARS-CoV-2. Immunization with these mosaic-RBD nanoparticles elicited polyclonal antibody responses that were cross-reactive as well as cross-neutralizing against sarbecoviruses strains both present and not present on the particles.
", "date": "2021", "date_type": "degree", "id_number": "CaltechTHESIS:06082021-015935441", "refereed": "FALSE", "official_url": "https://resolver.caltech.edu/CaltechTHESIS:06082021-015935441", "related_url": { "items": [ { "description": "Article adapted for ch. 2", "type": "doi", "url": "https://doi.org/10.1371/journal.pone.0247963" }, { "description": "Article adapted for ch. 3", "type": "doi", "url": "https://doi.org/10.1126/science.abf6840" }, { "description": "BioRxiv article adapted for appendix A", "type": "doi", "url": "https://doi.org/10.1101/2021.04.23.441195" }, { "description": "Article adapted for Appendix B", "type": "doi", "url": "https://doi.org/10.1073/pnas.1615939113" } ] }, "rights": "No commercial reproduction, distribution, display or performance rights in this work are provided.", "collection": "CaltechTHESIS", "reviewer": "Kathy Johnson", "deposited_by": "Alexander Cohen", "deposited_on": "2021-06-09 00:20:43", "doi": "10.7907/r33z-kj46", "divisions": { "items": [ "div_bbe" ] }, "institution": "California Institute of Technology", "thesis_type": "phd", "thesis_advisor": { "items": [ { "email": "bjorkman@caltech.edu", "id": "Bjorkman-P-J", "name": { "family": "Bjorkman", "given": "Pamela J." }, "orcid": "0000-0002-2277-3990", "role": "advisor" } ] }, "thesis_committee": { "items": [ { "email": "evroth@cco.caltech.edu", "id": "Rothenberg-E-V", "name": { "family": "Rothenberg", "given": "Ellen V." }, "orcid": "0000-0002-3901-347X", "role": "chair" }, { "email": "clemons@caltech.edu", "id": "Clemons-W-M", "name": { "family": "Clemons", "given": "William M." }, "orcid": "0000-0002-0021-889X", "role": "member" }, { "email": "sarkis@caltech.edu", "id": "Mazmanian-S-K", "name": { "family": "Mazmanian", "given": "Sarkis K." }, "orcid": "0000-0003-2713-1513", "role": "member" }, { "email": "david.scott@usuhs.edu", "id": "Scott D-W", "name": { "family": "Scott", "given": "David W." }, "orcid": "0000-0003-2708-4251", "role": "member" }, { "email": "bjorkman@caltech.edu", "id": "Bjorkman-P-J", "name": { "family": "Bjorkman", "given": "Pamela J." }, "orcid": "0000-0002-2277-3990", "role": "member" } ] }, "thesis_degree": "PHD", "thesis_degree_grantor": "California Institute of Technology", "thesis_defense_date": "2021-05-13", "gradofc_approval_date": "2021-06-08", "review_status": "approved", "option_major": { "items": [ "biochem" ] }, "copyright_statement": "Author's Rights Authorization: I hereby certify that, if appropriate, I have obtained a written permission statement from the owner(s) of each third party copyrighted matter to be included in my thesis, dissertation, or project report, allowing distribution as specified below. I certify that the version I submitted here is the same as that approved by my advisory committee.\n\nI hereby grant to California Institute of Technology or its agents the non-exclusive license to archive and make accessible, under the conditions specified under \"Thesis Availability\" in this submission, my thesis, dissertation, or project report in whole or in part in all forms of media, now or hereafter known. I retain all other ownership rights to the copyright of the thesis, dissertation, or project report. 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"main": "indexcodes.txt", "media_duration": "0", "media_aspect_ratio": "0", "media_sample_start": "0", "media_sample_stop": "0", "relation": { "items": [ { "type": "http://eprints.org/relation/isVersionOf", "uri": "/id/document/97210" }, { "type": "http://eprints.org/relation/isVolatileVersionOf", "uri": "/id/document/97210" }, { "type": "http://eprints.org/relation/isIndexCodesVersionOf", "uri": "/id/document/97210" } ] } } ], "eprint_status": "archive", "userid": 11758, "dir": "disk0/00/01/14/13", "datestamp": "2019-03-18 17:21:38", "lastmod": "2023-11-08 00:16:02", "status_changed": "2019-03-18 17:21:38", "type": "thesis", "metadata_visibility": "show", "creators": { "items": [ { "email": "wanghaoqingyimo@gmail.com", "id": "Wang-Haoqing", "name": { "family": "Wang", "given": "Haoqing" }, "orcid": "0000-0003-0277-3018", "show_email": "NO" } ] }, "title": "Structure and Dynamics of HIV-1 Env Trimer", "ispublished": "unpub", "full_text_status": "public", "keywords": "HIV-1 envelope; viral membrane fusion; cryoelectron microscopy", "abstract": "The human immunodeficiency virus-1 (HIV-1) infects CD4+ helper T cells by fusing its lipid membrane to the host cell plasma membrane. HIV-1 Envelope (Env) glycoprotein, a trimer of gp120-gp41 heterodimers, is the fusion machinery that mediates viral and host cell membrane fusion, which is initiated by interaction between the host cell receptor CD4 and viral glycoprotein gp120. Receptor binding induces conformational changes in the Env trimer such that coreceptor CCR5/CXCR4 can bind to gp120 and trigger subsequent membrane fusion steps. Previous cryo-electron tomography (cryoET) and spectroscopy studies have shown that CD4 binding induces changes in Env trimer from the closed, prefusion conformation to an open, CD4-bound conformation. However, the CD4-bound Env trimer is dynamic and flexible such that structural biology study of CD4-bound Env trimer is difficult.
\r\n\r\nAs the sole glycoprotein located on HIV-1 viral surface, Env trimer is the only target for neutralizing antibodies. Since HIV-1 mutates rapidly, most neutralizing antibodies are strain-specific. However, a small percent of HIV-1 infected patients can develop broadly neutralizing antibodies (bNAbs) that neutralize a wide spectrum of viruses. In 2011, our collaborator isolated a bNAb called 8ANC195. To understand how 8ANC195 recognizes Env trimer and prevents infection, we used a combination of structural biology and biochemistry tools. Interestingly, we found that 8ANC195 can recognize Env trimer in both its prefusion and CD4-bound conformations by targeting an epitope at gp120-gp41 interface. Furthermore, 8ANC195 stabilizes the Env-CD4 complex, allowing us to investigate the conformational changes induced by CD4 in atomic resolution. By solving and comparing single-particle cryo-EM structures of Env trimer in complex with CD4 and/or antibodies, we found that: 1) CD4 binding induces coreceptor binding site exposure through a \u03b2-sheet rearrangements in each gp120 monomer. Several key residues allosterically regulate this coreceptor binding site exposure. 2) CD4 binding induces Env trimer opening together with gp41 conformational changes, which represents an intermediate between prefusion gp41 and postfusion gp41. 3) Env trimer opening is necessary but not sufficient for coreceptor binding site exposure, while CD4 binding induces both, some antibodies can open Env trimer without exposing the coreceptor binding site. These conclusions further illuminate how Env trimer mediates membrane fusion and inform potential strategies blocking viral entry.
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"media_aspect_ratio": "0", "media_sample_start": "0", "media_sample_stop": "0", "relation": { "items": [ { "type": "http://eprints.org/relation/isVersionOf", "uri": "/id/document/72506" }, { "type": "http://eprints.org/relation/isVolatileVersionOf", "uri": "/id/document/72506" }, { "type": "http://eprints.org/relation/isIndexCodesVersionOf", "uri": "/id/document/72506" } ] } } ], "eprint_status": "archive", "userid": 9983, "dir": "disk0/00/00/98/64", "datestamp": "2016-06-16 20:40:45", "lastmod": "2023-11-08 00:16:02", "status_changed": "2016-06-16 20:40:45", "type": "thesis", "metadata_visibility": "show", "creators": { "items": [ { "email": "rachelgalimidi@gmail.com", "id": "Galimidi-Rachel-P", "name": { "family": "Galimidi", "given": "Rachel P." }, "show_email": "YES" } ] }, "title": "Combating HIV with Novel Antibody Architectures ", "ispublished": "unpub", "full_text_status": "public", "keywords": "HIV ; Antibody ; Engineering ", "abstract": "More than 30 years has passed since the discovery of Human Immunodeficiency Virus (HIV) yet it remains one of the most important current threats to global public health. HIV is a T-lymphotrophic retrovirus that is the causative agent of Acquired Immune Deficiency Syndrome, and despite decades of research, there remains no cure. Vaccines are most effective when they are able to induce broadly neutralizing antibodies at concentrations capable of blocking viral infection. Notwithstanding all of the effort, a successful vaccine that is capable of inducing complete protection from the immune system has yet to be found. In this thesis, the first chapter provides a history of the discovery of HIV, the origins of the virus, description of the HIV genome, focusing primarily on the envelope glycoprotein, a trimeric spike on the surface of the HIV virion necessary for viral fusion and the sole epitope for broadly neutralizing antibodies. Lastly, the first chapter reviews an overview of the antiviral immune response specifically the role of humoral immune branch and broadly neutralizing antibodies, as well as their limitations in protection against HIV. Antibodies developed during HIV-1 infection lose efficacy as the viral spike mutates. In addition to structural features of HIV\u2019s envelope spike that facilitate antibody evasion, we proposed that the low-density and limited lateral mobility of HIV spikes impedes bivalent binding by antibodies. The resulting predominantly monovalent binding minimizes avidity and thereby high affinity binding and potent neutralization, thus expanding the range of HIV mutations permitting antibody evasion. The work described in subsequent chapters attempts to overcome HIV\u2019s evasion strategy of low spike density through the design of novel antibody architectures.
\r\n\t\r\nWe postulated that anti-HIV-1 spike antibodies primarily bind monovalently because HIV\u2019s low spike density impedes bivalent binding through inter-spike crosslinking, and the spike trimer structure prohibits bivalent binding through intra-spike crosslinking. Monovalent binding reduces avidity and neutralization potency, thus expanding the range of mutations permitting antibody evasion. To test this idea, we engineered antibody-based molecules capable of bivalent binding through intra-spike crosslinking. We used DNA as a \u201cmolecular ruler\u201d to measure intra-epitope distances on virion-bound spikes and to construct intra-spike crosslinking molecules. Optimal bivalent reagents exhibited up to 2.5 orders of magnitude of increased potency (>100-fold average increases across a virus panel) and identified conformational states of virion-bound spikes. The demonstration that intra-spike crosslinking lowers the concentration of antibodies required for neutralization supports the hypothesis that low spike densities facilitate antibody evasion and the use of molecules capable of intra-spike crosslinking for therapy or passive protection. These results shed light on dynamic spike conformations and are relevant to therapeutic interventions.
\r\n", "date": "2016", "date_type": "degree", "id_number": "CaltechTHESIS:06082016-141626444", "refereed": "FALSE", "official_url": "https://resolver.caltech.edu/CaltechTHESIS:06082016-141626444", "related_url": { "items": [ { "description": "Article adapted for ch. 2", "type": "doi", "url": "http://dx.doi.org/10.1128/mBio.00296-15" }, { "description": "Article adapted for ch. 2", "type": "doi", "url": "http://dx.doi.org/10.1073/pnas.1304288110" }, { "description": "Article adapted for ch. 2", "type": "doi", "url": "http://dx.doi.org/10.1128/JVI.01528-09" }, { "description": "Article adapted for ch. 3", "type": "doi", "url": "http://dx.doi.org/10.1016/j.cell.2015.01.016" }, { "description": "Article adapted for ch. 4", "type": "doi", "url": "http://dx.doi.org/10.1093/protein/gzu043" }, { "description": "Article adapted for Appendix B", "type": "doi", "url": "http://dx.doi.org/10.1128/JVI.05848-11" } ] }, "rights": "No commercial reproduction, distribution, display or performance rights in this work are provided.", "funders": { "items": [ { "agency": "NIH Director's Pioneer Award" } ] }, "collection": "CaltechTHESIS", "reviewer": "Kathy Johnson", "suggestions": "Restricted to Caltech community only until 31 December 2016. Released 13 February 2017.", "deposited_by": "Rachel Galimidi", "deposited_on": "2016-06-16 20:40:45", "doi": "10.7907/Z9QC01FR", "divisions": { "items": [ "div_bbe" ] }, "institution": "California Institute of Technology", "thesis_type": "phd", "thesis_advisor": { "items": [ { "email": "bjorkman@caltech.edu", "id": "Bjorkman-P-J", "name": { "family": "Bjorkman", "given": "Pamela J." }, "role": "advisor" }, { "email": "baltimo@caltech.edu", "id": "Baltimore-D-L", "name": { "family": "Baltimore", "given": "David L." }, "role": "co-advisor" } ] }, "thesis_committee": { "items": [ { "email": "sarkis@caltech.edu", "id": "Mazmanian-S-K", "name": { "family": "Mazmanian", "given": "Sarkis K." }, "role": "chair" }, { "email": "clemons@caltech.edu", "id": "Clemons-W-M", "name": { "family": "Clemons", "given": "William M." }, "role": "member" }, { "email": "evroth@caltech.edu", "id": "Rothenberg-E-V", "name": { "family": "Rothenberg", "given": "Ellen V." }, "role": "member" }, { "email": "jzack@ucla.edu", "id": "Zack-J-A", "name": { "family": "Zack", "given": "Jerome" }, "role": "member" } ] }, "thesis_degree": "PHD", "thesis_degree_grantor": "California Institute of Technology", "thesis_defense_date": "2016-02-05", "gradofc_approval_date": "2016-06-16", "thesis_awards": "Milton and Francis Clauser Doctoral Prize, 2016. Demetriades-Tsafka-Kokkalis Prize in Biotechnology or Related Fields, 2016. Lawrence L. and Audrey W. Ferguson Prize, 2016.", "review_status": "approved", "option_major": { "items": [ "immun" ] }, "copyright_statement": "Author's Rights Authorization: I hereby certify that, if appropriate, I have obtained a written permission statement from the owner(s) of each third party copyrighted matter to be included in my thesis, dissertation, or project report, allowing distribution as specified below. I certify that the version I submitted here is the same as that approved by my advisory committee.\n\nI hereby grant to California Institute of Technology or its agents the non-exclusive license to archive and make accessible, under the conditions specified under \"Thesis Availability\" in this submission, my thesis, dissertation, or project report in whole or in part in all forms of media, now or hereafter known. I retain all other ownership rights to the copyright of the thesis, dissertation, or project report. I also retain the right to use in future works (such as articles or books) all or part of this thesis, dissertation, or project report.", "resource_type": "thesis", "pub_year": "2016", "author_list": "Galimidi, Rachel P.", "advisor_list": "Bjorkman, Pamela J. and Baltimore, David L.", "comittee_list": "Mazmanian, Sarkis K.; Clemons, William M.; et el." }, { "id": "https://thesis.library.caltech.edu/id/eprint/9270", "eprint_id": 9270, "rev_number": 43, "documents": [ { "id": "/id/document/66313", "doc_id": 66313, "rev_number": 3, "files": [ { "id": "/id/file/184684", "fileid": 184684, "datasetid": "document", "objectid": 66313, "filename": "Owens_PhD_Thesis.pdf", "mime_type": "application/pdf", "hash": "999e2151d4ddd2141d518b20f4db751e", "hash_type": "MD5", "filesize": 6620974, "mtime": "2016-05-11 05:51:12", "url": "/9270/7/Owens_PhD_Thesis.pdf" } ], "eprint_id": 9270, "pos": 7, "placement": 7, "mime_type": "application/pdf", "format": "application/pdf", "language": "en", "security": 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"media_aspect_ratio": "0", "media_sample_start": "0", "media_sample_stop": "0", "relation": { "items": [ { "type": "http://eprints.org/relation/isVersionOf", "uri": "/id/document/66313" }, { "type": "http://eprints.org/relation/isVolatileVersionOf", "uri": "/id/document/66313" }, { "type": "http://eprints.org/relation/isIndexCodesVersionOf", "uri": "/id/document/66313" } ] } } ], "eprint_status": "archive", "userid": 6536, "dir": "disk0/00/00/92/70", "datestamp": "2016-05-16 16:51:24", "lastmod": "2023-11-08 00:16:02", "status_changed": "2016-05-16 16:51:24", "type": "thesis", "metadata_visibility": "show", "creators": { "items": [ { "email": "gwen.e.owens@gmail.com", "id": "Owens-Gwen-Ellen", "name": { "family": "Owens", "given": "Gwen Ellen" }, "orcid": "0000-0003-0793-1994", "show_email": "NO" } ] }, "title": "Biochemical and Biophysical Characterization of Huntingtin", "ispublished": "unpub", "full_text_status": "public", "keywords": "Huntingtin; Huntington's disease; Polyglutamine; X-ray crystallography", "abstract": "Huntington\u2019s disease (HD) is a fatal autosomal dominant neurodegenerative disease. HD has no cure, and patients pass away 10-20 years after the onset of symptoms. The causal mutation for HD is a trinucleotide repeat expansion in exon 1 of the huntingtin gene that leads to a polyglutamine (polyQ) repeat expansion in the N-terminal region of the huntingtin protein. Interestingly, there is a threshold of 37 polyQ repeats under which little or no disease exists; and above which, patients invariably show symptoms of HD. The huntingtin protein is a 350 kDa protein with unclear function. As the polyQ stretch expands, its propensity to aggregate increases with polyQ length. Models for polyQ toxicity include formation of aggregates that recruit and sequester essential cellular proteins, or altered function producing improper interactions between mutant huntingtin and other proteins. In both models, soluble expanded polyQ may be an intermediate state that can be targeted by potential therapeutics.
