Structural basis for activation of the complement system by component C4 cleavage
An essential aspect of innate immunity is recognition of molecular patterns on the surface of pathogens or altered self through the lectin and classical pathways, two of the three well-established activation pathways of the complement system. This recognition causes activation of the MASP-2 or the C...
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Veröffentlicht in: | Proceedings of the National Academy of Sciences - PNAS 2012-09, Vol.109 (38), p.15425-15430 |
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creator | Kidmose, Rune T Laursen, Nick S Dobó, József Kjaer, Troels R Sirotkina, Sofia Yatime, Laure Sottrup-Jensen, Lars Thiel, Steffen Gál, Péter Andersen, Gregers R |
description | An essential aspect of innate immunity is recognition of molecular patterns on the surface of pathogens or altered self through the lectin and classical pathways, two of the three well-established activation pathways of the complement system. This recognition causes activation of the MASP-2 or the C1s serine proteases followed by cleavage of the protein C4. Here we present the crystal structures of the 203-kDa human C4 and the 245-kDa C4⋅MASP-2 substrate⋅enzyme complex. When C4 binds to MASP-2, substantial conformational changes in C4 are induced, and its scissile bond region becomes ordered and inserted into the protease catalytic site in a manner canonical to serine proteases. In MASP-2, an exosite located within the CCP domains recognizes the C4 C345C domain 60 Å from the scissile bond. Mutations in C4 and MASP-2 residues at the C345C–CCP interface inhibit the intermolecular interaction and C4 cleavage. The possible assembly of the huge in vivo enzyme–substrate complex consisting of glycan-bound mannan-binding lectin, MASP-2, and C4 is discussed. Our own and prior functional data suggest that C1s in the classical pathway of complement activated by, e.g., antigen–antibody complexes, also recognizes the C4 C345C domain through a CCP exosite. Our results provide a unified structural framework for understanding the early and essential step of C4 cleavage in the elimination of pathogens and altered self through two major pathways of complement activation. |
doi_str_mv | 10.1073/pnas.1208031109 |
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This recognition causes activation of the MASP-2 or the C1s serine proteases followed by cleavage of the protein C4. Here we present the crystal structures of the 203-kDa human C4 and the 245-kDa C4⋅MASP-2 substrate⋅enzyme complex. When C4 binds to MASP-2, substantial conformational changes in C4 are induced, and its scissile bond region becomes ordered and inserted into the protease catalytic site in a manner canonical to serine proteases. In MASP-2, an exosite located within the CCP domains recognizes the C4 C345C domain 60 Å from the scissile bond. Mutations in C4 and MASP-2 residues at the C345C–CCP interface inhibit the intermolecular interaction and C4 cleavage. The possible assembly of the huge in vivo enzyme–substrate complex consisting of glycan-bound mannan-binding lectin, MASP-2, and C4 is discussed. Our own and prior functional data suggest that C1s in the classical pathway of complement activated by, e.g., antigen–antibody complexes, also recognizes the C4 C345C domain through a CCP exosite. Our results provide a unified structural framework for understanding the early and essential step of C4 cleavage in the elimination of pathogens and altered self through two major pathways of complement activation.</description><identifier>ISSN: 0027-8424</identifier><identifier>EISSN: 1091-6490</identifier><identifier>DOI: 10.1073/pnas.1208031109</identifier><identifier>PMID: 22949645</identifier><language>eng</language><publisher>United States: National Academy of Sciences</publisher><subject>active sites ; Antigens ; Binding Sites ; Biochemistry, Molecular Biology ; Biological Sciences ; complement ; Complement activation ; Complement C4 - chemistry ; Complement system ; Crystal structure ; Crystallography - methods ; Electrostatics ; enzyme substrates ; Enzymes ; HEK293 Cells ; Humans ; Hydrogen bonds ; Immunity, Innate ; Immunology ; innate immunity ; Lectins ; Life Sciences ; Mannans - chemistry ; Mannose-Binding Protein-Associated Serine Proteases - chemistry ; Molecular Conformation ; Molecules ; Mutation ; Pathogens ; Pattern recognition ; Proteases ; Protein Binding ; Protein Conformation ; Protein