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Structures of C1-IgG1 provide insights into how danger pattern recognition activates complement
Danger patterns on microbes or damaged host cells bind and activate C1, inducing innate immune responses and clearance through the complement cascade. How these patterns trigger complement initiation remains elusive. Here, we present cryo-electron microscopy analyses of C1 bound to monoclonal antibo...
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Published in: | Science (American Association for the Advancement of Science) 2018-02, Vol.359 (6377), p.794-797 |
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creator | Ugurlar, Deniz Howes, Stuart C de Kreuk, Bart-Jan Koning, Roman I de Jong, Rob N Beurskens, Frank J Schuurman, Janine Koster, Abraham J Sharp, Thomas H Parren, Paul W H I Gros, Piet |
description | Danger patterns on microbes or damaged host cells bind and activate C1, inducing innate immune responses and clearance through the complement cascade. How these patterns trigger complement initiation remains elusive. Here, we present cryo-electron microscopy analyses of C1 bound to monoclonal antibodies in which we observed heterogeneous structures of single and clustered C1-immunoglobulin G1 (IgG1) hexamer complexes. Distinct C1q binding sites are observed on the two Fc-CH2 domains of each IgG molecule. These are consistent with known interactions and also reveal additional interactions, which are supported by functional IgG1-mutant analysis. Upon antibody binding, the C1q arms condense, inducing rearrangements of the C1r
s
proteases and tilting C1q's cone-shaped stalk. The data suggest that C1r may activate C1s within single, strained C1 complexes or between neighboring C1 complexes on surfaces. |
doi_str_mv | 10.1126/science.aao4988 |
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proteases and tilting C1q's cone-shaped stalk. The data suggest that C1r may activate C1s within single, strained C1 complexes or between neighboring C1 complexes on surfaces.</description><identifier>ISSN: 0036-8075</identifier><identifier>EISSN: 1095-9203</identifier><identifier>DOI: 10.1126/science.aao4988</identifier><identifier>PMID: 29449492</identifier><language>eng</language><publisher>United States: The American Association for the Advancement of Science</publisher><subject>Alarmins - chemistry ; Alarmins - ultrastructure ; Antibodies, Monoclonal - chemistry ; Antibodies, Monoclonal - ultrastructure ; Avidity ; Binding Sites ; Complement ; Complement Activation ; Complement C1 - chemistry ; Complement C1 - ultrastructure ; Complement component C1 ; Complement component C1q ; Cryoelectron Microscopy ; Damage ; Electron microscopy ; Hazards ; Hexamers ; Humans ; Immune clearance ; Immune response ; Immune system ; Immunoglobulin G ; Immunoglobulin G - chemistry ; Immunoglobulin G - genetics ; Immunoglobulin G - ultrastructure ; Immunoglobulins ; Initiation complex ; Innate immunity ; Microscopy ; Monoclonal antibodies ; Mutagenesis ; Pattern recognition</subject><ispartof>Science (American Association for the Advancement of Science), 2018-02, Vol.359 (6377), p.794-797</ispartof><rights>Copyright © 2018 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.</rights><rights>Copyright © 2018 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c366t-2f28c2356364df8b0a608868d7be0417bc152ceae978055b26d07876c01618043</citedby><cites>FETCH-LOGICAL-c366t-2f28c2356364df8b0a608868d7be0417bc152ceae978055b26d07876c01618043</cites><orcidid>0000-0001-8841-3851 ; 0000-0001-6129-1882 ; 0000-0002-4365-3859 ; 0000-0002-9738-9926 ; 0000-0002-9300-6633 ; 0000-0002-7165-5771 ; 0000-0003-1717-2549 ; 0000-0002-1990-2333 ; 0000-0002-7782-2585 ; 0000-0001-6736-7147</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>314,780,784,2884,2885,27924,27925</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/29449492$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Ugurlar, Deniz</creatorcontrib><creatorcontrib>Howes, Stuart C</creatorcontrib><creatorcontrib>de Kreuk, Bart-Jan</creatorcontrib><creatorcontrib>Koning, Roman I</creatorcontrib><creatorcontrib>de Jong, Rob N</creatorcontrib><creatorcontrib>Beurskens, Frank J</creatorcontrib><creatorcontrib>Schuurman, Janine</creatorcontrib><creatorcontrib>Koster, Abraham J</creatorcontrib><creatorcontrib>Sharp, Thomas H</creatorcontrib><creatorcontrib>Parren, Paul W H