\r\n\r\nIn the first study described herein, the conformation of soluble, expanded polyQ was determined to be linear and extended using equilibrium gel filtration and small-angle X-ray scattering. While attempts to purify and crystallize domains of the huntingtin protein were unsuccessful, the aggregation of huntingtin exon 1 was investigated using other biochemical techniques including dynamic light scattering, turbidity analysis, Congo red staining, and thioflavin T fluorescence. Chapter 4 describes crystallization experiments sent to the International Space Station and determination of the X-ray crystal structure of the anti-polyQ Fab MW1. In the final study, multimeric fibronectin type III (FN3) domain proteins were engineered to bind with high avidity to expanded polyQ tracts in mutant huntingtin exon 1. Surface plasmon resonance was used to observe binding of monomeric and multimeric FN3 proteins with huntingtin.
", "date": "2016", "date_type": "degree", "id_number": "CaltechTHESIS:11042015-142900908", "refereed": "FALSE", "official_url": "https://resolver.caltech.edu/CaltechTHESIS:11042015-142900908", "related_url": { "items": [ { "description": "Article adapted for Ch. 2", "type": "doi", "url": "http://dx.doi.org/10.1016/j.jmb.2015.05.023" } ] }, "rights": "No commercial reproduction, distribution, display or performance rights in this work are provided.", "funders": { "items": [ { "agency": "Center for the Advancement of Science in Space" }, { "agency": "W. R. Hearst Endowed Scholarship" }, { "agency": "National Institutes of Health", "grant_number": "5T32GM007616" }, { "agency": "National Institutes of Health", "grant_number": "5T32GM008042" } ] }, "collection": "CaltechTHESIS", "reviewer": "Kathy Johnson", "suggestions": "Restricted to Caltech community only until 10 June 2017. // Released to public view 09132017", "deposited_by": "Gwen Owens", "deposited_on": "2016-05-16 16:51:24", "doi": "10.7907/Z9TM7835", "divisions": { "items": [ "div_chem" ] }, "institution": "California Institute of Technology", "thesis_type": "phd", "thesis_advisor": { "items": [ { "email": "bjorkman@caltech.edu", "id": "Bjorkman-P-J", "name": { "family": "Bjorkman", "given": "Pamela J." }, "role": "advisor" } ] }, "thesis_committee": { "items": [ { "email": "dcrees@caltech.edu", "id": "Rees-D-C", "name": { "family": "Rees", "given": "Douglas C." }, "role": "chair" }, { "email": "phillips@pboc.caltech.edu", "id": "Phillips-R-B", "name": { "family": "Phillips", "given": "Robert B." }, "role": "member" }, { "email": "zinnk@caltech.edu", "id": "Zinn-K-G", "name": { "family": "Zinn", "given": "Kai George" }, "role": "member" }, { "email": "bjorkman@caltech.edu", "id": "Bjorkman-P-J", "name": { "family": "Bjorkman", "given": "Pamela J." }, "role": "member" } ] }, "thesis_degree": "PHD", "thesis_degree_grantor": "California Institute of Technology", "thesis_defense_date": "2015-10-29", "gradofc_approval_date": "2016-05-13", "thesis_awards": "Gerald S. Levey, M.D., Medical Scientist Scholarship", "review_status": "approved", "option_major": { "items": [ "biochem" ] }, "copyright_statement": "Author's Rights Authorization: I hereby certify that, if appropriate, I have obtained a written permission statement from the owner(s) of each third party copyrighted matter to be included in my thesis, dissertation, or project report, allowing distribution as specified below. I certify that the version I submitted here is the same as that approved by my advisory committee.\n\nI hereby grant to California Institute of Technology or its agents the non-exclusive license to archive and make accessible, under the conditions specified under \"Thesis Availability\" in this submission, my thesis, dissertation, or project report in whole or in part in all forms of media, now or hereafter known. I retain all other ownership rights to the copyright of the thesis, dissertation, or project report. I also retain the right to use in future works (such as articles or books) all or part of this thesis, dissertation, or project report.", "resource_type": "thesis", "pub_year": "2016", "author_list": "Owens, Gwen Ellen", "advisor_list": "Bjorkman, Pamela J.", "comittee_list": "Rees, Douglas C.; Phillips, Robert B.; et el." }, { "id": "https://thesis.library.caltech.edu/id/eprint/8878", "eprint_id": 8878, "rev_number": 26, "documents": [ { "id": "/id/document/56220", "doc_id": 56220, "rev_number": 4, "files": [ { "id": "/id/file/160249", "fileid": 160249, "datasetid": "document", "objectid": 56220, "filename": "Wu_Yunji_2015_thesis.pdf", "mime_type": "application/pdf", "hash": "89e5e3a9a9f34651c6eb2c243a092e0f", "hash_type": "MD5", "filesize": 64667179, "mtime": "2015-05-22 02:53:59", "url": "/8878/1/Wu_Yunji_2015_thesis.pdf" } ], "eprint_id": 8878, "pos": 1, "placement": 1, "mime_type": "application/pdf", "format": "application/pdf", "language": "en", "security": "public", "license": 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"media_aspect_ratio": "0", "media_sample_start": "0", "media_sample_stop": "0", "relation": { "items": [ { "type": "http://eprints.org/relation/isVersionOf", "uri": "/id/document/56220" }, { "type": "http://eprints.org/relation/isVolatileVersionOf", "uri": "/id/document/56220" }, { "type": "http://eprints.org/relation/isIndexCodesVersionOf", "uri": "/id/document/56220" } ] } } ], "eprint_status": "archive", "userid": 10311, "dir": "disk0/00/00/88/78", "datestamp": "2015-05-26 21:20:59", "lastmod": "2023-11-08 00:16:03", "status_changed": "2015-05-26 21:20:59", "type": "thesis", "metadata_visibility": "show", "creators": { "items": [ { "email": "yunji.wu@gmail.com", "id": "Wu-Yunji", "name": { "family": "Wu", "given": "Yunji" }, "show_email": "NO" } ] }, "title": "Structural Characterizations of the Dimeric Anti-HIV Antibody 2G12 and the HIV-2 Envelope Glycoprotein", "ispublished": "unpub", "full_text_status": "public", "keywords": "HIV, antibodies, X-ray crystallography, single particle electron microscopy", "abstract": "More than thirty years after the discovery that Human Immunodeficiency Virus (HIV) was the causative agent of Acquired Immunodeficiency Syndrome (AIDS), the disease remains pandemic as long as no effective universal vaccine is found. Over 34 million individuals in the world are infected with the virus, and the vast majority of them have no access to the antiretroviral therapies that have largely reduced HIV to a chronic disease in the developed world. The first chapter of this thesis introduces the history of the virus. The key to the infectious mechanism of the virus lies in its envelope glycoprotein (Env), a trimeric spike on the viral surface that utilizes host T cell receptors for entry. Though HIV-1 Env is immunogenic, most infected patients do not mount an effective neutralizing antibody response against it. Broadly-neutralizing anti-Env antibodies (bNAbs) present in the serum of a minority of infected individuals are usually sufficient to prevent the progression to full blown AIDS. Thus, the molecular details of these bNAbs as well as the antibody-antigen interface are of prime interest for structural studies, as insight gained would contribute to the design of a more effective immunogen and potential vaccine candidate. The second chapter of this thesis describes the low-resolution crystal structure of one such antibody, 2G12 dimer, which targets a high mannose epitope on the surface of Env. Patients infected with HIV-2, a related virus with ~35% sequence identity in the Env region, can generally mount a robust antibody response sufficient for viral control for reasons still unknown. The final two chapters of this thesis focus on the first reported structural studies of HIV-2 Env, the molecular details of which may inform HIV-1 therapy and immunogen design. ", "date": "2015", "date_type": "degree", "id_number": "CaltechTHESIS:05212015-194407438", "refereed": "FALSE", "official_url": "https://resolver.caltech.edu/CaltechTHESIS:05212015-194407438", "related_url": { "items": [ { "description": "Article adapted for Chapter 2", "type": "pmc", "url": "http://www.ncbi.nlm.nih.gov/pubmed/24316082" } ] }, "rights": "No commercial reproduction, distribution, display or performance rights in this work are provided.", "funders": { "items": [ { "agency": "NIH", "grant_number": "2 R37AI041239-06A1" }, { "agency": "NIH ", "grant_number": "5 T32 GM 7616-33" }, { "agency": "Bill and Melinda Gates Foundation", "grant_number": "CAVD" } ] }, "collection": "CaltechTHESIS", "reviewer": "Kathy Johnson", "suggestions": "Restricted to Caltech community only until 12 June 2016. Released 6/14/2016.", "deposited_by": "Yunji Wu", "deposited_on": "2015-05-26 21:20:59", "doi": "10.7907/Z98050K6", "divisions": { "items": [ "div_bbe" ] }, "institution": "California Institute of Technology", "thesis_type": "phd", "thesis_advisor": { "items": [ { "email": "bjorkman@caltech.edu", "id": "Bjorkman-P-J", "name": { "family": "Bjorkman", "given": "Pamela J." }, "role": "advisor" } ] }, "thesis_committee": { "items": [ { "email": "dchan@caltech.edu", "id": "Chan-D-C", "name": { "family": "Chan", "given": "David C." }, "role": "chair" }, { "email": "baltimo@caltech.edu", "id": "Baltimore-D-L", "name": { "family": "Baltimore", "given": "David L." }, "role": "member" }, { "email": "dcrees@caltech.edu", "id": "Rees-D-C", "name": { "family": "Rees", "given": "Douglas C." }, "role": "member" }, { "email": "bjorkman@caltech.edu", "id": "Bjorkman-P-J", "name": { "family": "Bjorkman", "given": "Pamela J." }, "role": "member" } ] }, "thesis_degree": "PHD", "thesis_degree_grantor": "California Institute of Technology", "thesis_defense_date": "2015-04-29", "gradofc_approval_date": "2015-05-26", "review_status": "approved", "option_major": { "items": [ "molbiochem" ] }, "copyright_statement": "Author's Rights Authorization: I hereby certify that, if appropriate, I have obtained a written permission statement from the owner(s) of each third party copyrighted matter to be included in my thesis, dissertation, or project report, allowing distribution as specified below. I certify that the version I submitted here is the same as that approved by my advisory committee.\n\nI hereby grant to California Institute of Technology or its agents the non-exclusive license to archive and make accessible, under the conditions specified under \"Thesis Availability\" in this submission, my thesis, dissertation, or project report in whole or in part in all forms of media, now or hereafter known. I retain all other ownership rights to the copyright of the thesis, dissertation, or project report. I also retain the right to use in future works (such as articles or books) all or part of this thesis, dissertation, or project report.", "resource_type": "thesis", "pub_year": "2015", "author_list": "Wu, Yunji", "advisor_list": "Bjorkman, Pamela J.", "comittee_list": "Chan, David C.; Baltimore, David L.; et el." }, { "id": "https://thesis.library.caltech.edu/id/eprint/8914", "eprint_id": 8914, "rev_number": 22, "documents": [ { "id": "/id/document/56989", "doc_id": 56989, "rev_number": 5, "files": [ { "id": "/id/file/161979", "fileid": 161979, "datasetid": "document", "objectid": 56989, "filename": "Thesis_Alysia_Ahmed_052915.pdf", "mime_type": "application/pdf", "hash": "7b535be4ab8ff25ce0d4db444974c2d3", "hash_type": "MD5", "filesize": 33527538, "mtime": "2015-05-29 13:55:07", "url": "/8914/1/Thesis_Alysia_Ahmed_052915.pdf" } ], "eprint_id": 8914, "pos": 1, "placement": 1, "mime_type": "application/pdf", "format": "application/pdf", "language": "en", "security": "public", "license": 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"media_aspect_ratio": "0", "media_sample_start": "0", "media_sample_stop": "0", "relation": { "items": [ { "type": "http://eprints.org/relation/isVersionOf", "uri": "/id/document/56989" }, { "type": "http://eprints.org/relation/isVolatileVersionOf", "uri": "/id/document/56989" }, { "type": "http://eprints.org/relation/isIndexCodesVersionOf", "uri": "/id/document/56989" } ] } } ], "eprint_status": "archive", "userid": 2165, "dir": "disk0/00/00/89/14", "datestamp": "2015-05-29 21:51:24", "lastmod": "2023-11-08 00:16:03", "status_changed": "2015-05-29 21:51:24", "type": "thesis", "metadata_visibility": "show", "creators": { "items": [ { "email": "alysiahmed@gmail.com", "id": "Ahmed-Alysia-Ashley", "name": { "family": "Ahmed", "given": "Alysia Ashley" }, "show_email": "NO" } ] }, "title": "Structural Characterization of Pro-inflammatory and Anti-inflammatory Immunoglobulin G Fc Proteins", "ispublished": "unpub", "full_text_status": "public", "keywords": "sialylated IgG Fc, inflammation, IVIG, ADCC, N-linked glycan, X-ray crystallography ", "abstract": "Immunoglobulin G (IgG) is central in mediating host defense due to its ability to target and eliminate invading pathogens. The fragment antigen binding (Fab) regions are responsible for antigen recognition; however the effector responses are encoded on the Fc region of IgG. IgG Fc displays considerable glycan heterogeneity, accounting for its complex effector functions of inflammation, modulation and immune suppression. Intravenous immunoglobulin G (IVIG) is pooled serum IgG from multiple donors and is used to treat individuals with autoimmune and inflammatory disorders such as rheumatoid arthritis and Kawasaki\u2019s disease, respectively. It contains all the subtypes of IgG (IgG1-4) and over 120 glycovariants due to variation of an Asparagine 297-linked glycan on the Fc. The species identified as the activating component of IVIG is sialylated IgG Fc. Comparisons of wild type Fc and sialylated Fc X-ray crystal structures suggests that sialylation causes an increase in conformational flexibility, which may be important for its anti-inflammatory properties.
\r\n\r\nAlthough glycan modifications can promote the anti-inflammatory properties of the Fc, there are amino acid substitutions that cause Fcs to initiate an enhanced immune response. Mutations in the Fc can cause up to a 100-fold increase in binding affinity to activating Fc gamma receptors located on immune cells, and have been shown to enhance antibody dependent cell-mediated cytotoxicity. This is important in developing therapeutic antibodies against cancer and infectious diseases. Structural studies of mutant Fcs in complex with activating receptors gave insight into new protein-protein interactions that lead to an enhanced binding affinity.
\r\n\r\nTogether these studies show how dynamic and diverse the Fc region is and how both protein and carbohydrate modifications can alter structure, leading to IgG Fc\u2019s switch from a pro-inflammatory to an anti-inflammatory protein.
", "date": "2015", "date_type": "degree", "id_number": "CaltechTHESIS:05292015-064617250", "refereed": "FALSE", "official_url": "https://resolver.caltech.edu/CaltechTHESIS:05292015-064617250", "related_url": { "items": [ { "description": "Article adapted for Chapter 2", "type": "doi", "url": "http://dx.doi.org/10.1016/j.jmb.2014.07.006" } ] }, "rights": "No commercial reproduction, distribution, display or performance rights in this work are provided.", "collection": "CaltechTHESIS", "reviewer": "Kathy Johnson", "suggestions": "Restricted to Caltech community only until 12 June 2016. Released 6/14/2016.\r\n", "deposited_by": "Alysia Ahmed", "deposited_on": "2015-05-29 21:51:24", "doi": "10.7907/Z9GT5K33", "divisions": { "items": [ "div_bbe" ] }, "institution": "California Institute of Technology", "thesis_type": "phd", "thesis_advisor": { "items": [ { "email": "bjorkman@caltech.edu", "id": "Bjorkman-P-J", "name": { "family": "Bjorkman", "given": "Pamela J." }, "role": "advisor" } ] }, "thesis_committee": { "items": [ { "email": "deshaies@its.caltech.edu", "id": "Deshaies-R-J", "name": { "family": "Deshaies", "given": "Raymond Joseph" }, "role": "chair" }, { "email": "dcrees@caltech.edu", "id": "Rees-D-C", "name": { "family": "Rees", "given": "Douglas C." }, "role": "member" }, { "email": "evroth@its.caltech.edu", "id": "Rothenberg-E-V", "name": { "family": "Rothenberg", "given": "Ellen V." }, "role": "member" }, { "email": "jcampbel@caltech.edu", "id": "Campbell-J-L", "name": { "family": "Campbell", "given": "Judith L." }, "role": "member" }, { "email": "bjorkman@caltech.edu", "id": "Bjorkman-P-J", "name": { "family": "Bjorkman", "given": "Pamela J." }, "role": "member" } ] }, "thesis_degree": "PHD", "thesis_degree_grantor": "California Institute of Technology", "thesis_defense_date": "2015-05-21", "gradofc_approval_date": "2015-05-29", "review_status": "approved", "option_major": { "items": [ "molbiochem" ] }, "copyright_statement": "Author's Rights Authorization: I hereby certify that, if appropriate, I have obtained a written permission statement from the owner(s) of each third party copyrighted matter to be included in my thesis, dissertation, or project report, allowing distribution as specified below. I certify that the version I submitted here is the same as that approved by my advisory committee.\n\nI hereby grant to California Institute of Technology or its agents the non-exclusive license to archive and make accessible, under the conditions specified under \"Thesis Availability\" in this submission, my thesis, dissertation, or project report in whole or in part in all forms of media, now or hereafter known. I retain all other ownership rights to the copyright of the thesis, dissertation, or project report. 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Engineering, Protein Design, HIV", "abstract": "Despite over 30 years of effort, an HIV-1 vaccine that elicits protective antibodies still does not exist. Recent clinical studies have identified that during natural infection about 20% of the population is capable of mounting a potent and protective antibody response. Closer inspection of these individuals reveal that a subset of these antibodies, recently termed potent VRC01-like (PVL), derive exclusively from a single human germline heavy chain gene. Induced clonal expansion of the B cell encoding this gene is the first step through which PVL antibodies may be elicited. Unfortunately, naturally occurring HIV gp120s fail to bind to this germline, and as a result cannot be used as the initial prime for a vaccine regimen. We have determined the crystal structure of an important germline antibody that is a promising target for vaccine design efforts, and have set out to engineer a more likely candidate using computationally-guided rational design.