Structure, Tertiary ; Proteins ; Proteins - chemistry ; Proteolysis ; Recombinant Proteins - chemistry ; serine proteinases ; Static Electricity ; Structural Biology ; Substrate Specificity</subject><ispartof>Proceedings of the National Academy of Sciences - PNAS, 2012-09, Vol.109 (38), p.15425-15430</ispartof><rights>copyright © 1993-2008 National Academy of Sciences of the United States of America</rights><rights>Copyright National Academy of Sciences Sep 18, 2012</rights><rights>Distributed under a Creative Commons Attribution 4.0 International License</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c559t-6bbbcac72439880ab20dac48930b5a65b139a1d1b3812b2ee7a2803189e6d1363</citedby><cites>FETCH-LOGICAL-c559t-6bbbcac72439880ab20dac48930b5a65b139a1d1b3812b2ee7a2803189e6d1363</cites><orcidid>0000-0002-3650-8012</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Uhttp://www.pnas.org/content/109/38.cover.gif</thumbnail><linktopdf>$$Uhttps://www.jstor.org/stable/pdf/41706420$$EPDF$$P50$$Gjstor$$H</linktopdf><linktohtml>$$Uhttps://www.jstor.org/stable/41706420$$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/22949645$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink><backlink>$$Uhttps://hal.umontpellier.fr/hal-02095670$$DView record in HAL$$Hfree_for_read</backlink></links><search><creatorcontrib>Kidmose, Rune T</creatorcontrib><creatorcontrib>Laursen, Nick S</creatorcontrib><creatorcontrib>Dobó, József</creatorcontrib><creatorcontrib>Kjaer, Troels R</creatorcontrib><creatorcontrib>Sirotkina, Sofia</creatorcontrib><creatorcontrib>Yatime, Laure</creatorcontrib><creatorcontrib>Sottrup-Jensen, Lars</creatorcontrib><creatorcontrib>Thiel, Steffen</creatorcontrib><creatorcontrib>Gál, Péter</creatorcontrib><creatorcontrib>Andersen, Gregers R</creatorcontrib><title>Structural basis for activation of the complement system by component C4 cleavage</title><title>Proceedings of the National Academy of Sciences - PNAS</title><addtitle>Proc Natl Acad Sci U S A</addtitle><description>An essential aspect of innate immunity is recognition of molecular patterns on the surface of pathogens or altered self through the lectin and classical pathways, two of the three well-established activation pathways of the complement system. This recognition causes activation of the MASP-2 or the C1s serine proteases followed by cleavage of the protein C4. Here we present the crystal structures of the 203-kDa human C4 and the 245-kDa C4⋅MASP-2 substrate⋅enzyme complex. When C4 binds to MASP-2, substantial conformational changes in C4 are induced, and its scissile bond region becomes ordered and inserted into the protease catalytic site in a manner canonical to serine proteases. In MASP-2, an exosite located within the CCP domains recognizes the C4 C345C domain 60 Å from the scissile bond. Mutations in C4 and MASP-2 residues at the C345C–CCP interface inhibit the intermolecular interaction and C4 cleavage. The possible assembly of the huge in vivo enzyme–substrate complex consisting of glycan-bound mannan-binding lectin, MASP-2, and C4 is discussed. Our own and prior functional data suggest that C1s in the classical pathway of complement activated by, e.g., antigen–antibody complexes, also recognizes the C4 C345C domain through a CCP exosite. Our results provide a unified structural framework for understanding the early and essential step of C4 cleavage in the elimination of pathogens and altered self through two major pathways of complement activation.</description><subject>active sites</subject><subject>Antigens</subject><subject>Binding Sites</subject><subject>Biochemistry, Molecular Biology</subject><subject>Biological Sciences</subject><subject>complement</subject><subject>Complement activation</subject><subject>Complement C4 - chemistry</subject><subject>Complement system</subject><subject>Crystal structure</subject><subject>Crystallography - methods</subject><subject>Electrostatics</subject><subject>enzyme substrates</subject><subject>Enzymes</subject><subject>HEK293 Cells</subject><subject>Humans</subject><subject>Hydrogen bonds</subject><subject>Immunity, Innate</subject><subject>Immunology</subject><subject>innate immunity</subject><subject>Lectins</subject><subject>Life Sciences</subject><subject>Mannans - chemistry</subject><subject>Mannose-Binding Protein-Associated Serine Proteases - chemistry</subject><subject>Molecular Conformation</subject><subject>Molecules</subject><subject>Mutation</subject><subject>Pathogens</subject><subject>Pattern