Structure of the membrane proximal external region of HIV-1 envelope glycoprotein
The membrane-proximal external region (MPER) of the HIV-1 envelope glycoprotein (Env) bears epitopes of broadly neutralizing antibodies (bnAbs) from infected individuals; it is thus a potential vaccine target. We report an NMR structure of the MPER and its adjacent transmembrane domain in bicelles t...
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| Veröffentlicht in: | Proceedings of the National Academy of Sciences - PNAS 2018-09, Vol.115 (38), p.E8892-E8899 |
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| creator | Fu, Qingshan Shaik, Md Munan Cai, Yongfei Ghantous, Fadi Piai, Alessandro Peng, Hanqin Rits-Volloch, Sophia Liu, Zhijun Harrison, Stephen C. Seaman, Michael S. Chen, Bing Chou, James J. |
| description | The membrane-proximal external region (MPER) of the HIV-1 envelope glycoprotein (Env) bears epitopes of broadly neutralizing antibodies (bnAbs) from infected individuals; it is thus a potential vaccine target. We report an NMR structure of the MPER and its adjacent transmembrane domain in bicelles that mimic a lipid-bilayer membrane. The MPER lies largely outside the lipid bilayer. It folds into a threefold cluster, stabilized mainly by conserved hydrophobic residues and potentially by interaction with phospholipid headgroups. Antigenic analysis and comparison with published images from electron cryotomography of HIV-1 Env on the virion surface suggest that the structure may represent a prefusion conformation of the MPER, distinct from the fusionintermediate state targeted by several well-studied bnAbs. Very slow bnAb binding indicates that infrequent fluctuations of the MPER structure give these antibodies occasional access to alternative conformations of MPER epitopes. Mutations in the MPER not only impede membrane fusion but also influence presentation of bnAb epitopes in other regions. These results suggest strategies for developing MPER-based vaccine candidates. |
| doi_str_mv | 10.1073/pnas.1807259115 |
| format | Article |
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We report an NMR structure of the MPER and its adjacent transmembrane domain in bicelles that mimic a lipid-bilayer membrane. The MPER lies largely outside the lipid bilayer. It folds into a threefold cluster, stabilized mainly by conserved hydrophobic residues and potentially by interaction with phospholipid headgroups. Antigenic analysis and comparison with published images from electron cryotomography of HIV-1 Env on the virion surface suggest that the structure may represent a prefusion conformation of the MPER, distinct from the fusionintermediate state targeted by several well-studied bnAbs. Very slow bnAb binding indicates that infrequent fluctuations of the MPER structure give these antibodies occasional access to alternative conformations of MPER epitopes. Mutations in the MPER not only impede membrane fusion but also influence presentation of bnAb epitopes in other regions. These results suggest strategies for developing MPER-based vaccine candidates.</description><identifier>ISSN: 0027-8424</identifier><identifier>EISSN: 1091-6490</identifier><identifier>DOI: 10.1073/pnas.1807259115</identifier><identifier>PMID: 30185554</identifier><language>eng</language><publisher>United States: National Academy of Sciences</publisher><subject>Antibodies ; Antigen presentation ; Antigens ; Biological Sciences ; Conformation ; env Gene Products, Human Immunodeficiency Virus - chemistry ; Epitopes ; Fusion ; Glycoproteins ; HIV ; HIV Antigens - chemistry ; HIV Antigens - immunology ; HIV-1 - chemistry ; HIV-1 - immunology ; Human immunodeficiency virus ; Hydrophobicity ; Immunoglobulin Fab Fragments - immunology ; Influence ; Lipid bilayers ; Lipid Bilayers - chemistry ; Lipids ; Magnetic Resonance Spectroscopy ; Medical imaging ; Membrane Fusion ; Membranes ; Mutation ; NMR ; Nuclear magnetic resonance ; Phospholipids ; PNAS Plus ; Protein Domains ; Proteins ; Studies ; Vaccines ; Variation ; Virion - chemistry ; Virion - immunology ; Virions</subject><ispartof>Proceedings of the National