I</creatorcontrib><creatorcontrib>Gros, Piet</creatorcontrib><title>Structures of C1-IgG1 provide insights into how danger pattern recognition activates complement</title><title>Science (American Association for the Advancement of Science)</title><addtitle>Science</addtitle><description>Danger patterns on microbes or damaged host cells bind and activate C1, inducing innate immune responses and clearance through the complement cascade. How these patterns trigger complement initiation remains elusive. Here, we present cryo-electron microscopy analyses of C1 bound to monoclonal antibodies in which we observed heterogeneous structures of single and clustered C1-immunoglobulin G1 (IgG1) hexamer complexes. Distinct C1q binding sites are observed on the two Fc-CH2 domains of each IgG molecule. These are consistent with known interactions and also reveal additional interactions, which are supported by functional IgG1-mutant analysis. Upon antibody binding, the C1q arms condense, inducing rearrangements of the C1r
s
proteases and tilting C1q's cone-shaped stalk. The data suggest that C1r may activate C1s within single, strained C1 complexes or between neighboring C1 complexes on surfaces.</description><subject>Alarmins - chemistry</subject><subject>Alarmins - ultrastructure</subject><subject>Antibodies, Monoclonal - chemistry</subject><subject>Antibodies, Monoclonal - ultrastructure</subject><subject>Avidity</subject><subject>Binding Sites</subject><subject>Complement</subject><subject>Complement Activation</subject><subject>Complement C1 - chemistry</subject><subject>Complement C1 - ultrastructure</subject><subject>Complement component C1</subject><subject>Complement component C1q</subject><subject>Cryoelectron Microscopy</subject><subject>Damage</subject><subject>Electron microscopy</subject><subject>Hazards</subject><subject>Hexamers</subject><subject>Humans</subject><subject>Immune clearance</subject><subject>Immune response</subject><subject>Immune system</subject><subject>Immunoglobulin G</subject><subject>Immunoglobulin G - chemistry</subject><subject>Immunoglobulin G - genetics</subject><subject>Immunoglobulin G - ultrastructure</subject><subject>Immunoglobulins</subject><subject>Initiation complex</subject><subject>Innate immunity</subject><subject>Microscopy</subject><subject>Monoclonal antibodies</subject><subject>Mutagenesis</subject><subject>Pattern recognition</subject><issn>0036-8075</issn><issn>1095-9203</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2018</creationdate><recordtype>article</recordtype><recordid>eNpdkEFP3DAQRi1UBNuFc2-VpV64ZHdsJ459rFYtRULiAJwjx5nsGm3sre2A-u8xYuHQ04w0bz59eoR8Y7BijMt1sg69xZUxodZKnZAFA91UmoP4QhYAQlYK2uacfE3pCaDctDgj51zXta41X5DuPsfZ5jliomGkG1bdbK8ZPcTw7Aakzie33eVUlhzoLrzQwfgtRnowOWP0NKINW--yC54am92zySXJhumwxwl9viCno9knvDzOJXn8_eth86e6vbu-2fy8rayQMld85Mpy0Ugh62FUPRgJSkk1tD1CzdresoZbNKhbBU3TczlAq1ppgUmmoBZLcvWeW5r_nTHlbnLJ4n5vPIY5dby4AKFU3RT0x3_oU5ijL-3eKN5wpVlbqPU7ZWNIKeLYHaKbTPzXMeje3HdH993Rffn4fsyd-wmHT_5DtngFTYaBMQ</recordid><startdate>20180216</startdate><enddate>20180216</enddate><creator>Ugurlar, Deniz</creator><creator>Howes, Stuart C</creator><creator>de Kreuk, Bart-Jan</creator><creator>Koning, Roman I</creator><creator>de Jong, Rob N</creator><creator>Beurskens, Frank J</creator><creator>Schuurman, Janine</creator><creator>Koster, Abraham J</creator><creator>Sharp, Thomas H</creator><creator>Parren, Paul W H I</creator><creator>Gros, Piet</creator><general>The American Association for the Advancement of Science</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>7QF</scope><scope>7QG</scope><scope>7QL</scope><scope>7QP</scope><scope>7QQ</scope><scope>7QR</scope><scope>7SC</scope><scope>7SE</scope><scope>7SN</scope><scope>7SP</scope><scope>7SR</scope><scope>7SS</scope><scope>7T7</scope><scope>7TA</scope><scope>7TB</scope><scope>7TK</scope><scope>7TM</scope><scope>7U5</scope><scope>7U9</scope><scope>8BQ</scope><scope>8FD</scope><scope>C1K</scope><scope>F28</scope><scope>FR3</scope><scope>H8D</scope><scope>H8G</scope><scope>H94</scope><scope>JG9</scope><scope>JQ2</scope><scope>K9.