\r\n\r\nIn addition to prevention efforts on the side of vaccine design, recently characterized broadly neutralizing anti-HIV antibodies have excellent potential for use in gene therapy and passive immunotherapy. The separation distance between functional Fabs on an antibody is important due to the sparse distribution of envelop spikes on HIV compared to other viruses. We set out to build and characterize novel antibody architectures by incorporating structured linkers into the hinge region of an anti-HIV antibody b12. The goal was to observe whether these linkers increased the arm-span of the IgG dimer. When incorporated, flexible Gly4Ser repeats did not result in detectable extensions of the IgG antigen binding domains, by contrast to linkers including more rigid domains such as \u03b22-microglobulin, Zn-\u03b12-glycoprotein, and tetratricopeptide repeats (TPRs). This study adds an additional set of linkers with varying lengths and rigidities to the available linker repertoire, which may be useful for the modification and construction of antibodies and other fusion proteins.
\r\n", "date": "2014", "date_type": "degree", "id_number": "CaltechTHESIS:06172014-114402762", "refereed": "FALSE", "official_url": "https://resolver.caltech.edu/CaltechTHESIS:06172014-114402762", "rights": "No commercial reproduction, distribution, display or performance rights in this work are provided.", "collection": "CaltechTHESIS", "reviewer": "Kathy Johnson", "suggestions": "Released to public view 1/23/2019 // Restricted to Caltech community only until 2019. ", "deposited_by": "Siduo Jiang", "deposited_on": "2014-10-28 19:12:29", "doi": "10.7907/SP19-9R34", "divisions": { "items": [ "div_bbe", "div_chem" ] }, "institution": "California Institute of Technology", "thesis_type": "senior_major", "thesis_advisor": { "items": [ { "email": "bjorkman@caltech.edu", "id": "Bjorkman-P-J", "name": { "family": "Bjorkman", "given": "Pamela J." }, "role": "advisor" }, { "email": "galimidi@caltech.edu", "id": "Galimidi-R-P", "name": { "family": "Galimidi", "given": "Rachel P." }, "role": "co-advisor" }, { "email": "apwest@caltech.edu", "id": "West-A-P", "name": { "family": "West", "given": "Anthony P." }, "role": "co-advisor" }, { "email": "ssievers@caltech.edu", "id": "Sievers-S-A", "name": { "family": "Sievers", "given": "Stuart A." }, "role": "co-advisor" } ] }, "thesis_committee": { "items": [ { "name": { "family": "None", "given": "None" } } ] }, "thesis_degree": "BS", "thesis_degree_grantor": "California Institute of Technology", "thesis_defense_date": "2014-06-06", "thesis_awards": "Arie J. Haagen-Smit Memorial Award, 2013. George W. Housner Award, 2014. Richard P. Schuster Memorial Prize, 2014.", "review_status": "approved", "option_major": { "items": [ "biology", "chemistry" ] }, "copyright_statement": "Author's Rights Authorization: I hereby certify that, if appropriate, I have obtained a written permission statement from the owner(s) of each third party copyrighted matter to be included in my thesis, dissertation, or project report, allowing distribution as specified below. I certify that the version I submitted here is the same as that approved by my advisory committee.\n\nI hereby grant to California Institute of Technology or its agents the non-exclusive license to archive and make accessible, under the conditions specified under \"Thesis Availability\" in this submission, my thesis, dissertation, or project report in whole or in part in all forms of media, now or hereafter known. I retain all other ownership rights to the copyright of the thesis, dissertation, or project report. I also retain the right to use in future works (such as articles or books) all or part of this thesis, dissertation, or project report.", "resource_type": "thesis", "pub_year": "2014", "author_list": "Jiang, Siduo (Stone)", "advisor_list": "Bjorkman, Pamela J.; Galimidi, Rachel P.; et el.", "comittee_list": "None, None" }, { "id": "https://thesis.library.caltech.edu/id/eprint/6156", "eprint_id": 6156, "rev_number": 86, "documents": [ { "id": "/id/document/11654", "doc_id": 11654, "rev_number": 7, "files": [ { "id": "/id/file/77300", "fileid": 77300, "datasetid": "document", "objectid": 11654, "filename": "1_Chapter_1.pdf", "mime_type": "application/pdf", "filesize": 2407494, "mtime": "2012-12-26 04:32:00", "url": "/6156/2/1_Chapter_1.pdf" } ], "eprint_id": 6156, "pos": 2, "placement": 3, "mime_type": "application/pdf", "format": "application/pdf", "format_desc": "Chapter 1: Introduction", "language": "en", "security": "public", "license": "other", "main": "1_Chapter_1.pdf", 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1354, "dir": "disk0/00/00/61/56", "datestamp": "2011-05-31 19:22:27", "lastmod": "2023-11-08 00:16:03", "status_changed": "2011-05-31 19:22:27", "type": "thesis", "metadata_visibility": "show", "creators": { "items": [ { "email": "fan@caltech.edu", "id": "Yang-Fan", "name": { "family": "Yang", "given": "Fan" }, "show_email": "NO" } ] }, "title": "Biochemical and Biophysical Characterizations of Immunoglobulin Superfamily Receptors Neogenin and L1", "ispublished": "unpub", "full_text_status": "public", "keywords": "immunoglobulin superfamily; hemojuvelin; neogenin; iron homeostasis; L1; cell adhesion; membrane mechanics ", "abstract": "Immunoglobulin (Ig) superfamily receptors function in a wide variety of developmental and metabolic processes. We are particularly interested to characterize two Ig superfamily receptors neogenin and L1. The first chapter of the thesis gives a brief review of the biological significance of neogenin and L1 and what has been learned in their functions. In Chapter 2, we described the localization of the hemojuvelin-binding epitope of neogenin to the membrane proximal fifth and sixth fibronectin type III (FNIII) domains, with the sixth FNIII domain contributing the majority of the binding. Chapter 3 presents the crystal structure of this hemojuvelin-binding fragment at 1.8 \u00c5, revealing a nearly linear domain arrangement. Hemojuvelin binding sites have been mapped to one face of the sixth FNIII domain based on sequence alignment between neogenin and DCC (Deleted in Colorectal Cancer), a molecule related to neogenin but does not bind to hemojuvelin. These results should also be informative in understanding the interaction between neogenin and repulsive guidance molecule (RGM), the closest homologue of hemojuvelin. The interaction between neogenin and RGM is known to regulate neuronal survival. Chapter 4, the second part of the thesis, describes our studies of L1-mediated homophilic adhesion using biophysical approaches. We built a basis shape model to describe L1-mediated homophilic adhesion between L1-coated giant unilamellar vesicles and flat substrate. Using confocal microscopy techniques, we were able to reconstruct the three-dimensional shape of an adhered vesicle. We developed an algorithm in order to derive adhesion strength from the configurations of adhered vesicles based on our basis shape model using energy minimization approach.", "date": "2011", "date_type": "degree", "id_number": "CaltechTHESIS:10242010-143824484", "refereed": "FALSE", "official_url": "https://resolver.caltech.edu/CaltechTHESIS:10242010-143824484", "rights": "No commercial reproduction, distribution, display or performance rights in this work are provided.", "collection": "CaltechTHESIS", "reviewer": "Kathy Johnson", "deposited_by": "Fan Yang", "deposited_on": "2011-05-31 19:22:27", "doi": "10.7907/Q8ET-K632", "divisions": { "items": [ "div_chem" ] }, "institution": "California Institute of Technology", "thesis_type": "phd", "thesis_advisor": { "items": [ { "email": "bjorkman@caltech.edu", "id": "Bjorkman-P-J", "name": { "family": "Bjorkman", "given": "Pamela J." }, "role": "advisor" } ] }, "thesis_committee": { "items": [ { "email": "dcrees@caltech.edu", "id": "Rees-D-C", "name": { "family": "Rees", "given": "Douglas C." }, "role": "chair" }, { "email": "phillips@phoc.caltech.edu", "id": "Phillips-R-B", "name": { "family": "Phillips", "given": "Robert B." }, "role": "member" }, { "email": "aron@caltech.edu", "id": "Kuppermann-A", "name": { "family": "Kuppermann", "given": "Aron" }, "role": "member" }, { "email": "bjorkman@caltech.edu", "id": "Bjorkman-P-J", "name": { "family": "Bjorkman", "given": "Pamela J." }, "role": "member" } ] }, "thesis_degree": "PHD", "thesis_degree_grantor": "California Institute of Technology", "thesis_defense_date": "2010-09-10", "gradofc_approval_date": "2011-05-31", "review_status": "approved", "option_major": { "items": [ "chemistry" ] }, "copyright_statement": "Author's Rights Authorization: I hereby certify that, if appropriate, I have obtained a written permission statement from the owner(s) of each third party copyrighted matter to be included in my thesis, dissertation, or project report, allowing distribution as specified below. I certify that the version I submitted here is the same as that approved by my advisory committee.\n\nI hereby grant to California Institute of Technology or its agents the non-exclusive license to archive and make accessible, under the conditions specified under \"Thesis Availability\" in this submission, my thesis, dissertation, or project report in whole or in part in all forms of media, now or hereafter known. I retain all other ownership rights to the copyright of the thesis, dissertation, or project report. I also retain the right to use in future works (such as articles or books) all or part of this thesis, dissertation, or project report.", "resource_type": "thesis", "pub_year": "2011", "author_list": "Yang, Fan", "advisor_list": "Bjorkman, Pamela J.", "comittee_list": "Rees, Douglas C.; Phillips, Robert B.; et el." }, { "id": "https://thesis.library.caltech.edu/id/eprint/2453", "eprint_id": 2453, "rev_number": 46, "documents": [ { "id": "/id/document/4659", "doc_id": 4659, "rev_number": 4, "files": [ { "id": "/id/file/26874", "fileid": 26874, "datasetid": "document", "objectid": 4659, "filename": "00Preliminaries.pdf", "mime_type": "application/pdf", "filesize": 118994, "mtime": "2012-12-26 02:51:34", "url": "/2453/1/00Preliminaries.pdf" } ], "eprint_id": 2453, "pos": 1, "placement": 2, "mime_type": "application/pdf", "format": "application/pdf", "format_desc": "00Preliminaries.pdf", "language": "en", "security": "public", "license": "other", "main": "00Preliminaries.pdf", 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"2009-07-06", "lastmod": "2023-11-08 00:16:03", "status_changed": "2009-09-25 02:37:48", "type": "thesis", "metadata_visibility": "show", "creators": { "items": [ { "email": "jsklein@caltech.edu", "id": "Klein-Joshua-Simon", "name": { "family": "Klein", "given": "Joshua Simon" }, "show_email": "NO" } ] }, "title": "Investigations in the Design and Characterization of HIV-1 Neutralizing Molecules", "ispublished": "unpub", "full_text_status": "public", "keywords": "AIDS; infectious disease", "abstract": "Human Immunodeficiency Virus (HIV) is a T-lymphotrophic retrovirus that is the causative agent of Acquired Immunodeficiency Syndrome and is estimated to currently infect approximately 40 million people worldwide. Life-extending therapies are credited for the precipitous drop in HIV-related mortality in developed countries, but their high costs prevent widespread distribution in developing countries. To date, all attempts to produce a vaccine capable of preventing or controlling an HIV infection have failed, but a comprehensive explanation for these failures has yet to emerge from the available data. In this thesis the first chapter provides an overview of the pandemic, the antigenic properties of gp120 and gp41, which are the two glycoproteins that comprise the outer envelope spike of the virus, and the broadly neutralizing antibodies that have been isolated against them. The second and third chapters discuss biophysical characterizations of these monoclonal antibodies and newly designed molecules derived from them. Based on a comparison of these data with pre-existing research, a novel hypothesis called the \"island effect\" was developed and is presented as a possible explanation for the consistent failure of the human immune system to respond to infection or vaccination with an effective humoral response. The final chapter summarizes ongoing investigations in the capacities of broadly neutralizing monoclonal antibodies to recruit antibody-dependent cellular cytotoxicity, a mechanism by which antibodies can trigger the lysis of HIV-infected cells by the innate immune system. ", "date": "2009", "date_type": "degree", "id_number": "CaltechETD:etd-06042009-131723", "refereed": "FALSE", "official_url": "https://resolver.caltech.edu/CaltechETD:etd-06042009-131723", "rights": "No commercial reproduction, distribution, display or performance rights in this work are provided.", "collection": "CaltechTHESIS", "reviewer": "Kathy Johnson", "deposited_by": "Imported from ETD-db", "deposited_on": "2009-07-06", "doi": "10.7907/QPEC-8Y25", "divisions": { "items": [ "div_biol" ] }, "institution": "California Institute of Technology", "thesis_type": "phd", "thesis_advisor": { "items": [ { "email": "bjorkman@caltech.edu", "id": "Bjorkman-P-J", "name": { "family": "Bjorkman", "given": "Pamela J." }, "role": "advisor" } ] }, "thesis_committee": { "items": [ { "email": "steve@mayo.caltech.edu", "id": "Mayo-S-L", "name": { "family": "Mayo", "given": "Stephen L." }, "role": "chair" }, { "email": "baltimo@caltech.edu", "id": "Baltimore-D-L", "name": { "family": "Baltimore", "given": "David L." }, "role": "member" }, { "email": "evroth@caltech.edu", "id": "Rothenberg-E-V", "name": { "family": "Rothenberg", "given": "Ellen V." }, "role": "member" }, { "email": "bjorkman@caltech.edu", "id": "Bjorkman-P-J", "name": { "family": "Bjorkman", "given": "Pamela J." }, "role": "member" } ] }, "thesis_degree": "PHD", "thesis_degree_grantor": "California Institute of Technology", "thesis_submitted_date": "2009-06-04", "thesis_defense_date": "2009-05-28", "thesis_approved_date": "2009-07-06", "gradofc_approval_date": "2009-07-06", "review_status": "approved", "option_major": { "items": [ "biochem" ] }, "copyright_statement": "I hereby certify that, if appropriate, I have obtained a written permission statement from the owner(s) of each third party copyrighted matter to be included in my thesis, dissertation, or project report, allowing distribution as specified below. I certify that the version I submitted is the same as that approved by my advisory committee.\n\nI hereby grant to California Institute of Technology or its agents the non-exclusive\nlicense to archive and make accessible, under the conditions specified below,\nmy thesis, dissertation, or project report in whole or in part in all forms of media, now or hereafter known. I retain all other ownership rights to the copyright of the thesis, dissertation or project report. I also retain the right to use in future works (such as articles or books) all or part of this thesis, dissertation, or project report.", "resource_type": "thesis", "pub_year": "2009", "author_list": "Klein, Joshua Simon", "advisor_list": "Bjorkman, Pamela J.", "comittee_list": "Mayo, Stephen L.; Baltimore, David L.; et el." }, { "id": "https://thesis.library.caltech.edu/id/eprint/4532", "eprint_id": 4532, "rev_number": 10, "documents": [ { "id": "/id/document/7351", "doc_id": 7351, "rev_number": 3, "files": [ { "id": "/id/file/44871", "fileid": 44871, "datasetid": "document", "objectid": 7351, "filename": "TesarThesisDONE111108.pdf", "mime_type": "application/pdf", "filesize": 22326275, "mtime": "2012-12-26 03:09:31", "url": "/4532/1/TesarThesisDONE111108.pdf" } ], "eprint_id": 4532, "pos": 1, "mime_type": "application/pdf", "format": "application/pdf", "language": "en", "security": "public", "license": "other", "main": "TesarThesisDONE111108.pdf", "media_duration": "0", "media_aspect_ratio": "0", "media_sample_start": "0", "media_sample_stop": "0", "content": "final", "relation": { "items": [ { "type": "http://eprints.org/relation/hasVolatileVersion", "uri": "/id/document/23876" }, { "type": "http://eprints.org/relation/haspreviewThumbnailVersion", "uri": "/id/document/23876" }, { "type": "http://eprints.org/relation/hasVersion", "uri": "/id/document/23876" } ] } }, { "id": "/id/document/13925", "doc_id": 13925, "rev_number": 3, "files": [ { "id": "/id/file/204382", "fileid": 204382, "datasetid": "document", "objectid": 13925, "filename": "Tesar_Devin_Brent_2009.PDF", "mime_type": "application/pdf", "filesize": 41183, "mtime": "2016-08-22 21:17:26", "url": "/4532/2/Tesar_Devin_Brent_2009.PDF" } ], "eprint_id": 4532, "pos": 2, "format": "application/pdf", "language": "en", "security": "internal", "license": "other", "main": "Tesar_Devin_Brent_2009.PDF", "media_duration": "0", "media_aspect_ratio": "0", "media_sample_start": "0", "media_sample_stop": "0", "content": "approvalform" }, { "id": "/id/document/23876", "doc_id": 23876, "rev_number": 2, "files": [ { "id": "/id/file/44869", "fileid": 44869, "datasetid": "document", "objectid": 23876, "filename": "preview.png", "mime_type": "image/png", "hash": "0217db28876f2caea8023f27680eccc2", "hash_type": "MD5", "filesize": 16478, "mtime": "2012-12-26 03:09:31", "url": "/4532/3/preview.png" } ], "eprint_id": 4532, "pos": 3, "placement": 3, "mime_type": "image/png", "format": "image/png", "language": "en", "security": "public", "license": "other", "main": "preview.png", "media_duration": "0", "media_aspect_ratio": "0", "media_sample_start": "0", "media_sample_stop": "0", "relation": { "items": [ { "type": "http://eprints.org/relation/isVolatileVersionOf", "uri": "/id/document/7351" }, { "type": "http://eprints.org/relation/ispreviewThumbnailVersionOf", "uri": "/id/document/7351" }, { "type": "http://eprints.org/relation/isVersionOf", "uri": "/id/document/7351" } ] } }, { "id": "/id/document/124366", "doc_id": 124366, "rev_number": 1, "files": [ { "id": "/id/file/369796", "fileid": 369796, "datasetid": "document", "objectid": 124366, "filename": "indexcodes.txt", "mime_type": "text/plain", "hash": "8ac6dc1cbe5853cc15a3d553b0896e98", "hash_type": "MD5", "filesize": 41256, "mtime": "2021-06-23 23:30:09", "url": "/4532/4/indexcodes.txt" } ], "eprint_id": 4532, "pos": 4, "placement": 4, "mime_type": "text/plain", "format": "other", "format_desc": "Generate index codes conversion from application/pdf to indexcodes", "language": "en", "security": "public", "license": "other", "main": "indexcodes.txt", "media_duration": "0", "media_aspect_ratio": "0", "media_sample_start": "0", "media_sample_stop": "0", "relation": { "items": [ { "type": "http://eprints.org/relation/isVersionOf", "uri": "/id/document/7351" }, { "type": "http://eprints.org/relation/isVolatileVersionOf", "uri": "/id/document/7351" }, { "type": "http://eprints.org/relation/isIndexCodesVersionOf", "uri": "/id/document/7351" } ] } } ], "eprint_status": "archive", "userid": 2, "dir": "disk0/00/00/45/32", "datestamp": "2008-12-04", "lastmod": "2023-11-08 00:16:03", "status_changed": "2009-09-25 03:20:14", "type": "thesis", "metadata_visibility": "show", "creators": { "items": [ { "email": "tesar@caltech.edu", "id": "Tesar-Devin-Brent", "name": { "family": "Tesar", "given": "Devin Brent" }, "show_email": "NO" } ] }, "title": "Investigations of the Mechanisms of Receptor-Mediated Immunoglobulin Transport in Mammals and Birds", "ispublished": "unpub", "full_text_status": "public", "keywords": "FcRn; immunoglobulins; MDCK; polarized epithelia; pssive immunity; receptor trafficking", "abstract": "The neonatal Fc receptor (FcRn) mediates the passive acquisition of humoral immunity in early pre- or post-natal mammals by transferring maternal IgG to the fetus or suckling newborn. In addition, FcRn serves to extend the serum half-life of IgG in adult mammals by protecting it from a default degradative pathway in vascular endothelial cells. For both of these functions, FcRn binds the Fc domain of IgG with high affinity at the acidic pH (\u22646.5) of the intestinal lumen and acidic endosomes, and releases the IgG at the slightly basic pH (~7.4) of blood. While the ability of FcRn to transcytose IgG bidirectionally in polarized cell models has been well documented, the specific mechanism(s) by which endocytosed IgG is sorted from other vesicular cargo and directed through a progression of endosomal compartments ultimately leading to the apical or basolateral membrane are poorly understood.