Academy of Sciences - PNAS, 2018-09, Vol.115 (38), p.E8892-E8899</ispartof><rights>Volumes 1–89 and 106–115, copyright as a collective work only; author(s) retains copyright to individual articles</rights><rights>Copyright National Academy of Sciences Sep 18, 2018</rights><rights>2018</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c509t-5172a21000617eeb12cd63dfbfec6cd542dc7934a0b2f8ca37ddb98beae3f70c3</citedby><cites>FETCH-LOGICAL-c509t-5172a21000617eeb12cd63dfbfec6cd542dc7934a0b2f8ca37ddb98beae3f70c3</cites><orcidid>0000-0002-5264-1980</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://www.jstor.org/stable/pdf/26531174$$EPDF$$P50$$Gjstor$$H</linktopdf><linktohtml>$$Uhttps://www.jstor.org/stable/26531174$$EHTML$$P50$$Gjstor$$H</linktohtml><link.rule.ids>230,315,728,781,785,804,886,27929,27930,53796,53798,58022,58255</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/30185554$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Fu, Qingshan</creatorcontrib><creatorcontrib>Shaik, Md Munan</creatorcontrib><creatorcontrib>Cai, Yongfei</creatorcontrib><creatorcontrib>Ghantous, Fadi</creatorcontrib><creatorcontrib>Piai, Alessandro</creatorcontrib><creatorcontrib>Peng, Hanqin</creatorcontrib><creatorcontrib>Rits-Volloch, Sophia</creatorcontrib><creatorcontrib>Liu, Zhijun</creatorcontrib><creatorcontrib>Harrison, Stephen C.</creatorcontrib><creatorcontrib>Seaman, Michael S.</creatorcontrib><creatorcontrib>Chen, Bing</creatorcontrib><creatorcontrib>Chou, James J.</creatorcontrib><title>Structure of the membrane proximal external region of HIV-1 envelope glycoprotein</title><title>Proceedings of the National Academy of Sciences - PNAS</title><addtitle>Proc Natl Acad Sci U S A</addtitle><description>The membrane-proximal external region (MPER) of the HIV-1 envelope glycoprotein (Env) bears epitopes of broadly neutralizing antibodies (bnAbs) from infected individuals; it is thus a potential vaccine target. We report an NMR structure of the MPER and its adjacent transmembrane domain in bicelles that mimic a lipid-bilayer membrane. The MPER lies largely outside the lipid bilayer. It folds into a threefold cluster, stabilized mainly by conserved hydrophobic residues and potentially by interaction with phospholipid headgroups. Antigenic analysis and comparison with published images from electron cryotomography of HIV-1 Env on the virion surface suggest that the structure may represent a prefusion conformation of the MPER, distinct from the fusionintermediate state targeted by several well-studied bnAbs. Very slow bnAb binding indicates that infrequent fluctuations of the MPER structure give these antibodies occasional access to alternative conformations of MPER epitopes. Mutations in the MPER not only impede membrane fusion but also influence presentation of bnAb epitopes in other regions. These results suggest strategies for developing MPER-based vaccine candidates.</description><subject>Antibodies</subject><subject>Antigen presentation</subject><subject>Antigens</subject><subject>Biological Sciences</subject><subject>Conformation</subject><subject>env Gene Products, Human Immunodeficiency Virus - chemistry</subject><subject>Epitopes</subject><subject>Fusion</subject><subject>Glycoproteins</subject><subject>HIV</subject><subject>HIV Antigens - chemistry</subject><subject>HIV Antigens - immunology</subject><subject>HIV-1 - chemistry</subject><subject>HIV-1 - immunology</subject><subject>Human immunodeficiency virus</subject><subject>Hydrophobicity</subject><subject>Immunoglobulin Fab Fragments - immunology</subject><subject>Influence</subject><subject>Lipid bilayers</subject><subject>Lipid Bilayers - chemistry</subject><subject>Lipids</subject><subject>Magnetic Resonance Spectroscopy</subject><subject>Medical imaging</subject><subject>Membrane Fusion</subject><subject>Membranes</subject><subject>Mutation</subject><subject>NMR</subject><subject>Nuclear magnetic resonance</subject><subject>Phospholipids</subject><subject>PNAS Plus</subject><subject>Protein Domains</subject><subject>Proteins</subject><subject>Studies</subject><subject>Vaccines</subject><subject>Variation</subject><subject>Virion - chemistry</subject><subject>Virion - immunology</subject><subject>Virions</subject><issn>0027-8424</issn><issn>1091-6490</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2018</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNpdkc1v1DAQxS0EokvhzAkUiQuXtB5_JhckVLW0UiVUFbhajjPZZpXEwXaq9r_H0Zbl4zQjzW-e3swj5C3QE6Can86TjSdQUc1kDSCfkQ3QGkolavqcbChluqwEE0fkVYw7SmktK_qSHHEKlZRSbMjNbQqLS0vAwndFusNixLEJdsJiDv6hH-1Q4EPCMOUm4Lb30wpeXv0oocDpHgc_Y7EdHp3PfMJ-ek1edHaI-OapHpPvF-ffzi7L669frs4-X5dO0jqVEjSzDLInBRqxAeZaxduu6dAp10rBWqdrLixtWFc5y3XbNnXVoEXeaer4Mfm0152XZsTW4ZSCHcwcsufwaLztzb-Tqb8zW39vFEiluMwCH58Egv-5YExm7KPDYcjH-yWa1RzngkOV0Q__oTu_rC9ZKRCMqoqrTJ3uKRd8jAG7gxmgZo3LrHGZP3Hljfd_33Dgf-eTgXd7YBeTD4c5U5IDaMF_AeIknDs</recordid><startdate>20180918</startdate><enddate>20180918</enddate><creator>Fu, Qingshan</creator><creator>Shaik, Md Munan</creator><creator>Cai, Yongfei</creator><creator>Ghantous, Fadi</creator><creator>Piai, Alessandro</creator><creator>Peng, Hanqin</creator><creator>Rits-Volloch, Sophia</creator><creator>Liu, Zhijun</creator><creator>Harrison, Stephen C.</creator><creator>Seaman, Michael S.</creator><creator>Chen, Bing</creator><creator>Chou, James J.</creator><general>National Academy of Sciences</general><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>7QG</scope><scope>7QL</scope><scope>7QP</scope><scope>7QR</scope><scope>7SN</scope><scope>7SS</scope><scope>7T5</scope><scope>7TK</scope><scope>7TM</scope><scope>7TO</scope><scope>7U9</scope><scope>8FD</scope><scope>C1K</scope><scope>FR3</scope><scope>H94</scope><scope>M7N</scope><scope>P64</scope><scope>RC3</scope><scope>7X8</scope><scope>5PM</scope><orcidid>https://orcid.org/0000-0002-5264-1980</orcidid></search><sort><creationdate>20180918</creationdate><title>Structure of the membrane proximal external region of HIV-1 envelope glycoprotein</title><author>Fu, Qingshan ; Shaik, Md Munan ; Cai, Yongfei ; Ghantous, Fadi ; Piai, Alessandro ; Peng, Hanqin ; Rits-Volloch, Sophia ; Liu, Zhijun ; Harrison, Stephen C. ; Seaman, Michael S. ; Chen, Bing ; Chou, James J.</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c509t-5172a21000617eeb12cd63dfbfec6cd542dc7934a0b2f8ca37ddb98beae3f70c3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2018</creationdate><topic>Antibodies</topic><topic>Antigen presentation</topic><topic>Antigens</topic><topic>Biological Sciences</topic><topic>Conformation</topic><topic>env Gene Products, Human Immunodeficiency Virus - chemistry</topic><topic>Epitopes</topic><topic>Fusion</topic><topic>Glycoproteins</topic><topic>HIV</topic><topic>HIV Antigens - chemistry</topic><topic>HIV Antigens - immunology</topic><topic>HIV-1 - chemistry</topic><topic>HIV-1 - immunology</topic><topic>Human immunodeficiency virus</topic><topic>Hydrophobicity</topic><topic>Immunoglobulin Fab Fragments - immunology</topic><topic>Influence</topic><topic>Lipid bilayers</topic><topic>Lipid Bilayers - chemistry</topic><topic>Lipids</topic><topic>Magnetic Resonance Spectroscopy</topic><topic>Medical imaging</topic><topic>Membrane Fusion</topic><topic>Membranes</topic><topic>Mutation</topic><topic>NMR</topic><topic>Nuclear magnetic resonance</topic><topic>Phospholipids</topic><topic>PNAS Plus</topic><topic>Protein Domains</topic><topic>Proteins</topic><topic>Studies</topic><topic>Vaccines</topic><topic>Variation</topic><topic>Virion - chemistry</topic><topic>Virion - immunology</topic><topic>Virions</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Fu, Qingshan</creatorcontrib><creatorcontrib>Shaik, Md Munan</creatorcontrib><creatorcontrib>Cai, Yongfei</creatorcontrib><creatorcontrib>Ghantous, Fadi</creatorcontrib><creatorcontrib>Piai, Alessandro</creatorcontrib><creatorcontrib>Peng, Hanqin</creatorcontrib><creatorcontrib>Rits-Volloch, Sophia</creatorcontrib><creatorcontrib>Liu, Zhijun</creatorcontrib><creatorcontrib>Harrison, Stephen C.</creatorcontrib><creatorcontrib>Seaman, Michael S.</creatorcontrib><creatorcontrib>Chen, Bing</creatorcontrib><creatorcontrib>Chou, James J.