</scope><scope>KR7</scope><scope>L7M</scope><scope>L~C</scope><scope>L~D</scope><scope>M7N</scope><scope>P64</scope><scope>RC3</scope><scope>7X8</scope><orcidid>https://orcid.org/0000-0001-8841-3851</orcidid><orcidid>https://orcid.org/0000-0001-6129-1882</orcidid><orcidid>https://orcid.org/0000-0002-4365-3859</orcidid><orcidid>https://orcid.org/0000-0002-9738-9926</orcidid><orcidid>https://orcid.org/0000-0002-9300-6633</orcidid><orcidid>https://orcid.org/0000-0002-7165-5771</orcidid><orcidid>https://orcid.org/0000-0003-1717-2549</orcidid><orcidid>https://orcid.org/0000-0002-1990-2333</orcidid><orcidid>https://orcid.org/0000-0002-7782-2585</orcidid><orcidid>https://orcid.org/0000-0001-6736-7147</orcidid></search><sort><creationdate>20180216</creationdate><title>Structures of C1-IgG1 provide insights into how danger pattern recognition activates complement</title><author>Ugurlar, Deniz ; Howes, Stuart C ; de Kreuk, Bart-Jan ; Koning, Roman I ; de Jong, Rob N ; Beurskens, Frank J ; Schuurman, Janine ; Koster, Abraham J ; Sharp, Thomas H ; Parren, Paul W H I ; Gros, Piet</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c366t-2f28c2356364df8b0a608868d7be0417bc152ceae978055b26d07876c01618043</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2018</creationdate><topic>Alarmins - 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Academic</collection><jtitle>Science (American Association for the Advancement of Science)</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Ugurlar, Deniz</au><au>Howes, Stuart C</au><au>de Kreuk, Bart-Jan</au><au>Koning, Roman I</au><au>de Jong, Rob N</au><au>Beurskens, Frank J</au><au>Schuurman, Janine</au><au>Koster, Abraham J</au><au>Sharp, Thomas H</au><au>Parren, Paul W H I</au><au>Gros, Piet</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Structures of C1-IgG1 provide insights into how danger pattern recognition activates complement</atitle><jtitle>Science (American Association for the Advancement of Science)</jtitle><addtitle>Science</addtitle><date>2018-02-16</date><risdate>2018</risdate><volume>359</volume><issue>6377</issue><spage>794</spage><epage>797</epage><pages>794-797</pages><issn>0036-8075</issn><eissn>1095-9203</eissn><abstract>Danger patterns on microbes or damaged host cells bind and activate C1, inducing innate immune responses and clearance through the complement cascade. How these patterns trigger complement initiation remains elusive. Here, we present cryo-electron microscopy analyses of C1 bound to monoclonal antibodies in which we observed heterogeneous structures of single and clustered C1-immunoglobulin G1 (IgG1) hexamer complexes. Distinct C1q binding sites are observed on the two Fc-CH2 domains of each IgG molecule. These are consistent with known interactions and also reveal additional interactions, which are supported by functional IgG1-mutant analysis. Upon antibody binding, the C1q arms condense, inducing rearrangements of the C1r
s
proteases and tilting C1q's cone-shaped stalk. The data suggest that C1r may activate C1s within single, strained C1 complexes or between neighboring C1 complexes on surfaces.</abstract><cop>United States</cop><pub>The American Association for the Advancement of Science</pub><pmid>29449492</pmid><doi>10.1126/science.aao4988</doi><tpages>4</tpages><orcidid>https://orcid.org/0000-0001-8841-3851</orcidid><orcidid>https://orcid.org/0000-0001-6129-1882</orcidid><orcidid>https://orcid.org/0000-0002-4365-3859</orcidid><orcidid>https://orcid.org/0000-0002-9738-9926</orcidid><orcidid>https://orcid.org/0000-0002-9300-6633</orcidid><orcidid>https://orcid.org/0000-0002-7165-5771</orcidid><orcidid>https://orcid.org/0000-0003-1717-2549</orcidid><orcidid>https://orcid.org/0000-0002-1990-2333</orcidid><orcidid>https://orcid.org/0000-0002-7782-2585</orcidid><orcidid>https://orcid.org/0000-0001-6736-7147</orcidid><oa>free_for_read</oa></addata></record> |
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subjects | Alarmins - chemistry Alarmins - ultrastructure Antibodies, Monoclonal - chemistry Antibodies, Monoclonal - ultrastructure Avidity Binding Sites Complement Complement Activation Complement C1 - chemistry Complement C1 - ultrastructure Complement component C1 Complement component C1q Cryoelectron Microscopy Damage Electron microscopy Hazards Hexamers Humans Immune clearance Immune response Immune system Immunoglobulin G Immunoglobulin G - chemistry Immunoglobulin G - genetics Immunoglobulin G - ultrastructure Immunoglobulins Initiation complex Innate immunity Microscopy Monoclonal antibodies Mutagenesis Pattern recognition |
title | Structures of C1-IgG1 provide insights into how danger pattern recognition activates complement |
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