Structure of Complement Component C2a: Implications for Convertase Formation and Substrate Binding

• Published in: Structure (London) Vol. 14; no. 10; pp. 1587 - 1597
• Main Authors: Milder, Fin J., Raaijmakers, Hans C.A., Vandeputte, Mitja D.A.A., Schouten, Arie, Huizinga, Eric G., Romijn, Roland A., Hemrika, Wieger, Roos, Anja, Daha, Mohamed R., Gros, Piet
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01-10-2006
• Subjects: Amino Acids - chemistry; Amino Acids - genetics; Catalytic Domain; Complement Activation; Complement C2a - chemistry; Complement C2a - genetics; Humans; Ligands; Models, Molecular; MOLIMMUNO; Mutation; Protein Structure, Secondary; Protein Structure, Tertiary; Recombinant Proteins - chemistry; Recombinant Proteins - genetics; Substrate Specificity; MOLIMMUNO
• ISSN: 0969-2126; 1878-4186
• DOI: 10.1016/j.str.2006.08.008

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.