Atomistic structure and dynamics of the human MHC-I peptide-loading complex
The major histocompatibility complex class-I (MHC-I) peptideloading complex (PLC) is a cornerstone of the human adaptive immune system, being responsible for processing antigens that allow killer T cells to distinguish between healthy and compromised cells. Based on a recent low-resolution cryo-elec...
Gespeichert in:
Veröffentlicht in: | Proceedings of the National Academy of Sciences - PNAS 2020-08, Vol.117 (34), p.20597-20606 |
---|---|
Hauptverfasser: | , , |
Format: | Artikel |
Sprache: | eng |
Schlagworte: | |
Online-Zugang: | Volltext |
Tags: |
Tag hinzufügen
Keine Tags, Fügen Sie den ersten Tag hinzu!
|
container_end_page | 20606 |
---|---|
container_issue | 34 |
container_start_page | 20597 |
container_title | Proceedings of the National Academy of Sciences - PNAS |
container_volume | 117 |
creator | Fisette, Olivier Schröder, Gunnar F. Schäfer, Lars V. |
description | The major histocompatibility complex class-I (MHC-I) peptideloading complex (PLC) is a cornerstone of the human adaptive immune system, being responsible for processing antigens that allow killer T cells to distinguish between healthy and compromised cells. Based on a recent low-resolution cryo-electron microscopy (cryo-EM) structure of this large membrane-bound protein complex, we report an atomistic model of the PLC and study its conformational dynamics on the multimicrosecond time scale using all-atom molecular dynamics (MD) simulations in an explicit lipid bilayer and water environment (1.6 million atoms in total). The PLC has a layered structure, with two editing modules forming a flexible protein belt surrounding a stable, catalytically active core. Tapasin plays a central role in the PLC, stabilizing the MHC-I binding groove in a conformation reminiscent of antigen-loaded MHC-I. The MHC-I–linked glycan steers a tapasin loop involved in peptide editing toward the binding groove. Tapasin conformational dynamics are also affected by calreticulin through a conformational selection mechanism that facilitates MHC-I recruitment into the complex. |
doi_str_mv | 10.1073/pnas.2004445117 |
format | Article |
fullrecord | <record><control><sourceid>jstor_pubme</sourceid><recordid>TN_cdi_pubmedcentral_primary_oai_pubmedcentral_nih_gov_7456110</recordid><sourceformat>XML</sourceformat><sourcesystem>PC</sourcesystem><jstor_id>26969031</jstor_id><sourcerecordid>26969031</sourcerecordid><originalsourceid>FETCH-LOGICAL-c509t-4ff715571fe31ad2bad41da03a4bf86ec1b228e8161db26400586acd0eb9079d3</originalsourceid><addsrcrecordid>eNpdkc1P3DAQxa2qqGy3PfdUZIlLL4HxR2LnUgmt2oIK4tKeLcd22KwSO9gOgv--2S4sH6c5vN88zZuH0BcCJwQEOx29TicUgHNeEiLeoQWBmhQVr-E9WgBQUUhO-SH6mNIGAOpSwgd0yKiQkglYoN9nOQxdyp3BKcfJ5Ck6rL3F9sHroTMJhxbntcPradAeX52vigs8ujF31hV90LbzN9iEYezd_Sd00Oo-uc-Pc4n-_vzxZ3VeXF7_ulidXRamhDoXvG0FKUtBWseItrTRlhOrgWnetLJyhjSUSidJRWxDKw5QykobC66pQdSWLdH3ne84NYOzxvkcda_G2A06PqigO_Va8d1a3YQ7JXhZEQKzwbdHgxhuJ5eyml9gXN9r78KUFOWMQ8k43aLHb9BNmKKf420pKeh_colOd5SJIaXo2v0xBNS2KLUtSj0XNW8cvcyw55-amYGvO2CTcoh7nVZ1VQMj7B9AYpjP</addsrcrecordid><sourcetype>Open Access Repository</sourcetype><iscdi>true</iscdi><recordtype>article</recordtype><pqid>2438723405</pqid></control><display><type>article</type><title>Atomistic structure and dynamics of the human MHC-I peptide-loading complex</title><source>Jstor Complete Legacy</source><source>MEDLINE</source><source>PubMed Central</source><source>Alma/SFX Local Collection</source><source>Free Full-Text Journals in Chemistry</source><creator>Fisette, Olivier ; Schröder, Gunnar F. ; Schäfer, Lars V.</creator><creatorcontrib>Fisette, Olivier ; Schröder, Gunnar F. ; Schäfer, Lars V.