\r\n\r\nWe wished to develop an in vitro system with which to study the trafficking behavior of rat FcRn in polarized epithelia. I developed such a model system using Madin-Darby Canine Kidney cells stably-transfected with the rat FcRn. The cells bind, endocytose, recycle and bidirectionally transcytose FcRn ligands, faithfully recapitulating the function of FcRn in the neonatal rodent gut. We used these cells to test whether or not the presence of two FcRn binding sites on an Fc ligand are required for transport. The results demonstrated that ligand bivalency is not strictly required for transport but does increase the transcytosis efficiency of the system, an interesting result in light of the fact that FcRn binds and transports a naturally monovalent ligand \u2013 serum albumin.
\r\n\r\nWe have used the FcRn-MDCK cells to study trafficking of the receptor in living cells using spinning disk confocal microscopy. For these studies I developed a recombinant Fc ligand containing a tandem dimer of fluorescent proteins on each chain and demonstrated that this ligand is brighter and more photostable than conventional chemically-labeled Fc molecules used in other confocal studies. Our FcRn-MDCK cells have also been used to examine trafficking events at the plasma membrane leading up to exocytosis though use of total internal reflection microscopy (TIRFM).
\r\n\r\nI also created a model system to study an avian Fc receptor present in yolk sac (FcRY). FcRY has been shown to bind IgY (the avian counterpart of IgG) with the same pH-dependence that FcRn exhibits for IgG. Transcytosis and recycling experiments using polarized rat inner medullary collecting duct (IMCD) cells stably transfected with the FcRY gene demonstrated that this receptor is a true functional equivalent of FcRn despite being structurally distinct from FcRn. This presents a striking example of convergent evolution and demonstrates that certain versatile protein folds can play key roles in more than one functional context within a complex organism.
\r\n", "date": "2009", "date_type": "degree", "id_number": "CaltechETD:etd-11122008-131536", "refereed": "FALSE", "official_url": "https://resolver.caltech.edu/CaltechETD:etd-11122008-131536", "rights": "No commercial reproduction, distribution, display or performance rights in this work are provided.", "collection": "CaltechTHESIS", "reviewer": "Kathy Johnson", "deposited_by": "Imported from ETD-db", "deposited_on": "2008-12-04", "doi": "10.7907/8M42-R866", "divisions": { "items": [ "div_biol" ] }, "institution": "California Institute of Technology", "thesis_type": "phd", "thesis_advisor": { "items": [ { "id": "Bjorkman-P-J", "name": { "family": "Bjorkman", "given": "Pamela J." }, "role": "advisor" } ] }, "thesis_committee": { "items": [ { "email": "bjorkman@caltech.edu", "id": "Bjorkman-P-J", "name": { "family": "Bjorkman", "given": "Pamela J." }, "role": "chair" }, { "email": "evroth@caltech.edu", "id": "Rothenberg-E-V", "name": { "family": "Rothenberg", "given": "Ellen V." }, "role": "member" }, { "email": "jensen@caltech.edu", "id": "Jensen-G-J", "name": { "family": "Jensen", "given": "Grant J." }, "role": "member" }, { "email": "sefraser@caltech.edu", "id": "Fraser-S-E", "name": { "family": "Fraser", "given": "Scott E." }, "role": "member" } ] }, "thesis_degree": "PHD", "thesis_degree_grantor": "California Institute of Technology", "thesis_submitted_date": "2008-11-12", "thesis_defense_date": "2008-09-12", "thesis_approved_date": "2008-12-04", "gradofc_approval_date": "2008-11-20", "review_status": "approved", "option_major": { "items": [ "biology" ] }, "copyright_statement": "I hereby certify that, if appropriate, I have obtained a written permission statement from the owner(s) of each third party copyrighted matter to be included in my thesis, dissertation, or project report, allowing distribution as specified below. I certify that the version I submitted is the same as that approved by my advisory committee.\n\nI hereby grant to California Institute of Technology or its agents the non-exclusive\nlicense to archive and make accessible, under the conditions specified below,\nmy thesis, dissertation, or project report in whole or in part in all forms of media, now or hereafter known. I retain all other ownership rights to the copyright of the thesis, dissertation or project report. I also retain the right to use in future works (such as articles or books) all or part of this thesis, dissertation, or project report.", "resource_type": "thesis", "pub_year": "2009", "author_list": "Tesar, Devin Brent", "advisor_list": "Bjorkman, Pamela J.", "comittee_list": "Bjorkman, Pamela J.; Rothenberg, Ellen V.; et el." }, { "id": "https://thesis.library.caltech.edu/id/eprint/1883", "eprint_id": 1883, "rev_number": 11, "documents": [ { "id": "/id/document/3193", "doc_id": 3193, "rev_number": 2, "files": [ { "id": "/id/file/19110", "fileid": 19110, "datasetid": "document", "objectid": 3193, "filename": "Adrian_Rice_Full_Thesis.pdf", "mime_type": "application/pdf", "filesize": 27472401, "mtime": "2012-12-26 02:43:33", "url": "/1883/1/Adrian_Rice_Full_Thesis.pdf" } ], "eprint_id": 1883, "pos": 1, "mime_type": "application/pdf", "format": "application/pdf", "format_desc": "Adrian_Rice_Full_Thesis.pdf", "language": "en", "security": "public", "license": "other", "main": "Adrian_Rice_Full_Thesis.pdf", "media_duration": "0", "media_aspect_ratio": "0", "media_sample_start": "0", "media_sample_stop": "0", "content": "final", "relation": { "items": [ { "type": "http://eprints.org/relation/hasVolatileVersion", "uri": "/id/document/19886" }, { "type": "http://eprints.org/relation/haspreviewThumbnailVersion", "uri": "/id/document/19886" }, { "type": "http://eprints.org/relation/hasVersion", "uri": "/id/document/19886" } ] } }, { "id": "/id/document/13905", "doc_id": 13905, "rev_number": 3, "files": [ { "id": "/id/file/202042", "fileid": 202042, "datasetid": "document", "objectid": 13905, "filename": "Rice_Adrian_Edward_2009.PDF", "mime_type": "application/pdf", "filesize": 42226, "mtime": "2016-08-22 21:15:17", "url": "/1883/2/Rice_Adrian_Edward_2009.PDF" } ], "eprint_id": 1883, "pos": 2, "format": "application/pdf", "language": "en", "security": "internal", "license": "other", "main": "Rice_Adrian_Edward_2009.PDF", "media_duration": "0", "media_aspect_ratio": "0", "media_sample_start": "0", "media_sample_stop": "0", "content": "approvalform" }, { "id": "/id/document/19886", "doc_id": 19886, "rev_number": 2, "files": [ { "id": "/id/file/19108", "fileid": 19108, "datasetid": "document", "objectid": 19886, "filename": "preview.png", "mime_type": "image/png", "hash": "7d84fec30acbdde0d24a7cc875e63d49", "hash_type": "MD5", "filesize": 16337, "mtime": "2012-12-26 02:43:33", "url": "/1883/3/preview.png" } ], "eprint_id": 1883, "pos": 3, "placement": 3, "mime_type": "image/png", "format": "image/png", "language": "en", "security": "public", "license": "other", "main": "preview.png", "media_duration": "0", "media_aspect_ratio": "0", "media_sample_start": "0", "media_sample_stop": "0", "relation": { "items": [ { "type": "http://eprints.org/relation/isVolatileVersionOf", "uri": "/id/document/3193" }, { "type": "http://eprints.org/relation/ispreviewThumbnailVersionOf", "uri": "/id/document/3193" }, { "type": "http://eprints.org/relation/isVersionOf", "uri": "/id/document/3193" } ] } }, { "id": "/id/document/121494", "doc_id": 121494, "rev_number": 1, "files": [ { "id": "/id/file/366886", "fileid": 366886, "datasetid": "document", "objectid": 121494, "filename": "indexcodes.txt", "mime_type": "text/plain", "hash": "16fadcee1c4fb5431498954ee047b3a9", "hash_type": "MD5", "filesize": 33477, "mtime": "2021-06-23 21:27:57", "url": "/1883/4/indexcodes.txt" } ], "eprint_id": 1883, "pos": 4, "placement": 4, "mime_type": "text/plain", "format": "other", "format_desc": "Generate index codes conversion from application/pdf to indexcodes", "language": "en", "security": "public", "license": "other", "main": "indexcodes.txt", "media_duration": "0", "media_aspect_ratio": "0", "media_sample_start": "0", "media_sample_stop": "0", "relation": { "items": [ { "type": "http://eprints.org/relation/isVersionOf", "uri": "/id/document/3193" }, { "type": "http://eprints.org/relation/isVolatileVersionOf", "uri": "/id/document/3193" }, { "type": "http://eprints.org/relation/isIndexCodesVersionOf", "uri": "/id/document/3193" } ] } } ], "eprint_status": "archive", "userid": 2, "dir": "disk0/00/00/18/83", "datestamp": "2009-05-29", "lastmod": "2023-11-08 00:16:03", "status_changed": "2009-09-25 02:18:50", "type": "thesis", "metadata_visibility": "show", "creators": { "items": [ { "email": "adrianr@caltech.edu", "id": "Rice-Adrian-Edward", "name": { "family": "Rice", "given": "Adrian Edward" }, "show_email": "NO" } ] }, "title": "Biophysical and Cell Biological Studies Characterizing the Vertebrate Iron Exporter Ferroportin", "ispublished": "unpub", "full_text_status": "public", "keywords": "ferroportin; hemochromatosis; hepcidin; live-cell imaging; membrane protein", "abstract": "Mammalian iron homeostasis is maintained by an intricate network of diverse proteins that constantly survey systemic iron levels and carefully regulate the uptake of iron from the diet. Control of this uptake is critically important because once iron is absorbed, mammals have no regulated mechanism for its removal. The portal through which iron enters the body is ferroportin, a multipass membrane protein expressed on the basolateral membrane of epithelial cells in the duodenum. The iron export function of ferroportin is primarily regulated by the serum peptide hormone hepcidin, which is secreted from the liver when systemic iron levels are high. Hepcidin acts as a negative regulator of iron uptake by binding to ferroportin at the cell surface and inducing its internalization and degradation. Genetic defects in ferroportin, hepcidin, or the proteins involved with sensing systemic iron levels lead to iron overload diseases known as hereditary hemochromatosis. Using the tools of biophysics and cell biology, we sought to study ferroportin and its interaction with hepcidin in order to better understand this critical bottleneck in iron uptake and how genetic defects within ferroportin might lead to disease. We developed the first protocols for the overexpression, detergent-solubilization, and purification of recombinant ferroportin. We determined that detergent-solubilized ferroportin is a monomer capable of binding hepcidin in vitro. We characterized the expression and subcellular localization of ferroportin in mammalian tissue culture and determined that both the amino- and carboxy-termini of ferroportin are cytosolic. We developed cell-based assays for the hepcidin-induced internalization of ferroportin and used these to characterize the route of internalization from the plasma membrane through early endosomes to degradative lysosomal compartments. Using live-cell imaging techniques, we showed that this internalization depended on intact microtubules. We expanded this cell-biological study to include sixteen disease-related ferroportin mutants and reported that each mutant was expressed on the plasma membrane like wild-type ferroportin, but that only a subset of the mutants were capable of being internalized by hepcidin. These studies form a foundation for future biophysical and cell-biological studies of ferroportin function. ", "date": "2009", "date_type": "degree", "id_number": "CaltechETD:etd-05192009-163326", "refereed": "FALSE", "official_url": "https://resolver.caltech.edu/CaltechETD:etd-05192009-163326", "rights": "No commercial reproduction, distribution, display or performance rights in this work are provided.", "collection": "CaltechTHESIS", "reviewer": "Kathy Johnson", "deposited_by": "Imported from ETD-db", "deposited_on": "2009-05-29", "doi": "10.7907/2P16-3X70", "divisions": { "items": [ "div_biol" ] }, "institution": "California Institute of Technology", "thesis_type": "phd", "thesis_advisor": { "items": [ { "id": "Bjorkman-P-J", "name": { "family": "Bjorkman", "given": "Pamela J." }, "role": "co-advisor" }, { "id": "Rees-D-C", "name": { "family": "Rees", "given": "Douglas C." }, "role": "co-advisor" } ] }, "thesis_committee": { "items": [ { "email": "dchan@caltech.edu", "id": "Chan-D-C", "name": { "family": "Chan", "given": "David C." }, "role": "chair" }, { "email": "dcrees@caltech.edu", "id": "Rees-D-C", "name": { "family": "Rees", "given": "Douglas C." }, "role": "member" }, { "email": "jensen@caltech.edu", "id": "Jensen-G-J", "name": { "family": "Jensen", "given": "Grant J." }, "role": "member" }, { "email": "hbgray@caltech.edu", "id": "Gray-H-B", "name": { "family": "Gray", "given": "Harry B." }, "role": "member" }, { "email": "bjorkman@caltech.edu", "id": "Bjorkman-P-J", "name": { "family": "Bjorkman", "given": "Pamela J." }, "role": "member" } ] }, "thesis_degree": "PHD", "thesis_degree_grantor": "California Institute of Technology", "thesis_submitted_date": "2009-05-19", "thesis_defense_date": "2009-04-29", "thesis_approved_date": "2009-05-29", "gradofc_approval_date": "2009-05-28", "review_status": "approved", "option_major": { "items": [ "biochem" ] }, "copyright_statement": "I hereby certify that, if appropriate, I have obtained a written permission statement from the owner(s) of each third party copyrighted matter to be included in my thesis, dissertation, or project report, allowing distribution as specified below. I certify that the version I submitted is the same as that approved by my advisory committee.