recognition</subject><subject>Proteases</subject><subject>Protein Binding</subject><subject>Protein Conformation</subject><subject>Protein Structure, Tertiary</subject><subject>Proteins</subject><subject>Proteins - chemistry</subject><subject>Proteolysis</subject><subject>Recombinant Proteins - chemistry</subject><subject>serine proteinases</subject><subject>Static Electricity</subject><subject>Structural Biology</subject><subject>Substrate Specificity</subject><issn>0027-8424</issn><issn>1091-6490</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2012</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNqFkk1vEzEQhi0EoiFw5gSsxAUOaWf8sWtfkKoIKFIkhErPlu04yUa762DvRsq_x9uEFHrhYkvzPvN6ZjyEvEa4RKjY1a4z6RIpSGCIoJ6QST5xVnIFT8kEgFYzySm_IC9S2gKAEhKekwtKFVclFxPy47aPg-uHaJrCmlSnYhViYVxf701fh64Iq6Lf-MKFdtf41nd9kQ6p921hD_fB0I2xOS9c483erP1L8mxlmuRfne4pufvy-ef8Zrb4_vXb_Hoxc0KoflZaa51xFeVMSQnGUlgax6ViYIUphUWmDC7RMonUUu8rQ8cupfLlElnJpuTT0Xc32NYvXS4jN6F3sW5NPOhgav2v0tUbvQ57zbiQTIhs8PFosHmUdnO90GMMaJ5XWcEeM_vh9FgMvwafet3WyfmmMZ0PQ9I4lsYFR_l_FDgyWrHc-JS8f4RuwxC7PLV7iiLlcqSujpSLIaXoV-diEfS4BXrcAv2wBTnj7d-jOfN_vj0DxQkYMx_slGZSo-B0RN4ckW3qQzwzHCsoOYWsvzvqKxO0Wcc66btbClgCIFUVU-w3dZrJfQ</recordid><startdate>20120918</startdate><enddate>20120918</enddate><creator>Kidmose, Rune T</creator><creator>Laursen, Nick S</creator><creator>Dobó, József</creator><creator>Kjaer, Troels R</creator><creator>Sirotkina, Sofia</creator><creator>Yatime, Laure</creator><creator>Sottrup-Jensen, Lars</creator><creator>Thiel, Steffen</creator><creator>Gál, Péter</creator><creator>Andersen, Gregers R</creator><general>National Academy of Sciences</general><general>National Acad Sciences</general><scope>FBQ</scope><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>7S9</scope><scope>L.6</scope><scope>1XC</scope><scope>5PM</scope><orcidid>https://orcid.org/0000-0002-3650-8012</orcidid></search><sort><creationdate>20120918</creationdate><title>Structural basis for activation of the complement system by component C4 cleavage</title><author>Kidmose, Rune T ; 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This recognition causes activation of the MASP-2 or the C1s serine proteases followed by cleavage of the protein C4. Here we present the crystal structures of the 203-kDa human C4 and the 245-kDa C4⋅MASP-2 substrate⋅enzyme complex. When C4 binds to MASP-2, substantial conformational changes in C4 are induced, and its scissile bond region becomes ordered and inserted into the protease catalytic site in a manner canonical to serine proteases. In MASP-2, an exosite located within the CCP domains recognizes the C4 C345C domain 60 Å from the scissile bond. Mutations in C4 and MASP-2 residues at the C345C–CCP interface inhibit the intermolecular interaction and C4 cleavage. The possible assembly of the huge in vivo enzyme–substrate complex consisting of glycan-bound mannan-binding lectin, MASP-2, and C4 is discussed. Our own and prior functional data suggest that C1s in the classical pathway of complement activated by, e.g., antigen–antibody complexes, also recognizes the C4 C345C domain through a CCP exosite. Our results provide a unified structural framework for understanding the early and essential step of C4 cleavage in the elimination of pathogens and altered self through two major pathways of complement activation.</abstract><cop>United States</cop><pub>National Academy of Sciences</pub><pmid>22949645</pmid><doi>10.1073/pnas.1208031109</doi><tpages>6</tpages><orcidid>https://orcid.org/0000-0002-3650-8012</orcidid><oa>free_for_read</oa></addata></record> |
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subjects | active sites Antigens Binding Sites Biochemistry, Molecular Biology Biological Sciences complement Complement activation Complement C4 - chemistry Complement system Crystal structure Crystallography - methods Electrostatics enzyme substrates Enzymes HEK293 Cells Humans Hydrogen bonds Immunity, Innate Immunology innate immunity Lectins Life Sciences Mannans - chemistry Mannose-Binding Protein-Associated Serine Proteases - chemistry Molecular Conformation Molecules Mutation Pathogens Pattern recognition Proteases Protein Binding Protein Conformation Protein Structure, Tertiary Proteins Proteins - chemistry Proteolysis Recombinant Proteins - chemistry serine proteinases Static Electricity Structural Biology Substrate Specificity |
title | Structural basis for activation of the complement system by component C4 cleavage |
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