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

Onderzoeksoutput: ArticleAcademicpeer review

Samenvatting

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 α7 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 α7, 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. © 2006 Elsevier Ltd. All rights reserved.
Originele taal-2English
Pagina's (van-tot)1587-97
Aantal pagina's11
TijdschriftStructure (London, England : 1993)
Volume14
Nummer van het tijdschrift10
DOI's
StatusPublished - 10 okt. 2006
Extern gepubliceerdJa

Keywords

  • aminozuren/chemie
  • complement C2a/chemie
  • complementactivatie
  • eiwitstructuur, secundair
  • eiwitstructuur, tertiair
  • katalytisch domein
  • liganden
  • mensen
  • modellen, moleculair
  • mutatie
  • recombinante eiwitten/chemie
  • substraatspecificiteit

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