\n\nI hereby grant to California Institute of Technology or its agents the non-exclusive\nlicense to archive and make accessible, under the conditions specified below,\nmy thesis, dissertation, or project report in whole or in part in all forms of media, now or hereafter known. I retain all other ownership rights to the copyright of the thesis, dissertation or project report. I also retain the right to use in future works (such as articles or books) all or part of this thesis, dissertation, or project report.", "resource_type": "thesis", "pub_year": "2009", "author_list": "Rice, Adrian Edward", "advisor_list": "Bjorkman, Pamela J. and Rees, Douglas C.", "comittee_list": "Chan, David C.; Rees, Douglas C.; et el." }, { "id": "https://thesis.library.caltech.edu/id/eprint/2084", "eprint_id": 2084, "rev_number": 15, "documents": [ { "id": "/id/document/3775", "doc_id": 3775, "rev_number": 2, "files": [ { "id": "/id/file/22145", "fileid": 22145, "datasetid": "document", "objectid": 3775, "filename": "Giannetti_dissertation.pdf", "mime_type": "application/pdf", "filesize": 31215100, "mtime": "2012-12-26 02:46:50", "url": "/2084/1/Giannetti_dissertation.pdf" } ], "eprint_id": 2084, "pos": 1, "mime_type": "application/pdf", "format": "application/pdf", "format_desc": "Giannetti_dissertation.pdf", "language": "en", "security": "public", "license": "other", "main": "Giannetti_dissertation.pdf", "media_duration": "0", "media_aspect_ratio": "0", "media_sample_start": "0", "media_sample_stop": "0", "content": "final", "relation": { "items": [ { "type": "http://eprints.org/relation/hasVolatileVersion", "uri": "/id/document/20439" }, { "type": "http://eprints.org/relation/haspreviewThumbnailVersion", "uri": "/id/document/20439" }, { "type": "http://eprints.org/relation/hasVersion", "uri": "/id/document/20439" } ] } }, { "id": "/id/document/20439", "doc_id": 20439, "rev_number": 2, "files": [ { "id": "/id/file/22143", "fileid": 22143, "datasetid": "document", "objectid": 20439, "filename": "preview.png", "mime_type": "image/png", "hash": "0d29da08e4e7007195982af816db9941", "hash_type": "MD5", "filesize": 15800, "mtime": "2012-12-26 02:46:50", "url": "/2084/2/preview.png" } ], "eprint_id": 2084, "pos": 2, "placement": 2, "mime_type": "image/png", "format": "image/png", "language": "en", "security": "public", "license": "other", "main": "preview.png", "media_duration": "0", "media_aspect_ratio": "0", "media_sample_start": "0", "media_sample_stop": "0", "relation": { "items": [ { "type": "http://eprints.org/relation/isVolatileVersionOf", "uri": "/id/document/3775" }, { "type": "http://eprints.org/relation/ispreviewThumbnailVersionOf", "uri": "/id/document/3775" }, { "type": "http://eprints.org/relation/isVersionOf", "uri": "/id/document/3775" } ] } }, { "id": "/id/document/122062", "doc_id": 122062, "rev_number": 1, "files": [ { "id": "/id/file/367456", "fileid": 367456, "datasetid": "document", "objectid": 122062, "filename": "indexcodes.txt", "mime_type": "text/plain", "hash": "304ca313141a55960328cebb853a35ce", "hash_type": "MD5", "filesize": 42545, "mtime": "2021-06-23 21:45:37", "url": "/2084/3/indexcodes.txt" } ], "eprint_id": 2084, "pos": 3, "placement": 3, "mime_type": "text/plain", "format": "other", "format_desc": "Generate index codes conversion from application/pdf to indexcodes", "language": "en", "security": "public", "license": "other", "main": "indexcodes.txt", "media_duration": "0", "media_aspect_ratio": "0", "media_sample_start": "0", "media_sample_stop": "0", "relation": { "items": [ { "type": "http://eprints.org/relation/isVersionOf", "uri": "/id/document/3775" }, { "type": "http://eprints.org/relation/isVolatileVersionOf", "uri": "/id/document/3775" }, { "type": "http://eprints.org/relation/isIndexCodesVersionOf", "uri": "/id/document/3775" } ] } } ], "eprint_status": "archive", "userid": 2, "dir": "disk0/00/00/20/84", "datestamp": "2004-05-27", "lastmod": "2023-11-08 00:16:03", "status_changed": "2022-11-07 23:33:14", "type": "thesis", "metadata_visibility": "show", "creators": { "items": [ { "id": "Giannetti-Anthony-Michael", "name": { "family": "Giannetti", "given": "Anthony Michael" }, "show_email": "NO" } ] }, "title": "Biochemical, Biophysical, and Cellular Investigations of the Interactions of Transferrin Receptor with Transferrin and the Hereditary Hemochromatosis Protein, HFE", "ispublished": "unpub", "full_text_status": "public", "keywords": "analytical ultracentrifugation; apo-Tf; Biacore; bivalent ligand; chinese hamster ovary; confocal microscopy; Fe-Tf; functional epitope; green fluorescent protein; hereditary hemochromatosis; heterodimer; HFE; iron; iron overload; protein engineering; protein-protein binding; sedimentation velocity; site directed mutagenesis; stoichiometry; structural epitope; surface plasmon resonance; TfR; tissue culture; transfection; transferrin receptor; TRVb", "abstract": "Hereditary hemochromatosis (HH) is a prevalent genetic disorder that results in the daily excess absorption of dietary iron. If untreated this disease leads to systemic organ failure and death. HH is caused by mutations to the gene coding for a protein called HFE, a type I transmembrane glycoprotein with a demonstrated role in regulating cellular iron homeostasis. HFE binds to the cell-surface receptor transferrin receptor (TfR), a dimeric type II transmembrane glycoprotein responsible for iron uptake into most mammalian cell types. TfR binds iron-loaded transferrin (Fe-Tf) from the blood and transports it to acidic recycling endosomes where iron is released from Fe-Tf in a TfR-facilitated process. Iron-free transferrin (apo-Tf) remains bound to TfR and is recycled to the cell surface, where apo-Tf rapidly dissociates from TfR upon exposure to the basic pH of blood. HFE and Fe-Tf can bind simultaneously to TfR to form a ternary complex, but HFE binding to TfR lowers the apparent affinity of the Fe-Tf/TfR interaction. This reduction could result from direct competition between HFE and Fe-Tf for receptor binding sites, from negative cooperativity, or both. We sought to understand the mechanism of HFE, Fe-Tf, and apo-Tf binding by TfR to help define HFE's role in iron homeostasis. We determined the binding constants for HFE, Fe-Tf, and apo-Tf to an extensive set of site-directed TfR mutants and discovered that HFE and Tf bind to an overlapping site on TfR, indicating the two proteins compete with each other for receptor binding. The mutagenesis results also identified differences in the contact points between TfR and the two forms of Tf, Fe-Tf and apo-Tf. By combining the mutations that are required for apo-Tf, but not Fe-Tf, binding we find that a highly conserved hydrophobic patch on the TfR surface is required for the receptor-mediated stimulation of iron release from Fe-Tf. From these data we propose a structure-based model for the mechanism of TfR-assisted iron release.
\r\n\r\nTo explore the mechanism of the HFE-induced affinity reduction for Fe-Tf binding by TfR, we engineered a heterodimeric TfR (hdTfR) that contains mutations such that one TfR chain binds only HFE and the other binds only Fe-Tf. Competition binding experiments using hdTfR demonstrate that TfR does not exhibit cooperativity in heterotropic ligand binding, suggesting that some or all of HFE's effects on iron homeostasis result from competition with Fe-Tf for TfR binding. Using transfected cell lines we show that HFE is dependent on its interactions with TfR for transport to endosomal compartments and that competition with extracellular Fe-Tf can alter HFE trafficking patterns. These data suggest that HFE's role in iron homeostasis is as a sensor of body iron status.
", "date": "2004", "date_type": "degree", "id_number": "CaltechETD:etd-05262004-173612", "refereed": "FALSE", "official_url": "https://resolver.caltech.edu/CaltechETD:etd-05262004-173612", "rights": "No commercial reproduction, distribution, display or performance rights in this work are provided.", "collection": "CaltechTHESIS", "reviewer": "Kathy Johnson", "deposited_by": "Imported from ETD-db", "deposited_on": "2004-05-27", "doi": "10.7907/06QJ-JW93", "divisions": { "items": [ "div_biol" ] }, "institution": "California Institute of Technology", "thesis_type": "phd", "thesis_advisor": { "items": [ { "email": "bjorkman@caltech.edu", "id": "Bjorkman-P-J", "name": { "family": "Bjorkman", "given": "Pamela J." }, "orcid": "0000-0002-2277-3990", "role": "advisor" } ] }, "thesis_committee": { "items": [ { "email": "dcrees@caltech.edu", "id": "Rees-D-C", "name": { "family": "Rees", "given": "Douglas C." }, "orcid": "0000-0003-4073-1185", "role": "chair" }, { "email": "dchan@caltech.edu", "id": "Chan-D-C", "name": { "family": "Chan", "given": "David C." }, "orcid": "0000-0002-0191-2154", "role": "member" }, { "email": "bjorkman@caltech.edu", "id": "Bjorkman-P-J", "name": { "family": "Bjorkman", "given": "Pamela J." }, "orcid": "0000-0002-2277-3990", "role": "member" }, { "email": "rroberts@caltech.edu", "id": "Roberts-R-W", "name": { "family": "Roberts", "given": "Richard W." }, "role": "member" } ] }, "thesis_degree": "PHD", "thesis_degree_grantor": "California Institute of Technology", "thesis_submitted_date": "2004-05-26", "thesis_defense_date": "2004-05-18", "thesis_approved_date": "2004-05-27", "review_status": "approved", "option_major": { "items": [ "biochem" ] }, "copyright_statement": "I hereby certify that, if appropriate, I have obtained a written permission statement from the owner(s) of each third party copyrighted matter to be included in my thesis, dissertation, or project report, allowing distribution as specified below. I certify that the version I submitted is the same as that approved by my advisory committee.\n\nI hereby grant to California Institute of Technology or its agents the non-exclusive\nlicense to archive and make accessible, under the conditions specified below,\nmy thesis, dissertation, or project report in whole or in part in all forms of media, now or hereafter known. I retain all other ownership rights to the copyright of the thesis, dissertation or project report. I also retain the right to use in future works (such as articles or books) all or part of this thesis, dissertation, or project report.", "resource_type": "thesis", "pub_year": "2004", "author_list": "Giannetti, Anthony Michael", "advisor_list": "Bjorkman, Pamela J.", "comittee_list": "Rees, Douglas C.; Chan, David C.; et el." }, { "id": "https://thesis.library.caltech.edu/id/eprint/2545", "eprint_id": 2545, "rev_number": 11, "documents": [ { "id": "/id/document/4804", "doc_id": 4804, "rev_number": 3, "files": [ { "id": "/id/file/27783", "fileid": 27783, "datasetid": "document", "objectid": 4804, "filename": "thesis.pdf", "mime_type": "application/pdf", "filesize": 3311617, "mtime": "2012-12-26 02:52:29", "url": "/2545/1/thesis.pdf" } ], "eprint_id": 2545, "pos": 1, "mime_type": "application/pdf", "format": "application/pdf", "format_desc": "thesis.pdf", "language": "en", "security": "public", "license": "other", "main": "thesis.pdf", "media_duration": "0", "media_aspect_ratio": "0", "media_sample_start": "0", "media_sample_stop": "0", "content": "final", "relation": { "items": [ { "type": "http://eprints.org/relation/hasVolatileVersion", "uri": "/id/document/21356" }, { "type": "http://eprints.org/relation/haspreviewThumbnailVersion", "uri": "/id/document/21356" }, { "type": "http://eprints.org/relation/hasVersion", "uri": "/id/document/21356" } ] } }, { "id": "/id/document/21356", "doc_id": 21356, "rev_number": 3, "files": [ { "id": "/id/file/27781", "fileid": 27781, "datasetid": "document", "objectid": 21356, "filename": "preview.png", "mime_type": "image/png", "hash": "07bccd82fde8beb15cd59143b7986143", "hash_type": "MD5", "filesize": 8118, "mtime": "2012-12-26 02:52:29", "url": "/2545/2/preview.png" } ], "eprint_id": 2545, "pos": 2, "placement": 2, "mime_type": "image/png", "format": "image/png", "language": "en", "security": "public", "license": "other", "main": "preview.png", "media_duration": "0", "media_aspect_ratio": "0", "media_sample_start": "0", "media_sample_stop": "0", "relation": { "items": [ { "type": "http://eprints.org/relation/isVolatileVersionOf", "uri": "/id/document/4804" }, { "type": "http://eprints.org/relation/ispreviewThumbnailVersionOf", "uri": "/id/document/4804" }, { "type": "http://eprints.org/relation/isVersionOf", "uri": "/id/document/4804" } ] } }, { "id": "/id/document/123031", "doc_id": 123031, "rev_number": 1, "files": [ { "id": "/id/file/368438", "fileid": 368438, "datasetid": "document", "objectid": 123031, "filename": "indexcodes.txt", "mime_type": "text/x-c", "hash": "d72a3abd14471378ad63096b0aa7772e", "hash_type": "MD5", "filesize": 27428, "mtime": "2021-06-23 22:16:31", "url": "/2545/3/indexcodes.txt" } ], "eprint_id": 2545, "pos": 3, "placement": 3, "mime_type": "text/x-c", "format": "other", "format_desc": "Generate index codes conversion from application/pdf to indexcodes", "language": "en", "security": "public", "license": "other", "main": "indexcodes.txt", "media_duration": "0", "media_aspect_ratio": "0", "media_sample_start": "0", "media_sample_stop": "0", "relation": { "items": [ { "type": "http://eprints.org/relation/isVersionOf", "uri": "/id/document/4804" }, { "type": "http://eprints.org/relation/isVolatileVersionOf", "uri": "/id/document/4804" }, { "type": "http://eprints.org/relation/isIndexCodesVersionOf", "uri": "/id/document/4804" } ] } } ], "eprint_status": "archive", "userid": 2, "dir": "disk0/00/00/25/45", "datestamp": "2002-06-13", "lastmod": "2023-11-08 00:16:03", "status_changed": "2009-09-25 02:40:08", "type": "thesis", "metadata_visibility": "show", "creators": { "items": [ { "email": "zsuzsi@caltech.edu", "id": "Hamburger-Zsuzsa-Andrea", "name": { "family": "Hamburger", "given": "Zsuzsa Andrea" }, "show_email": "NO" } ] }, "title": "Crystallographic Studies of Invasin, a Bacterial Adhesion Molecule from Yersinia pseudotuberculosis", "ispublished": "unpub", "full_text_status": "public", "keywords": "bacterial pathogenesis; integrin; invasin", "abstract": "Bacterial pathogens, such as Yersinia pseudotuberculosis, must bind and enter normally non-phagocytic cells to establish infection. The protein responsible for mediating uptake of the bacterium is a 986-residue outer membrane protein called invasin. Invasin binds to several members of the beta 1 integrin family, presumably activating a reorganization of the host cytoskeleton to form pseudopods that envelop the bacterium. Integrin binding has been localized to the extracellular region of invasin (Inv497) comprised by the COOH-terminal 497 residues. In order to gain insight into host cell entry by Yersinia pseudotuberculosis, we solved the 2.3 \u0160crystal structure of Inv497. The structure reveals five domains that form a 180 \u0160rod with structural similarities to tandem fibronectin-III domains. The integrin-binding surfaces of invasin and fibronectin include similarly located key residues, but in the context of different folds and surface shapes. The structures of invasin and fibronectin provide an example of convergent evolution, in which invasin presents an optimized surface for integrin binding compared with host substrates. We have also initiated structural analyses of the NH2-terminal ~500 residues of invasin, which are required for outer membrane localization and for presentation of the integrin-binding region of invasin. We expressed this region of invasin as inclusion bodies in E. coli, and refolded the protein in the presence of detergents. We have also obtained microcrystals of this membrane protein. Circular dichroism studies indicate that this region of invasin is composed of mainly beta-structure. As the transmembrane regions of outer membrane proteins of known structure are beta-barrels, this region of invasin is also presumed to fold into such a structure. Proteolysis experiments suggest that the NH2-terminal 70 amino acids of invasin may form a separate domain from the invasin transmembrane region, analogous to that found in another outer membrane protein, the sucrose-specific porin ScrY. Equilibrium sedimentation analytical ultracentrifugation studies