Structure of complement component C2A: implications for convertase formation and substrate binding

Fin J Milder, Hans C A Raaijmakers, Mitja D A A Vandeputte, Arie Schouten, Eric G Huizinga, Roland A Romijn, Wieger Hemrika, Anja Roos, Mohamed R Daha, Piet Gros

Research output: Contribution to journalArticleAcademicpeer-review

Abstract

C2a provides the catalytic center to the convertase complexes of the classical and lectin-binding pathways of complement activation. We determined two crystal structures of full-length C2a, with and without a pseudo ligand bound. Both structures reveal a near-active conformation of the catalytic center of the serine protease domains, while the von Willebrand factor A-type domains display an intermediate activation state of helix alpha7 with an open, activated metal-ion-dependent adhesion site. The open adhesion site likely serves to enhance the affinity for the ligand C4b, similar to "inside-out" signaling in integrins. Surprisingly, the N-terminal residues of C2a are buried in a crevice near helix alpha7, indicative of a structural switch between C2 and C2a. Extended loops on the protease domain possibly envelop the protruding anaphylatoxin domain of the substrate C3. Together with a putative substrate-induced completion of the oxyanion hole, this may contribute to the high substrate specificity of the convertases.

Original languageEnglish
Pages (from-to)1587-97
Number of pages11
JournalStructure (London, England : 1993)
Volume14
Issue number10
DOIs
Publication statusPublished - 10 Oct 2006
Externally publishedYes

Keywords

  • amino acids/chemistry
  • catalytic domain
  • complement activation
  • complement C2a/chemistry
  • humans
  • ligands
  • models, molecular
  • mutation
  • protein structure, secondary
  • protein structure, tertiary
  • recombinant proteins/chemistry
  • substrate specificity

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