title: Structure of complement component C2A: implications for convertase formation and substrate binding.
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.
authors.affiliation: Crystal and Structural Chemistry, Bijvoet Center for Biomolecular Research, Faculty of Science, Utrecht University, 3584 CH Utrecht, The Netherlands.
authors.forename: Fin J
authors.initials: FJ
authors.lastname: Milder
authors.forename: Hans C A
authors.initials: HC
authors.lastname: Raaijmakers
authors.forename: Mitja D A A
authors.initials: MD
authors.lastname: Vandeputte
authors.forename: Arie
authors.initials: A
authors.lastname: Schouten
authors.forename: Eric G
authors.initials: EG
authors.lastname: Huizinga
authors.forename: Roland A
authors.initials: RA
authors.lastname: Romijn
authors.forename: Wieger
authors.initials: W
authors.lastname: Hemrika
authors.forename: Anja
authors.initials: A
authors.lastname: Roos
authors.forename: Mohamed R
authors.initials: MR
authors.lastname: Daha
authors.forename: Piet
authors.initials: P
authors.lastname: Gros
mesh_terms: D000596:Amino Acids / Q000737:chemistry / Q000235:genetics; D020134:Catalytic Domain; D003167:Complement Activation; D050678:Complement C2a / Q000737:chemistry* / Q000235:genetics; D006801:Humans; D008024:Ligands; D008958:Models, Molecular; D009154:Mutation; D017433:Protein Structure, Secondary; D017434:Protein Structure, Tertiary; D011994:Recombinant Proteins / Q000737:chemistry / Q000235:genetics; D013379:Substrate Specificity
chemical_list: D000596:Amino Acids; D008024:Ligands; D011994:Recombinant Proteins; D050678:Complement C2a