indicate the protein is monomeric in solution. Black bilayer experiments suggest that this region of the protein does not contain a pore and thus plays the role of an outer membrane anchor for the presentation of the integrin-binding domain on the cell surface", "date": "2002", "date_type": "degree", "id_number": "CaltechETD:etd-06112002-135418", "refereed": "FALSE", "official_url": "https://resolver.caltech.edu/CaltechETD:etd-06112002-135418", "rights": "No commercial reproduction, distribution, display or performance rights in this work are provided.", "collection": "CaltechTHESIS", "deposited_by": "Imported from ETD-db", "deposited_on": "2002-06-13", "doi": "10.7907/NKAY-AB98", "divisions": { "items": [ "div_biol" ] }, "institution": "California Institute of Technology", "thesis_type": "phd", "thesis_advisor": { "items": [ { "id": "Bjorkman-P-J", "name": { "family": "Bjorkman", "given": "Pamela J." }, "role": "advisor" } ] }, "thesis_committee": { "items": [ { "email": "steve@mayo.caltech.edu", "id": "Mayo-S-L", "name": { "family": "Mayo", "given": "Stephen L." }, "role": "chair" }, { "email": "dcrees@caltech.edu", "id": "Rees-D-C", "name": { "family": "Rees", "given": "Douglas C." }, "role": "member" }, { "email": "evroth@caltech.edu", "id": "Rothenberg-E-V", "name": { "family": "Rothenberg", "given": "Ellen V." }, "role": "member" }, { "email": "mbronner@caltech.edu", "id": "Bronner-M-E", "name": { "family": "Bronner", "given": "Marianne E." }, "role": "member" }, { "email": "bjorkman@caltech.edu", "id": "Bjorkman-P-J", "name": { "family": "Bjorkman", "given": "Pamela J." }, "role": "member" } ] }, "thesis_degree": "PHD", "thesis_degree_grantor": "California Institute of Technology", "thesis_submitted_date": "2002-06-11", "thesis_defense_date": "2002-05-09", "thesis_approved_date": "2002-06-13", "review_status": "approved", "option_major": { "items": [ "biology" ] }, "copyright_statement": "I hereby certify that, if appropriate, I have obtained and attached hereto a written permission statement from the owner(s) of each third party copyrighted matter to be included in my thesis, dissertation, or project report, allowing distribution as specified below. I certify that the version I submitted is the same as that approved by my advisory committee.\n\nI hereby grant to California Institute of Technology or its agents the non-exclusive\nlicense to archive and make accessible, under the conditions specified below,\nmy thesis, dissertation, or project report in whole or in part in all forms of media, now or hereafter known. I retain all other ownership rights to the copyright of the thesis, dissertation or project report. I also retain the right to use in future works (such as articles or books) all or part of this thesis, dissertation, or project report.", "resource_type": "thesis", "pub_year": "2002", "author_list": "Hamburger, Zsuzsa Andrea", "advisor_list": "Bjorkman, Pamela J.", "comittee_list": "Mayo, Stephen L.; Rees, Douglas C.; et el." }, { "id": "https://thesis.library.caltech.edu/id/eprint/8116", "eprint_id": 8116, "rev_number": 34, "documents": [ { "id": "/id/document/46449", "doc_id": 46449, "rev_number": 5, "files": [ { "id": "/id/file/136116", "fileid": 136116, "datasetid": "document", "objectid": 46449, "filename": "Martin 2001.zip", "mime_type": "application/x-zip", "hash": "9b3d8279be4bbc951096bc055deb510e", "hash_type": "MD5", "filesize": 120363836, "mtime": "2014-03-07 23:41:33", "url": "/8116/7/Martin 2001.zip" } ], "eprint_id": 8116, "pos": 7, "placement": 7, "mime_type": "application/x-zip", "format": "application/zip", "format_desc": "TIFF", "language": "en", "security": "internal", "license": "other", "main": "Martin 2001.zip", "media_duration": "0", "media_aspect_ratio": "0", "media_sample_start": "0", "media_sample_stop": "0", "content": "archival" }, { "id": "/id/document/46450", "doc_id": 46450, "rev_number": 3, "files": [ { "id": "/id/file/136124", "fileid": 136124, "datasetid": "document", "objectid": 46450, "filename": "Martin 2001.pdf", "mime_type": "application/pdf", "hash": "3c76f077df77f9da49adcbde4350bca4", "hash_type": "MD5", "filesize": 49029072, "mtime": "2014-03-07 23:50:55", "url": "/8116/8/Martin 2001.pdf" } ], "eprint_id": 8116, "pos": 8, "placement": 8, "mime_type": "application/pdf", "format": "application/pdf", "language": "en", "security": "public", "license": "other", "main": "Martin 2001.pdf", "media_duration": "0", "media_aspect_ratio": "0", "media_sample_start": "0", "media_sample_stop": "0", "content": "final" }, { "id": "/id/document/46451", "doc_id": 46451, "rev_number": 3, "files": [ { "id": "/id/file/136128", "fileid": 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"/id/document/46450" } ] } }, { "id": "/id/document/128830", "doc_id": 128830, "rev_number": 1, "files": [ { "id": "/id/file/374266", "fileid": 374266, "datasetid": "document", "objectid": 128830, "filename": "indexcodes.txt", "mime_type": "text/plain", "hash": "6421cebbc44a59b87933010ce2801793", "hash_type": "MD5", "filesize": 67670, "mtime": "2021-06-24 03:13:51", "url": "/8116/13/indexcodes.txt" } ], "eprint_id": 8116, "pos": 13, "placement": 13, "mime_type": "text/plain", "format": "other", "format_desc": "Generate index codes conversion from application/pdf to indexcodes", "language": "en", "security": "public", "license": "other", "main": "indexcodes.txt", "media_duration": "0", "media_aspect_ratio": "0", "media_sample_start": "0", "media_sample_stop": "0", "relation": { "items": [ { "type": "http://eprints.org/relation/isVersionOf", "uri": "/id/document/46450" }, { "type": "http://eprints.org/relation/isVolatileVersionOf", "uri": "/id/document/46450" }, { "type": "http://eprints.org/relation/isIndexCodesVersionOf", "uri": "/id/document/46450" } ] } } ], "eprint_status": "archive", "userid": 50, "dir": "disk0/00/00/81/16", "datestamp": "2014-03-07 23:56:03", "lastmod": "2023-11-08 00:16:03", "status_changed": "2014-03-07 23:56:03", "type": "thesis", "metadata_visibility": "show", "creators": { "items": [ { "id": "Martin-Warham-Lance", "name": { "family": "Martin", "given": "Warham Lance" }, "show_email": "NO" } ] }, "title": "Protein-Protein Recognition: The Neonatal Fc Receptor and Immunoglobulin G", "ispublished": "unpub", "full_text_status": "public", "keywords": "Biochemistry and Molecular Biophysics", "abstract": "The neonatal Fc receptor (FcRn) binds the Fc portion of immunoglobulin G (IgG)\r\nat the acidic pH of endosomes or the gut and releases IgG at the alkaline pH of blood.\r\nFcRn is responsible for the maternofetal transfer of IgG and for rescuing endocytosed\r\nIgG from a default degradative pathway. We investigated how FcRn interacts with IgG\r\nby constructing a heterodimeric form of the Fc (hdFc) that contains one FcRn binding\r\nsite. This molecule was used to characterize the interaction between one FcRn molecule\r\nand one Fc and to determine under what conditions FcRn forms a dimer. The hdFc binds\r\none FcRn molecule at pH 6.0 with a Kd of 80 nM. In solution and with FcRn anchored to\r\nsolid supports, the heterodimeric Fc does not induce a dimer of FcRn molecules. FcRnhdFc\r\ncomplex crystals were obtained and the complex structure was solved to 2.8 \u00c5\r\nresolution. Analysis of this structure refined the understanding of the mechanism of the\r\npH-dependent binding, shed light on the role played by carbohydrates in the Fc binding,\r\nand provided insights on how to design therapeutic IgG antibodies with longer serum\r\nhalf-lives. The FcRn-hdFc complex in the crystal did not contain the FcRn dimer. To\r\ncharacterize the tendency of FcRn to form a dimer in a membrane we analyzed the\r\ntendency of the hdFc to induce cross-phosphorylation of FcRn-tyrosine kinase chimeras.\r\nWe also constructed FcRn-cyan and FcRn-yellow fluorescent proteins and have analyzed\r\nthe tendency of these molecules to exhibit fluorescence resonance energy transfer. As of\r\nnow, neither of these analyses have lead to conclusive results. In the process of acquiring\r\nthe context to appreciate the structure of the FcRn-hdFc interface, we developed a study\r\nof 171 other nonobligate protein-protein interfaces that includes an original principal\r\ncomponent analysis of the quantifiable aspects of these interfaces.", "date": "2001", "date_type": "degree", "id_number": "CaltechTHESIS:03072014-143524462", "refereed": "FALSE", "official_url": "https://resolver.caltech.edu/CaltechTHESIS:03072014-143524462", "rights": "No commercial reproduction, distribution, display or performance rights in this work are provided.", "collection": "CaltechTHESIS", "reviewer": "Tony Diaz", "deposited_on": "2014-03-07 23:56:03", "doi": "10.7907/9ek6-6833", "divisions": { "items": [ "div_biol" ] }, "institution": "California Institute of Technology", "thesis_type": "phd", "thesis_advisor": { "items": [ { "id": "Bjorkman-P-J", "name": { "family": "Bjorkman", "given": "Pamela J." }, "orcid": "0000-0002-2277-3990", "role": "advisor" }, { "id": "Meyerowitz-E-M", "name": { "family": "Meyerowitz", "given": "Elliot M." }, "role": "co-advisor" } ] }, "thesis_committee": { "items": [ { "id": "Rees-D-C", "name": { "family": "Rees", "given": "Douglas C." }, "orcid": "0000-0003-4073-1185", "role": "chair" }, { "id": "Bjorkman-P-J", "name": { "family": "Bjorkman", "given": "Pamela J." }, "orcid": "0000-0002-2277-3990", "role": "member" }, { "id": "Fraser-S-E", "name": { "family": "Fraser", "given": "Scott E." }, "orcid": "0000-0002-5377-0223", "role": "member" }, { "id": "Rothenberg-E-V", "name": { "family": "Rothenberg", "given": "Ellen V." }, "orcid": "0000-0002-3901-347X", "role": "member" } ] }, "thesis_degree": "PHD", "thesis_degree_grantor": "California Institute of Technology", "thesis_defense_date": "2001-05-17", "review_status": "approved", "option_major": { "items": [ "biochem" ] }, "copyright_statement": "Author's Rights Authorization: I hereby certify that, if appropriate, I have obtained a written permission statement from the owner(s) of each third party copyrighted matter to be included in my thesis, dissertation, or project report, allowing distribution as specified below. I certify that the version I submitted here is the same as that approved by my advisory committee.\n\nI hereby grant to California Institute of Technology or its agents the non-exclusive license to archive and make accessible, under the conditions specified under \"Thesis Availability\" in this submission, my thesis, dissertation, or project report in whole or in part in all forms of media, now or hereafter known. I retain all other ownership rights to the copyright of the thesis, dissertation, or project report. I also retain the right to use in future works (such as articles or books) all or part of this thesis, dissertation, or project report.", "resource_type": "thesis", "pub_year": "2001", "author_list": "Martin, Warham Lance", "advisor_list": "Bjorkman, Pamela J. and Meyerowitz, Elliot M.", "comittee_list": "Rees, Douglas C.; Bjorkman, Pamela J.; et el." }, { "id": "https://thesis.library.caltech.edu/id/eprint/8119", "eprint_id": 8119, "rev_number": 28, "documents": [ { "id": "/id/document/46477", "doc_id": 46477, "rev_number": 3, "files": [ { "id": "/id/file/136203", "fileid": 136203, "datasetid": "document", "objectid": 46477, "filename": "Liu 2001.pdf", "mime_type": "application/pdf", "hash": "e4ed6901138c315206506819dadddc91", "hash_type": "MD5", "filesize": 89772038, "mtime": "2014-03-10 21:13:11", "url": "/8119/1/Liu 2001.pdf" } ], "eprint_id": 8119, "pos": 1, "placement": 1, "mime_type": "application/pdf", "format": "application/pdf", "language": "en", "security": "public", 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"0", "media_sample_stop": "0", "content": "archival" } ], "eprint_status": "archive", "userid": 50, "dir": "disk0/00/00/81/19", "datestamp": "2014-03-10 22:43:00", "lastmod": "2023-11-08 00:16:03", "status_changed": "2014-03-10 22:43:00", "type": "thesis", "metadata_visibility": "show", "creators": { "items": [ { "id": "Liu-Yang-Biology", "name": { "family": "Liu", "given": "Yang" }, "show_email": "NO" } ] }, "title": "Molecular Mechanism of Sulfated Carbohydrate Recognition: Structural and Biochemical Studies of the Cysteine-Rich Domain of Mannose Receptor", "ispublished": "unpub", "full_text_status": "public", "keywords": "Biology", "abstract": "Mannose receptor (MR) is widely expressed on macrophages, immature dendritic\r\ncells, and a variety of epithelial and endothelial cells. It is a 180 kD type I transmembrane\r\nreceptor whose extracellular region consists of three parts: the amino-terminal cysteine-rich\r\ndomain (Cys-MR); a fibronectin type II-like domain; and a series of eight tandem C-type\r\nlectin carbohydrate recognition domains (CRDs). Two portions of MR have distinct\r\ncarbohydrate recognition properties: Cys-MR recognizes sulfated carbohydrates and the\r\ntandem CRD region binds terminal mannose, fucose, and N-acetyl-glucosamine (GlcNAc).\r\nThe dual carbohydrate binding specificity allows MR to interact with sulfated and nonsulfated\r\npolysaccharide chains, and thereby facilitating the involvement of MR in\r\nimmunological and physiological processes. The immunological functions of MR include\r\nantigen capturing (through binding non-sulfated carbohydrates) and antigen targeting\r\n(through binding sulfated carbohydrates), and the physiological roles include rapid clearance\r\nof circulatory luteinizing hormone (LH), which bears polysaccharide chains terminating with\r\nsulfated and non-sulfated carbohydrates.
\r\n\r\nWe have crystallized and determined the X-ray structures of unliganded Cys-MR (2.0\r\n\u00c5) and Cys-MR complexed with different ligands, including Hepes (1.7 \u00c5), 4SO_4-N-Acetylgalactosamine\r\n(4SO_4-GalNAc; 2.2 \u00c5), 3SO_4-Lewis^x (2.2 \u00c5), 3S04-Lewis^a (1.9 \u00c5),\r\nand 6SO_4-GalNAc (2.5 \u00c5). The overall structure of Cys-MR consists of 12 anti-parallel \u03b2-strands\r\narranged in three lobes with approximate three fold internal symmetry. The structure\r\ncontains three disulfide bonds, formed by the six cysteines in the Cys-MR sequence. The\r\nligand-binding site is located in a neutral pocket within the third lobe, in which the sulfate\r\ngroup of ligand is buried. Our results show that optimal binding is achieved by a\r\ncarbohydrate ligand with a sulfate group that anchors the ligand by forming numerous\r\nhydrogen bonds and a sugar ring that makes ring-stacking interactions with Trpll7 of CysMR.\r\nUsing a fluorescence-based assay, we characterized the binding affinities between CysMR\r\nand its ligands, and rationalized the derived affinities based upon the crystal structures.\r\nThese studies reveal the mechanism of sulfated carbohydrate recognition by Cys-MR and\r\nfacilitate our understanding of the role of Cys-MR in MR recognition of its ligands.
