Structural basis for activation of the complement system by component C4 cleavage

Rune T. Kidmose, Nick S. Laursen, J. Dobó, Troels R. Kjaer, Sofia Sirotkina, Laure Yatime, Lars Sottrup-Jensen, Steffen Thiel, P. Gál, Gregers R. Andersen

Research output: Contribution to journalArticle

58 Citations (Scopus)

Abstract

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.

Original languageEnglish
Pages (from-to)15425-15430
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume109
Issue number38
DOIs
Publication statusPublished - Sep 18 2012

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Mannose-Binding Protein-Associated Serine Proteases
Complement C4
Complement Activation
Serine Proteases
Classical Complement Pathway
Mannose-Binding Lectin
Antigen-Antibody Complex
Lectins
Innate Immunity
Polysaccharides
Catalytic Domain
Peptide Hydrolases
Mutation
Enzymes

Keywords

  • Crystallography
  • Pattern recognition
  • Proteolysis
  • Structural biology

ASJC Scopus subject areas

  • General

Cite this

Structural basis for activation of the complement system by component C4 cleavage. / Kidmose, Rune T.; Laursen, Nick S.; Dobó, J.; Kjaer, Troels R.; Sirotkina, Sofia; Yatime, Laure; Sottrup-Jensen, Lars; Thiel, Steffen; Gál, P.; Andersen, Gregers R.

In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 109, No. 38, 18.09.2012, p. 15425-15430.

Research output: Contribution to journalArticle

Kidmose, RT, Laursen, NS, Dobó, J, Kjaer, TR, Sirotkina, S, Yatime, L, Sottrup-Jensen, L, Thiel, S, Gál, P & Andersen, GR 2012, 'Structural basis for activation of the complement system by component C4 cleavage', Proceedings of the National Academy of Sciences of the United States of America, vol. 109, no. 38, pp. 15425-15430. https://doi.org/10.1073/pnas.1208031109
Kidmose, Rune T. ; Laursen, Nick S. ; Dobó, J. ; Kjaer, Troels R. ; Sirotkina, Sofia ; Yatime, Laure ; Sottrup-Jensen, Lars ; Thiel, Steffen ; Gál, P. ; Andersen, Gregers R. / Structural basis for activation of the complement system by component C4 cleavage. In: Proceedings of the National Academy of Sciences of the United States of America. 2012 ; Vol. 109, No. 38. pp. 15425-15430.
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