</creatorcontrib><description>The major histocompatibility complex class-I (MHC-I) peptideloading complex (PLC) is a cornerstone of the human adaptive immune system, being responsible for processing antigens that allow killer T cells to distinguish between healthy and compromised cells. Based on a recent low-resolution cryo-electron microscopy (cryo-EM) structure of this large membrane-bound protein complex, we report an atomistic model of the PLC and study its conformational dynamics on the multimicrosecond time scale using all-atom molecular dynamics (MD) simulations in an explicit lipid bilayer and water environment (1.6 million atoms in total). The PLC has a layered structure, with two editing modules forming a flexible protein belt surrounding a stable, catalytically active core. Tapasin plays a central role in the PLC, stabilizing the MHC-I binding groove in a conformation reminiscent of antigen-loaded MHC-I. The MHC-I–linked glycan steers a tapasin loop involved in peptide editing toward the binding groove. Tapasin conformational dynamics are also affected by calreticulin through a conformational selection mechanism that facilitates MHC-I recruitment into the complex.</description><identifier>ISSN: 0027-8424</identifier><identifier>EISSN: 1091-6490</identifier><identifier>DOI: 10.1073/pnas.2004445117</identifier><identifier>PMID: 32788370</identifier><language>eng</language><publisher>United States: National Academy of Sciences</publisher><subject>Adaptive systems ; Antigen processing ; Antigens ; Binding ; Biological Sciences ; Calreticulin ; Calreticulin - metabolism ; Computer simulation ; Cryoelectron Microscopy ; Editing ; Electron microscopy ; Glycan ; Grooves ; Histocompatibility Antigens Class I - metabolism ; Histocompatibility Antigens Class I - ultrastructure ; Humans ; Immune system ; Lipid bilayers ; Lipids ; Loads (forces) ; Lymphocytes ; Lymphocytes T ; Major histocompatibility complex ; Membrane proteins ; Membrane Transport Proteins - metabolism ; Membrane Transport Proteins - ultrastructure ; Molecular dynamics ; Molecular Dynamics Simulation ; Peptides ; Polysaccharides - metabolism ; Protein Disulfide-Isomerases - metabolism ; Proteins ; Tapasin</subject><ispartof>Proceedings of the National Academy of Sciences - PNAS, 2020-08, Vol.117 (34), p.20597-20606</ispartof><rights>Copyright National Academy of Sciences Aug 25, 2020</rights><rights>2020</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c509t-4ff715571fe31ad2bad41da03a4bf86ec1b228e8161db26400586acd0eb9079d3</citedby><cites>FETCH-LOGICAL-c509t-4ff715571fe31ad2bad41da03a4bf86ec1b228e8161db26400586acd0eb9079d3</cites><orcidid>0000-0002-8498-3061 ; 0000-0002-8043-4655</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://www.jstor.org/stable/pdf/26969031$$EPDF$$P50$$Gjstor$$H</linktopdf><linktohtml>$$Uhttps://www.jstor.org/stable/26969031$$EHTML$$P50$$Gjstor$$H</linktohtml><link.rule.ids>230,314,723,776,780,799,881,27901,27902,53766,53768,57992,58225</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/32788370$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Fisette, Olivier</creatorcontrib><creatorcontrib>Schröder, Gunnar F.</creatorcontrib><creatorcontrib>Schäfer, Lars V.</creatorcontrib><title>Atomistic structure and dynamics of the human MHC-I peptide-loading complex</title><title>Proceedings of the National Academy of Sciences - PNAS</title><addtitle>Proc Natl Acad Sci U S A</addtitle><description>The major histocompatibility complex class-I (MHC-I) peptideloading complex (PLC) is a cornerstone of the human adaptive immune system, being responsible for processing antigens that allow killer T cells to distinguish between healthy and compromised cells. Based on a recent low-resolution cryo-electron microscopy (cryo-EM) structure of this large membrane-bound protein complex, we report an atomistic model of the PLC and study its conformational dynamics on the multimicrosecond time scale using all-atom molecular dynamics (MD) simulations in an explicit lipid bilayer and water environment (1.6 million atoms in total). The PLC has a layered structure, with two editing modules forming a flexible protein belt surrounding a stable, catalytically active core. Tapasin plays a central role in the PLC, stabilizing the MHC-I binding groove in a conformation reminiscent of antigen-loaded MHC-I. The MHC-I–linked glycan steers a tapasin loop involved in peptide editing toward the binding groove. Tapasin conformational dynamics are also affected by calreticulin through a conformational selection mechanism that facilitates MHC-I recruitment into the complex.