\r\n", "date": "2001", "date_type": "degree", "id_number": "CaltechTHESIS:03102014-140846235", "refereed": "FALSE", "official_url": "https://resolver.caltech.edu/CaltechTHESIS:03102014-140846235", "rights": "No commercial reproduction, distribution, display or performance rights in this work are provided.", "collection": "CaltechTHESIS", "reviewer": "Tony Diaz", "deposited_on": "2014-03-10 22:43:00", "doi": "10.7907/fj0v-hx76", "divisions": { "items": [ "div_biol" ] }, "institution": "California Institute of Technology", "thesis_type": "phd", "thesis_advisor": { "items": [ { "id": "Bjorkman-P-J", "name": { "family": "Bjorkman", "given": "Pamela J." }, "orcid": "0000-0002-2277-3990", "role": "advisor" }, { "id": "Meyerowitz-E-M", "name": { "family": "Meyerowitz", "given": "Elliot M." }, "orcid": "0000-0003-4798-5153", "role": "co-advisor" } ] }, "thesis_committee": { "items": [ { "id": "Bjorkman-P-J", "name": { "family": "Bjorkman", "given": "Pamela J." }, "orcid": "0000-0002-2277-3990", "role": "chair" }, { "id": "Deshaies-R-J", "name": { "family": "Deshaies", "given": "Raymond Joseph" }, "orcid": "0000-0002-3671-9354", "role": "member" }, { "id": "Mayo-S-L", "name": { "family": "Mayo", "given": "Stephen L." }, "orcid": "0000-0002-9785-5018", "role": "member" }, { "id": "Rees-D-C", "name": { "family": "Rees", "given": "Douglas C." }, "orcid": "0000-0003-4073-1185", "role": "member" }, { "id": "Rothenberg-E-V", "name": { "family": "Rothenberg", "given": "Ellen V." }, "orcid": "0000-0002-3901-347X", "role": "member" }, { "id": "Meyerowitz-E-M", "name": { "family": "Meyerowitz", "given": "Elliot M." }, "orcid": "0000-0003-4798-5153", "role": "member" } ] }, "thesis_degree": "PHD", "thesis_degree_grantor": "California Institute of Technology", "thesis_defense_date": "2000-09-14", "review_status": "approved", "option_major": { "items": [ "biology" ] }, "copyright_statement": "Author's Rights Authorization: I hereby certify that, if appropriate, I have obtained a written permission statement from the owner(s) of each third party copyrighted matter to be included in my thesis, dissertation, or project report, allowing distribution as specified below. I certify that the version I submitted here is the same as that approved by my advisory committee.\n\nI hereby grant to California Institute of Technology or its agents the non-exclusive license to archive and make accessible, under the conditions specified under \"Thesis Availability\" in this submission, my thesis, dissertation, or project report in whole or in part in all forms of media, now or hereafter known. I retain all other ownership rights to the copyright of the thesis, dissertation, or project report. I also retain the right to use in future works (such as articles or books) all or part of this thesis, dissertation, or project report.", "resource_type": "thesis", "pub_year": "2001", "author_list": "Liu, Yang", "advisor_list": "Bjorkman, Pamela J. and Meyerowitz, Elliot M.", "comittee_list": "Bjorkman, Pamela J.; Deshaies, Raymond Joseph; et el." }, { "id": "https://thesis.library.caltech.edu/id/eprint/7182", "eprint_id": 7182, "rev_number": 20, "documents": [ { "id": "/id/document/15187", "doc_id": 15187, "rev_number": 5, "files": [ { "id": "/id/file/99195", "fileid": 99195, "datasetid": "document", "objectid": 15187, "filename": "Vaughn_de_1998.pdf", "mime_type": "application/pdf", "filesize": 21770345, "mtime": "2012-12-26 04:44:49", "url": "/7182/1/Vaughn_de_1998.pdf" } ], "eprint_id": 7182, "pos": 1, "mime_type": "application/pdf", "format": "application/pdf", "language": "en", "security": "public", "license": "other", "main": "Vaughn_de_1998.pdf", "media_duration": "0", "media_aspect_ratio": "0", "media_sample_start": "0", "media_sample_stop": "0", "content": "final", "relation": { "items": [ { "type": "http://eprints.org/relation/hasVolatileVersion", "uri": "/id/document/28155" }, { "type": "http://eprints.org/relation/haspreviewThumbnailVersion", "uri": "/id/document/28155" }, { "type": "http://eprints.org/relation/hasVersion", "uri": "/id/document/28155" } ] } }, { "id": "/id/document/15188", "doc_id": 15188, "rev_number": 3, "files": [ { "id": "/id/file/207989", "fileid": 207989, "datasetid": "document", "objectid": 15188, "filename": "Vaughn_de_1998.zip", "mime_type": "application/zip", "filesize": 122822169, "mtime": "2016-08-22 21:24:13", "url": "/7182/2/Vaughn_de_1998.zip" } ], "eprint_id": 7182, "pos": 2, "format": "application/zip", "format_desc": "TIFF", "language": "en", "security": "internal", "license": "other", "main": "Vaughn_de_1998.zip", "media_duration": "0", "media_aspect_ratio": "0", "media_sample_start": "0", "media_sample_stop": "0", "content": "final" }, { "id": "/id/document/28155", "doc_id": 28155, "rev_number": 3, "files": [ { "id": "/id/file/99193", "fileid": 99193, "datasetid": "document", "objectid": 28155, "filename": "preview.png", "mime_type": "image/png", "hash": "da260cd64e55c1f51d7d46eb79dd0ceb", "hash_type": "MD5", "filesize": 99810, "mtime": "2012-12-26 04:44:49", "url": "/7182/3/preview.png" } ], "eprint_id": 7182, "pos": 3, "placement": 3, "mime_type": "image/png", "format": "image/png", "language": "en", "security": "public", "license": "other", "main": "preview.png", "media_duration": "0", "media_aspect_ratio": "0", "media_sample_start": "0", "media_sample_stop": "0", "relation": { "items": [ { "type": "http://eprints.org/relation/isVolatileVersionOf", "uri": "/id/document/15187" }, { "type": "http://eprints.org/relation/ispreviewThumbnailVersionOf", "uri": "/id/document/15187" }, { "type": "http://eprints.org/relation/isVersionOf", "uri": "/id/document/15187" } ] } }, { "id": "/id/document/127633", "doc_id": 127633, "rev_number": 1, "files": [ { "id": "/id/file/373069", "fileid": 373069, "datasetid": "document", "objectid": 127633, "filename": "indexcodes.txt", "mime_type": "text/x-c", "hash": "3523f2b202f1dac4524e81eccb404df3", "hash_type": "MD5", "filesize": 45942, "mtime": "2021-06-24 01:55:35", "url": "/7182/4/indexcodes.txt" } ], "eprint_id": 7182, "pos": 4, "placement": 4, "mime_type": "text/x-c", "format": "other", "format_desc": "Generate index codes conversion from application/pdf to indexcodes", "language": "en", "security": "public", "license": "other", "main": "indexcodes.txt", "media_duration": "0", "media_aspect_ratio": "0", "media_sample_start": "0", "media_sample_stop": "0", "relation": { "items": [ { "type": "http://eprints.org/relation/isVersionOf", "uri": "/id/document/15187" }, { "type": "http://eprints.org/relation/isVolatileVersionOf", "uri": "/id/document/15187" }, { "type": "http://eprints.org/relation/isIndexCodesVersionOf", "uri": "/id/document/15187" } ] } } ], "eprint_status": "archive", "userid": 87, "dir": "disk0/00/00/71/82", "datestamp": "2012-08-06 21:19:36", "lastmod": "2023-11-08 00:16:03", "status_changed": "2012-08-06 21:19:36", "type": "thesis", "metadata_visibility": "show", "creators": { "items": [ { "id": "Vaughn-D-E", "name": { "family": "Vaughn", "given": "Daniel E." }, "show_email": "NO" } ] }, "title": "Molecular mechanism of pH dependent antibody binding: Structure/function studies on the neonatal Fc receptor", "ispublished": "unpub", "full_text_status": "public", "keywords": "Biology", "abstract": "The work described here is an investigation of the molecular mechanism of pH\r\ndependent immunoglobulin G (IgG) binding by the neonatal Fc receptor (FcRn). FcRn\r\nbinds IgG at acidic, but not alkaline pHs, in two important physiological processes. These\r\nprocesses are the acquisition of passive immunity by the fetus or newborn and protecting\r\nIgG from a default degradative pathway.
\r\n\r\nA biosensor assay is used to characterize the interaction of a soluble form of FcRn\r\nwith IgG. Immobilization of FcRn on the biosensor surface reproduces the high affinity\r\nIgG binding observed for membrane bound FcRn, whereas immobilization of IgG results\r\nin lower affinity binding similar to that of the FcRn/IgG interaction in solution. The\r\nstatistical method of cross-validation is used to show that there are two classes of noninteracting binding sites. The IgG binding interaction is characterized for several mutant FcRns with designed amino acid substitutions. These mutations map the functional IgG\r\nbinding site on FcRn.
\r\n\r\nThe structure of FcRn at an alkaline pH is described. This structure determination\r\nreveals an extensive carbohydrate mediated interaction between the dimer related FeRn\r\nmolecules. The physiological relevance of this interaction is discussed in the context of the FcRn dimerization literature. A further refined structure of FcRn at an acidic pH is\r\ndescribed that includes additional carbohydrate structure. These structures are compared\r\nwith specific attention to the pH dependence of FcRn stability and IgG affinity. Finally, a\r\nmechanism for pH dependent antibody binding to FcRn is proposed based on these structures and the body of structure/function literature concerning this interaction.
", "date": "1998", "date_type": "degree", "id_number": "CaltechTHESIS:08062012-111300229", "refereed": "FALSE", "official_url": "https://resolver.caltech.edu/CaltechTHESIS:08062012-111300229", "rights": "No commercial reproduction, distribution, display or performance rights in this work are provided.", "collection": "CaltechTHESIS", "reviewer": "Tony Diaz", "deposited_by": "Benjamin Perez", "deposited_on": "2012-08-06 21:19:36", "doi": "10.7907/bzyh-hn75", "divisions": { "items": [ "div_biol" ] }, "institution": "California Institute of Technology", "thesis_type": "phd", "thesis_advisor": { "items": [ { "email": "bjorkman@caltech.edu", "id": "Bjorkman-P-J", "name": { "family": "Bjorkman", "given": "Pamela J." }, "role": "advisor" } ] }, "thesis_committee": { "items": [ { "name": { "family": "Unknown", "given": "Unknown" } } ] }, "thesis_degree": "PHD", "thesis_degree_grantor": "California Institute of Technology", "thesis_defense_date": "1997-07-07", "review_status": "approved", "option_major": { "items": [ "biology" ] }, "copyright_statement": "Author's Rights Authorization: I hereby certify that, if appropriate, I have obtained a written permission statement from the owner(s) of each third party copyrighted matter to be included in my thesis, dissertation, or project report, allowing distribution as specified below. I certify that the version I submitted here is the same as that approved by my advisory committee.\n\nI hereby grant to California Institute of Technology or its agents the non-exclusive license to archive and make accessible, under the conditions specified under \"Thesis Availability\" in this submission, my thesis, dissertation, or project report in whole or in part in all forms of media, now or hereafter known. I retain all other ownership rights to the copyright of the thesis, dissertation, or project report. I also retain the right to use in future works (such as articles or books) all or part of this thesis, dissertation, or project report.", "resource_type": "thesis", "pub_year": "1998", "author_list": "Vaughn, Daniel E.", "advisor_list": "Bjorkman, Pamela J.", "comittee_list": "Unknown, Unknown" }, { "id": "https://thesis.library.caltech.edu/id/eprint/7664", "eprint_id": 7664, "rev_number": 22, "documents": [ { "id": "/id/document/37957", "doc_id": 37957, "rev_number": 3, "files": [ { "id": "/id/file/117791", "fileid": 117791, "datasetid": "document", "objectid": 37957, "filename": "Huber 1994.zip", "mime_type": "application/x-zip", "hash": "b49e7eb7f3a3496c9035f10bbe52cb54", "hash_type": "MD5", "filesize": 128962252, "mtime": "2013-05-03 23:27:18", "url": "/7664/1/Huber 1994.zip" } ], "eprint_id": 7664, "pos": 1, "placement": 1, "mime_type": "application/x-zip", "format": "application/zip", "format_desc": "TIFF", "language": "en", "security": "internal", "license": "other", "main": "Huber 1994.zip", "media_duration": "0", "media_aspect_ratio": "0", "media_sample_start": "0", "media_sample_stop": "0", "content": "final" }, { "id": "/id/document/37958", "doc_id": 37958, "rev_number": 3, "files": [ { "id": "/id/file/117794", "fileid": 117794, "datasetid": "document", "objectid": 37958, "filename": "Huber 1994.pdf", "mime_type": "application/pdf", "hash": "58fb6fa8543c33a410647ce95f0ac1b9", "hash_type": "MD5", "filesize": 30504317, "mtime": "2013-05-03 23:45:16", "url": "/7664/2/Huber 1994.pdf" } ], "eprint_id": 7664, "pos": 2, "placement": 2, "mime_type": "application/pdf", "format": "application/pdf", "language": "en", "security": "public", "license": "other", "main": "Huber 1994.pdf", "media_duration": "0", "media_aspect_ratio": "0", "media_sample_start": "0", "media_sample_stop": "0", "content": "final" }, { "id": "/id/document/37959", "doc_id": 37959, "rev_number": 3, "files": [ { "id": "/id/file/117798", "fileid": 117798, "datasetid": "document", "objectid": 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"/id/document/128159", "doc_id": 128159, "rev_number": 1, "files": [ { "id": "/id/file/373595", "fileid": 373595, "datasetid": "document", "objectid": 128159, "filename": "indexcodes.txt", "mime_type": "text/plain", "hash": "7d8cc76462e03487afc123307a00a1eb", "hash_type": "MD5", "filesize": 52577, "mtime": "2021-06-24 02:34:47", "url": "/7664/7/indexcodes.txt" } ], "eprint_id": 7664, "pos": 7, "placement": 7, "mime_type": "text/plain", "format": "other", "format_desc": "Generate index codes conversion from application/pdf to indexcodes", "language": "en", "security": "public", "license": "other", "main": "indexcodes.txt", "media_duration": "0", "media_aspect_ratio": "0", "media_sample_start": "0", "media_sample_stop": "0", "relation": { "items": [ { "type": "http://eprints.org/relation/isVersionOf", "uri": "/id/document/37958" }, { "type": "http://eprints.org/relation/isVolatileVersionOf", "uri": "/id/document/37958" }, { "type": "http://eprints.org/relation/isIndexCodesVersionOf", "uri": "/id/document/37958" } ] } } ], "eprint_status": "archive", "userid": 50, "dir": "disk0/00/00/76/64", "datestamp": "2013-05-06 15:01:28", "lastmod": "2023-11-08 00:16:03", "status_changed": "2013-05-06 15:01:28", "type": "thesis", "metadata_visibility": "show", "creators": { "items": [ { "id": "Huber-A-H", "name": { "family": "Huber", "given": "Andrew Henry" }, "show_email": "NO" } ] }, "title": "A biochemical and structural characterization of Drosophila neuroglian", "ispublished": "unpub", "full_text_status": "public", "keywords": "Biology", "abstract": "A number of cell-cell interactions in the nervous system are mediated by\r\nimmunoglobulin gene superfamily members. For example, neuroglian, a homophilic\r\nneural cell adhesion molecule in Drosophila, has an extracellular portion comprising six C-\r\n2 type immunoglobulin-like domains followed by five fibronectin type III (FnIII) repeats.\r\nNeuroglian shares this domain organization and significant sequence identity with Ll, a\r\nmurine neural adhesion molecule that could be a functional homologue. Here I report the\r\ncrystal structure of a proteolytic fragment containing the first two FnIII repeats of\r\nneuroglian (NgFn 1,2) at 2.0\u00c5. The interpretation of photomicrographs of rotary\r\nshadowed Ng, the entire extracellular portion of neuroglian, and NgFnl-5, the five\r\nneuroglian Fn III domains, is also discussed.
\r\n\r\nThe structure of NgFn 1,2 consists of two roughly cylindrical \u03b2-barrel structural motifs\r\narranged in a head-to-tail fashion with the domains meeting at an angle of ~120, as defined\r\nby the cylinder axes. The folding topology of each domain is identical to that previously\r\nobserved for single FnIII domains from tenascin and fibronectin. The domains of\r\nNgFn1,2 are related by an approximate two fold screw axis that is nearly parallel to the\r\nlongest dimension of the fragment. Assuming this relative orientation is a general property\r\nof tandem FnIII repeats, the multiple tandem FnIII domains in neuroglian and other\r\nproteins are modeled as thin straight rods with two domain zig-zag repeats. When\r\ncombined with the dimensions of pairs of tandem immunoglobulin-like domains from CD4\r\nand CD2, this model suggests that neuroglian is a long narrow molecule (20 - 30 \u00c5 in\r\ndiameter) that extends up to 370\u00c5 from the cell surface.
\r\n\r\nIn photomicrographs, rotary shadowed Ng and NgFn1-5 appear to be highly flexible\r\nrod-like molecules. NgFn 1-5 is observed to bend in at least two positions and has a mean\r\ntotal length consistent with models generated from the NgFn1,2 structure. Ng molecules have up to four bends and a mean total length of 392 \u00c5, consistent with a head-to-tail\r\npacking of neuroglian's C2-type domains.