</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>Animal Behavior Abstracts</collection><collection>Bacteriology Abstracts (Microbiology B)</collection><collection>Calcium & Calcified Tissue Abstracts</collection><collection>Chemoreception Abstracts</collection><collection>Ecology Abstracts</collection><collection>Entomology Abstracts (Full archive)</collection><collection>Immunology Abstracts</collection><collection>Neurosciences Abstracts</collection><collection>Nucleic Acids Abstracts</collection><collection>Oncogenes and Growth Factors Abstracts</collection><collection>Virology and AIDS Abstracts</collection><collection>Technology Research Database</collection><collection>Environmental Sciences and Pollution Management</collection><collection>Engineering Research Database</collection><collection>AIDS and Cancer Research Abstracts</collection><collection>Algology Mycology and Protozoology Abstracts (Microbiology C)</collection><collection>Biotechnology and BioEngineering Abstracts</collection><collection>Genetics Abstracts</collection><collection>MEDLINE - Academic</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>Proceedings of the National Academy of Sciences - PNAS</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Fu, Qingshan</au><au>Shaik, Md Munan</au><au>Cai, Yongfei</au><au>Ghantous, Fadi</au><au>Piai, Alessandro</au><au>Peng, Hanqin</au><au>Rits-Volloch, Sophia</au><au>Liu, Zhijun</au><au>Harrison, Stephen C.</au><au>Seaman, Michael S.</au><au>Chen, Bing</au><au>Chou, James J.</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Structure of the membrane proximal external region of HIV-1 envelope glycoprotein</atitle><jtitle>Proceedings of the National Academy of Sciences - PNAS</jtitle><addtitle>Proc Natl Acad Sci U S A</addtitle><date>2018-09-18</date><risdate>2018</risdate><volume>115</volume><issue>38</issue><spage>E8892</spage><epage>E8899</epage><pages>E8892-E8899</pages><issn>0027-8424</issn><eissn>1091-6490</eissn><abstract>The membrane-proximal external region (MPER) of the HIV-1 envelope glycoprotein (Env) bears epitopes of broadly neutralizing antibodies (bnAbs) from infected individuals; it is thus a potential vaccine target. We report an NMR structure of the MPER and its adjacent transmembrane domain in bicelles that mimic a lipid-bilayer membrane. The MPER lies largely outside the lipid bilayer. It folds into a threefold cluster, stabilized mainly by conserved hydrophobic residues and potentially by interaction with phospholipid headgroups. Antigenic analysis and comparison with published images from electron cryotomography of HIV-1 Env on the virion surface suggest that the structure may represent a prefusion conformation of the MPER, distinct from the fusionintermediate state targeted by several well-studied bnAbs. Very slow bnAb binding indicates that infrequent fluctuations of the MPER structure give these antibodies occasional access to alternative conformations of MPER epitopes. Mutations in the MPER not only impede membrane fusion but also influence presentation of bnAb epitopes in other regions. These results suggest strategies for developing MPER-based vaccine candidates.</abstract><cop>United States</cop><pub>National Academy of Sciences</pub><pmid>30185554</pmid><doi>10.1073/pnas.1807259115</doi><orcidid>https://orcid.org/0000-0002-5264-1980</orcidid><oa>free_for_read</oa></addata></record> |
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| subjects | Antibodies Antigen presentation Antigens Biological Sciences Conformation env Gene Products, Human Immunodeficiency Virus - chemistry Epitopes Fusion Glycoproteins HIV HIV Antigens - chemistry HIV Antigens - immunology HIV-1 - chemistry HIV-1 - immunology Human immunodeficiency virus Hydrophobicity Immunoglobulin Fab Fragments - immunology Influence Lipid bilayers Lipid Bilayers - chemistry Lipids Magnetic Resonance Spectroscopy Medical imaging Membrane Fusion Membranes Mutation NMR Nuclear magnetic resonance Phospholipids PNAS Plus Protein Domains Proteins Studies Vaccines Variation Virion - chemistry Virion - immunology Virions |
| title | Structure of the membrane proximal external region of HIV-1 envelope glycoprotein |
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