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
Hauptverfasser: 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
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container_title Proceedings of the National Academy of Sciences - PNAS
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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.
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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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