\r\n", "date": "1994", "date_type": "degree", "id_number": "CaltechTHESIS:05032013-161139911", "refereed": "FALSE", "official_url": "https://resolver.caltech.edu/CaltechTHESIS:05032013-161139911", "rights": "No commercial reproduction, distribution, display or performance rights in this work are provided.", "collection": "CaltechTHESIS", "reviewer": "Tony Diaz", "deposited_on": "2013-05-06 15:01:28", "doi": "10.7907/43ng-md46", "divisions": { "items": [ "div_biol" ] }, "institution": "California Institute of Technology", "thesis_type": "phd", "thesis_advisor": { "items": [ { "id": "Bjorkman-P-J", "name": { "family": "Bjorkman", "given": "Pamela J." }, "role": "advisor" } ] }, "thesis_committee": { "items": [ { "name": { "family": "Unknown", "given": "Unknown" } } ] }, "thesis_degree": "PHD", "thesis_degree_grantor": "California Institute of Technology", "thesis_defense_date": "1994-05-31", "review_status": "approved", "option_major": { "items": [ "biology" ] }, "copyright_statement": "Author's Rights Authorization: I hereby certify that, if appropriate, I have obtained a written permission statement from the owner(s) of each third party copyrighted matter to be included in my thesis, dissertation, or project report, allowing distribution as specified below. I certify that the version I submitted here is the same as that approved by my advisory committee.\n\nI hereby grant to California Institute of Technology or its agents the non-exclusive license to archive and make accessible, under the conditions specified under \"Thesis Availability\" in this submission, my thesis, dissertation, or project report in whole or in part in all forms of media, now or hereafter known. I retain all other ownership rights to the copyright of the thesis, dissertation, or project report. I also retain the right to use in future works (such as articles or books) all or part of this thesis, dissertation, or project report.", "resource_type": "thesis", "pub_year": "1994", "author_list": "Huber, Andrew Henry", "advisor_list": "Bjorkman, Pamela J.", "comittee_list": "Unknown, Unknown" }, { "id": "https://thesis.library.caltech.edu/id/eprint/7275", "eprint_id": 7275, "rev_number": 21, "documents": [ { "id": "/id/document/16245", "doc_id": 16245, "rev_number": 5, "files": [ { "id": "/id/file/101247", "fileid": 101247, "datasetid": "document", "objectid": 16245, "filename": "Clark_sm_1993.pdf", "mime_type": "application/pdf", "filesize": 37671547, "mtime": "2012-12-26 04:45:55", "url": "/7275/1/Clark_sm_1993.pdf" } ], "eprint_id": 7275, "pos": 1, "mime_type": "application/pdf", "format": "application/pdf", "language": "en", "security": "public", "license": "other", "main": "Clark_sm_1993.pdf", "media_duration": "0", "media_aspect_ratio": "0", "media_sample_start": "0", "media_sample_stop": "0", "content": "final", "relation": { "items": [ { "type": "http://eprints.org/relation/hasVolatileVersion", "uri": "/id/document/28239" }, { "type": "http://eprints.org/relation/haspreviewThumbnailVersion", "uri": "/id/document/28239" }, { "type": "http://eprints.org/relation/hasVersion", "uri": "/id/document/28239" } ] } }, { "id": "/id/document/16246", "doc_id": 16246, "rev_number": 3, "files": [ { "id": "/id/file/208054", "fileid": 208054, "datasetid": "document", "objectid": 16246, "filename": "Clark_sm_1993.zip", "mime_type": "application/zip", "filesize": 124122403, "mtime": "2016-08-22 21:24:23", "url": "/7275/2/Clark_sm_1993.zip" } ], "eprint_id": 7275, "pos": 2, "format": "application/zip", "format_desc": "TIFF", "language": "en", "security": "internal", "license": "other", "main": "Clark_sm_1993.zip", "media_duration": "0", "media_aspect_ratio": "0", "media_sample_start": "0", "media_sample_stop": "0", "content": "final" }, { "id": "/id/document/28239", "doc_id": 28239, "rev_number": 3, "files": [ { "id": "/id/file/101245", "fileid": 101245, "datasetid": "document", "objectid": 28239, "filename": "preview.png", "mime_type": "image/png", "hash": "324f98d7912ef0cca3b849a0d10b8cce", "hash_type": "MD5", "filesize": 27117, "mtime": "2012-12-26 04:45:55", "url": "/7275/3/preview.png" } ], "eprint_id": 7275, "pos": 3, "placement": 3, "mime_type": "image/png", "format": "image/png", "language": "en", "security": "public", "license": "other", "main": "preview.png", "media_duration": "0", "media_aspect_ratio": "0", "media_sample_start": "0", "media_sample_stop": "0", "relation": { "items": [ { "type": "http://eprints.org/relation/isVolatileVersionOf", "uri": "/id/document/16245" }, { "type": "http://eprints.org/relation/ispreviewThumbnailVersionOf", "uri": "/id/document/16245" }, { "type": "http://eprints.org/relation/isVersionOf", "uri": "/id/document/16245" } ] } }, { "id": "/id/document/127733", "doc_id": 127733, "rev_number": 1, "files": [ { "id": "/id/file/373169", "fileid": 373169, "datasetid": "document", "objectid": 127733, "filename": "indexcodes.txt", "mime_type": "text/x-c", "hash": "699f19d1492ee5dbb0a9cf3e3dbf0e0b", "hash_type": "MD5", "filesize": 68560, "mtime": "2021-06-24 02:01:36", "url": "/7275/4/indexcodes.txt" } ], "eprint_id": 7275, "pos": 4, "placement": 4, "mime_type": "text/x-c", "format": "other", "format_desc": "Generate index codes conversion from application/pdf to indexcodes", "language": "en", "security": "public", "license": "other", "main": "indexcodes.txt", "media_duration": "0", "media_aspect_ratio": "0", "media_sample_start": "0", "media_sample_stop": "0", "relation": { "items": [ { "type": "http://eprints.org/relation/isVersionOf", "uri": "/id/document/16245" }, { "type": "http://eprints.org/relation/isVolatileVersionOf", "uri": "/id/document/16245" }, { "type": "http://eprints.org/relation/isIndexCodesVersionOf", "uri": "/id/document/16245" } ] } } ], "eprint_status": "archive", "userid": 104, "dir": "disk0/00/00/72/75", "datestamp": "2012-11-19 19:12:32", "lastmod": "2023-11-08 00:16:03", "status_changed": "2012-11-19 19:12:32", "type": "thesis", "metadata_visibility": "show", "creators": { "items": [ { "id": "Clark-S-M", "name": { "family": "Clark", "given": "Steven Manning" }, "show_email": "NO" } ] }, "title": "Advances in scanning force microscopy of biological structures", "ispublished": "unpub", "full_text_status": "public", "keywords": "Biology", "abstract": "A multifacted approach to the imaging of biological structures by scanning force microscopy is described. The major problems addressed are the distortion of biological samples by excessive forces applied by the cantilever stylus and sample motion relative to the imaging substrate.
\r\n\r\nThe first two chapters discuss the design of digital signal processor based scanning force microscope control electronics and a novel microscope head that eliminates the application of excessive forces to the sample caused\r\nby electronic or vibrational noise.
\r\n\r\nThe third chapter presents a novel use of chemical vapor deposition for application of heterofunctional alkoxysilanes to scanning force microscopy imaging subsrates. This technique provides imaging substrates which have chemical groups that can be used for sample immobilization without compromising substrate smoothness. The use of the chemically derivatized substrates for scanning force microscopy is also explored.
\r\n\r\nThe final chapter presents high resolution images of bovine liver catalase micro-crystals. The images of the protein micro-crystals show resolution on the order of 2 to 3 nanometers allowing the visualization of individual catalase tetramers. To our knowledge this is the first report of images of protein micro-crystals taken by scanning force microscopy which have resolution comparable to that of electron microscopy.
\r\n", "date": "1993", "date_type": "degree", "id_number": "CaltechTHESIS:11192012-103302776", "refereed": "FALSE", "official_url": "https://resolver.caltech.edu/CaltechTHESIS:11192012-103302776", "rights": "No commercial reproduction, distribution, display or performance rights in this work are provided.", "collection": "CaltechTHESIS", "reviewer": "Tony Diaz", "deposited_by": "Dan Anguka", "deposited_on": "2012-11-19 19:12:32", "doi": "10.7907/0vhp-pk35", "divisions": { "items": [ "div_biol" ] }, "institution": "California Institute of Technology", "thesis_type": "phd", "thesis_advisor": { "items": [ { "id": "Bjorkman-P-J", "name": { "family": "Bjorkman", "given": "Pamela J." }, "role": "advisor" } ] }, "thesis_committee": { "items": [ { "id": "Revel-J", "name": { "family": "Revel", "given": "Jean-Paul" }, "role": "member" }, { "id": "Baldeschwieler-J-D", "name": { "family": "Baldeschwieler", "given": "John D." }, "role": "member" }, { "id": "Rees-D-C", "name": { "family": "Rees", "given": "Douglas C." }, "role": "member" }, { "id": "Hood-L-E", "name": { "family": "Hood", "given": "Leroy E." }, "role": "member" }, { "id": "Fraser-S-E", "name": { "family": "Fraser", "given": "Scott E." }, "role": "member" }, { "id": "Wold-B-J", "name": { "family": "Wold", "given": "Barbara J." }, "role": "member" } ] }, "thesis_degree": "PHD", "thesis_degree_grantor": "California Institute of Technology", "thesis_defense_date": "1992-11-23", "review_status": "approved", "option_major": { "items": [ "biology" ] }, "copyright_statement": "Author's Rights Authorization: I hereby certify that, if appropriate, I have obtained a written permission statement from the owner(s) of each third party copyrighted matter to be included in my thesis, dissertation, or project report, allowing distribution as specified below. I certify that the version I submitted here is the same as that approved by my advisory committee.\n\nI hereby grant to California Institute of Technology or its agents the non-exclusive license to archive and make accessible, under the conditions specified under \"Thesis Availability\" in this submission, my thesis, dissertation, or project report in whole or in part in all forms of media, now or hereafter known. I retain all other ownership rights to the copyright of the thesis, dissertation, or project report. I also retain the right to use in future works (such as articles or books) all or part of this thesis, dissertation, or project report.", "resource_type": "thesis", "pub_year": "1993", "author_list": "Clark, Steven Manning", "advisor_list": "Bjorkman, Pamela J.", "comittee_list": "Revel, Jean-Paul; Baldeschwieler, John D.; et el." }, { "id": "https://thesis.library.caltech.edu/id/eprint/6671", "eprint_id": 6671, "rev_number": 24, "documents": [ { "id": "/id/document/13622", "doc_id": 13622, "rev_number": 4, "files": [ { "id": "/id/file/88442", "fileid": 88442, "datasetid": "document", "objectid": 13622, "filename": "Wang_w_1992.pdf", "mime_type": "application/pdf", "filesize": 56468825, "mtime": "2012-12-26 04:38:49", "url": "/6671/1/Wang_w_1992.pdf" } ], "eprint_id": 6671, "pos": 1, "mime_type": "application/pdf", "format": "application/pdf", "language": "en", "security": "public", "license": "other", "main": "Wang_w_1992.pdf", "media_duration": "0", "media_aspect_ratio": "0", "media_sample_start": "0", "media_sample_stop": "0", "content": "final" }, { "id": "/id/document/13623", "doc_id": 13623, "rev_number": 3, "files": [ { "id": "/id/file/207525", "fileid": 207525, "datasetid": "document", "objectid": 13623, "filename": "Wang_w_1992.zip", "mime_type": "application/zip", "filesize": 142397333, "mtime": "2016-08-22 21:23:14", "url": "/6671/2/Wang_w_1992.zip" } ], "eprint_id": 6671, "pos": 2, "format": "application/zip", "format_desc": "TIF", "language": "en", "security": "internal", "license": "other", "main": "Wang_w_1992.zip", "media_duration": "0", "media_aspect_ratio": "0", "media_sample_start": "0", "media_sample_stop": "0", "content": "final" }, { "id": "/id/document/127043", "doc_id": 127043, "rev_number": 1, "files": [ { "id": "/id/file/372477", "fileid": 372477, "datasetid": "document", "objectid": 127043, "filename": "indexcodes.txt", "mime_type": "text/plain", "hash": "e84ceb4f05a546935d82193a96a9ca70", "hash_type": "MD5", "filesize": 32942, "mtime": "2021-06-24 01:22:22", "url": "/6671/3/indexcodes.txt" } ], "eprint_id": 6671, "pos": 3, "placement": 3, "mime_type": "text/plain", "format": "other", "format_desc": "Generate index codes conversion from application/pdf to indexcodes", "language": "en", "security": "public", "license": "other", "main": "indexcodes.txt", "media_duration": "0", "media_aspect_ratio": "0", "media_sample_start": "0", "media_sample_stop": "0", "relation": { "items": [ { "type": "http://eprints.org/relation/isVersionOf", "uri": "/id/document/13622" }, { "type": "http://eprints.org/relation/isVolatileVersionOf", "uri": "/id/document/13622" }, { "type": "http://eprints.org/relation/isIndexCodesVersionOf", "uri": "/id/document/13622" } ] } } ], "eprint_status": "archive", "userid": 50, "dir": "disk0/00/00/66/71", "datestamp": "2011-09-16 21:59:31", "lastmod": "2023-11-08 00:16:03", "status_changed": "2011-09-16 21:59:31", "type": "thesis", "metadata_visibility": "show", "creators": { "items": [ { "id": "Wang-Wen-Ching", "name": { "family": "Wang", "given": "Wen-Ching" }, "show_email": "NO" } ] }, "title": "Expression, structural and functional studies of fasciclin I", "ispublished": "unpub", "full_text_status": "public", "keywords": "Chemistry", "abstract": "Fasciclin I is a cell surface glycoprotein thought to be involved in growth cone guidance in the embryonic insect nervous system. It is expressed on the cell surfaces of all\r\nperipheral nervous system (PNS) axons, a subset of central nervous system (CNS) axons and on some nonneuronal cells. Fly embryos bearing mutations eliminating expression of\r\nboth fasciclin I and the Abelson tyrosine kinase exhibit a severe phenotype in which many axon pathways fail to form. Fasciclin I mediates homophilic adhesion in transfected tissue culture cells, suggesting that it may affect growth cone guidance through homophilic interactions. To facilitate structure-function studies of fasciclin I, we have generated mammalian (CHO) cell lines expressing fasciclin I at a high level. The expressed fasciclin I\r\nprotein was released from the cell surface in a soluble form by phospholipase C treatment. Milligram quantities of soluble expressed fasciclin I were purified on an immunoaffinity column. Large single crystals were obtained that diffracted to ~5 \u00c5 resolution which is\r\ninsufficient for a structure determination to atomic resolution by x-ray crystallography. In an effort to produce a form of fasciclin I more amenable to crystallization, we also generated CHO and Drosophila cell (S2) lines that produce a truncated form of fasciclin I.\r\nThe soluble fasciclin I expressed in S2 cells contains significantly less carbohydrate (~15 kDa) as compared to the molecules expressed in CHO cells. Therefore, S2-derived\r\nfasciclin I may be more suitable for crystallization. Biochemical characterization of the expressed fasciclin I indicates that fasciclin I exists as a monomer in solution, an observation consistent with homophilic interaction properties only if the interaction is of low affinity. Electron micrographs of fasciclin I suggest that it has a compact rectangular shape with no obvious flexible linker regions, in contrast to what has been seen in electron\r\nmicroscopic studies of other adhesion molecules. Circular dichroism analysis suggests that fasciclin I contains significant amounts of \u03b1-helical structure, which together with the electron microscopic results, suggests that its structure is substantially different from the \u03b2-sheet structures predicted for adhesion molecules that are members of the immunoglobulin superfamily and/or contain fibronectin III repeats. Future structural and functional studies of fasciclin I will ultimately increase our understanding of neuronal cell surface recognition\r\nand axon guidance.\r\n", "date": "1992", "date_type": "degree", "id_number": "CaltechTHESIS:09152011-080428062", "refereed": "FALSE", "official_url": "https://resolver.caltech.edu/CaltechTHESIS:09152011-080428062", "rights": "No commercial reproduction, distribution, display or performance rights in this work are provided.", "collection": "CaltechTHESIS", "reviewer": "Katrhy Johnson", "deposited_on": "2011-09-16 21:59:31", "doi": "10.7907/ykbt-jt41", "divisions": { "items": [ "div_chem" ] }, "institution": "California Institute of Technology", "thesis_type": "phd", "thesis_advisor": { "items": [ { "id": "Bjorkman-P-J", "name": { "family": "Bjorkman", "given": "Pamela J." }, "role": "advisor" }, { "id": "Zinn-K-G", "name": { "family": "Zinn", "given": "Kai George" }, "role": "advisor" }, { "id": "Baldeschwieler-J-D", "name": { "family": "Baldeschwieler", "given": "John D." }, "role": "advisor" } ] }, "thesis_committee": { "items": [ { "name": { "family": "Unknown", "given": "Unknown" } } ] }, "thesis_degree": "PHD", "thesis_degree_grantor": "California Institute of Technology", "thesis_defense_date": "1992-05-22", "review_status": "approved", "option_major": { "items": [ "chemistry" ] }, "copyright_statement": "Author's Rights Authorization: I hereby certify that, if appropriate, I have obtained a written permission statement from the owner(s) of each third party copyrighted matter to be included in my thesis, dissertation, or project report, allowing distribution as specified below. I certify that the version I submitted here is the same as that approved by my advisory committee.\n\nI hereby grant to California Institute of Technology or its agents the non-exclusive license to archive and make accessible, under the conditions specified under \"Thesis Availability\" in this submission, my thesis, dissertation, or project report in whole or in part in all forms of media, now or hereafter known. I retain all other ownership rights to the copyright of the thesis, dissertation, or project report. I also retain the right to use in future works (such as articles or books) all or part of this thesis, dissertation, or project report.", "resource_type": "thesis", "pub_year": "1992", "author_list": "Wang, Wen-Ching", "advisor_list": "Bjorkman, Pamela J.; Zinn, Kai George; et el.", "comittee_list": "Unknown, Unknown" } ]