</description><subject>Adaptive systems</subject><subject>Antigen processing</subject><subject>Antigens</subject><subject>Binding</subject><subject>Biological Sciences</subject><subject>Calreticulin</subject><subject>Calreticulin - metabolism</subject><subject>Computer simulation</subject><subject>Cryoelectron Microscopy</subject><subject>Editing</subject><subject>Electron microscopy</subject><subject>Glycan</subject><subject>Grooves</subject><subject>Histocompatibility Antigens Class I - metabolism</subject><subject>Histocompatibility Antigens Class I - ultrastructure</subject><subject>Humans</subject><subject>Immune system</subject><subject>Lipid bilayers</subject><subject>Lipids</subject><subject>Loads (forces)</subject><subject>Lymphocytes</subject><subject>Lymphocytes T</subject><subject>Major histocompatibility complex</subject><subject>Membrane proteins</subject><subject>Membrane Transport Proteins - metabolism</subject><subject>Membrane Transport Proteins - ultrastructure</subject><subject>Molecular dynamics</subject><subject>Molecular Dynamics Simulation</subject><subject>Peptides</subject><subject>Polysaccharides - metabolism</subject><subject>Protein Disulfide-Isomerases - metabolism</subject><subject>Proteins</subject><subject>Tapasin</subject><issn>0027-8424</issn><issn>1091-6490</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2020</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNpdkc1P3DAQxa2qqGy3PfdUZIlLL4HxR2LnUgmt2oIK4tKeLcd22KwSO9gOgv--2S4sH6c5vN88zZuH0BcCJwQEOx29TicUgHNeEiLeoQWBmhQVr-E9WgBQUUhO-SH6mNIGAOpSwgd0yKiQkglYoN9nOQxdyp3BKcfJ5Ck6rL3F9sHroTMJhxbntcPradAeX52vigs8ujF31hV90LbzN9iEYezd_Sd00Oo-uc-Pc4n-_vzxZ3VeXF7_ulidXRamhDoXvG0FKUtBWseItrTRlhOrgWnetLJyhjSUSidJRWxDKw5QykobC66pQdSWLdH3ne84NYOzxvkcda_G2A06PqigO_Va8d1a3YQ7JXhZEQKzwbdHgxhuJ5eyml9gXN9r78KUFOWMQ8k43aLHb9BNmKKf420pKeh_colOd5SJIaXo2v0xBNS2KLUtSj0XNW8cvcyw55-amYGvO2CTcoh7nVZ1VQMj7B9AYpjP</recordid><startdate>20200825</startdate><enddate>20200825</enddate><creator>Fisette, Olivier</creator><creator>Schröder, Gunnar F.</creator><creator>Schäfer, Lars V.</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/0000-0002-8498-3061</orcidid><orcidid>https://orcid.org/0000-0002-8043-4655</orcidid></search><sort><creationdate>20200825</creationdate><title>Atomistic structure and dynamics of the human MHC-I peptide-loading complex</title><author>Fisette, Olivier ; Schröder, Gunnar F. ; Schäfer, Lars V.</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c509t-4ff715571fe31ad2bad41da03a4bf86ec1b228e8161db26400586acd0eb9079d3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2020</creationdate><topic>Adaptive systems</topic><topic>Antigen processing</topic><topic>Antigens</topic><topic>Binding</topic><topic>Biological Sciences</topic><topic>Calreticulin</topic><topic>Calreticulin - metabolism</topic><topic>Computer simulation</topic><topic>Cryoelectron Microscopy</topic><topic>Editing</topic><topic>Electron microscopy</topic><topic>Glycan</topic><topic>Grooves</topic><topic>Histocompatibility Antigens Class I - metabolism</topic><topic>Histocompatibility Antigens Class I - ultrastructure</topic><topic>Humans</topic><topic>Immune system</topic><topic>Lipid bilayers</topic><topic>Lipids</topic><topic>Loads (forces)</topic><topic>Lymphocytes</topic><topic>Lymphocytes T</topic><topic>Major histocompatibility complex</topic><topic>Membrane proteins</topic><topic>Membrane Transport Proteins - metabolism</topic><topic>Membrane Transport Proteins - ultrastructure</topic><topic>Molecular dynamics</topic><topic>Molecular Dynamics Simulation</topic><topic>Peptides</topic><topic>Polysaccharides - metabolism</topic><topic>Protein Disulfide-Isomerases - metabolism</topic><topic>Proteins</topic><topic>Tapasin</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Fisette, Olivier</creatorcontrib><creatorcontrib>Schröder, Gunnar F.</creatorcontrib><creatorcontrib>Schäfer, Lars V.</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>Fisette, Olivier</au><au>Schröder, Gunnar F.</au><au>Schäfer, Lars V.</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Atomistic structure and dynamics of the human MHC-I peptide-loading complex</atitle><jtitle>Proceedings of the National Academy of Sciences - PNAS</jtitle><addtitle>Proc Natl Acad Sci U S A</addtitle><date>2020-08-25</date><risdate>2020</risdate><volume>117</volume><issue>34</issue><spage>20597</spage><epage>20606</epage><pages>20597-20606</pages><issn>0027-8424</issn><eissn>1091-6490</eissn><abstract>The major histocompatibility complex class-I (MHC-I) peptideloading complex (PLC) is a cornerstone of the human adaptive immune system, being responsible for processing antigens that allow killer T cells to distinguish between healthy and compromised cells. Based on a recent low-resolution cryo-electron microscopy (cryo-EM) structure of this large membrane-bound protein complex, we report an atomistic model of the PLC and study its conformational dynamics on the multimicrosecond time scale using all-atom molecular dynamics (MD) simulations in an explicit lipid bilayer and water environment (1.6 million atoms in total). The PLC has a layered structure, with two editing modules forming a flexible protein belt surrounding a stable, catalytically active core. Tapasin plays a central role in the PLC, stabilizing the MHC-I binding groove in a conformation reminiscent of antigen-loaded MHC-I. The MHC-I–linked glycan steers a tapasin loop involved in peptide editing toward the binding groove. Tapasin conformational dynamics are also affected by calreticulin through a conformational selection mechanism that facilitates MHC-I recruitment into the complex.</abstract><cop>United States</cop><pub>National Academy of Sciences</pub><pmid>32788370</pmid><doi>10.1073/pnas.2004445117</doi><tpages>10</tpages><orcidid>https://orcid.org/0000-0002-8498-3061</orcidid><orcidid>https://orcid.org/0000-0002-8043-4655</orcidid><oa>free_for_read</oa></addata></record> |
fulltext | fulltext |
identifier | ISSN: 0027-8424 |
ispartof | Proceedings of the National Academy of Sciences - PNAS, 2020-08, Vol.117 (34), p.20597-20606 |
issn | 0027-8424 1091-6490 |
language | eng |
recordid | cdi_pubmedcentral_primary_oai_pubmedcentral_nih_gov_7456110 |
source | Jstor Complete Legacy; MEDLINE; PubMed Central; Alma/SFX Local Collection; Free Full-Text Journals in Chemistry |
subjects | Adaptive systems Antigen processing Antigens Binding Biological Sciences Calreticulin Calreticulin - metabolism Computer simulation Cryoelectron Microscopy Editing Electron microscopy Glycan Grooves Histocompatibility Antigens Class I - metabolism Histocompatibility Antigens Class I - ultrastructure Humans Immune system Lipid bilayers Lipids Loads (forces) Lymphocytes Lymphocytes T Major histocompatibility complex Membrane proteins Membrane Transport Proteins - metabolism Membrane Transport Proteins - ultrastructure Molecular dynamics Molecular Dynamics Simulation Peptides Polysaccharides - metabolism Protein Disulfide-Isomerases - metabolism Proteins Tapasin |
title | Atomistic structure and dynamics of the human MHC-I peptide-loading complex |
url | https://sfx.bib-bvb.de/sfx_tum?ctx_ver=Z39.88-2004&ctx_enc=info:ofi/enc:UTF-8&ctx_tim=2025-02-10T05%3A21%3A23IST&url_ver=Z39.88-2004&url_ctx_fmt=infofi/fmt:kev:mtx:ctx&rfr_id=info:sid/primo.exlibrisgroup.com:primo3-Article-jstor_pubme&rft_val_fmt=info:ofi/fmt:kev:mtx:journal&rft.genre=article&rft.atitle=Atomistic%20structure%20and%20dynamics%20of%20the%20human%20MHC-I%20peptide-loading%20complex&rft.jtitle=Proceedings%20of%20the%20National%20Academy%20of%20Sciences%20-%20PNAS&rft.au=Fisette,%20Olivier&rft.date=2020-08-25&rft.volume=117&rft.issue=34&rft.spage=20597&rft.epage=20606&rft.pages=20597-20606&rft.issn=0027-8424&rft.eissn=1091-6490&rft_id=info:doi/10.1073/pnas.2004445117&rft_dat=%3Cjstor_pubme%3E26969031%3C/jstor_pubme%3E%3Curl%3E%3C/url%3E&disable_directlink=true&sfx.directlink=off&sfx.report_link=0&rft_id=info:oai/&rft_pqid=2438723405&rft_id=info:pmid/32788370&rft_jstor_id=26969031&rfr_iscdi=true |