title: The structure of C2b, a fragment of complement component C2 produced during C3 convertase formation.
abstract: The second component of complement (C2) is a multi-domain serine protease that provides catalytic activity for the C3 and C5 convertases of the classical and lectin pathways of human complement. The formation of these convertases requires the Mg(2+)-dependent binding of C2 to C4b and the subsequent cleavage of C2 by C1s or MASP2, respectively. The crystal structure of full-length C2 is not yet available, although the structure of its C-terminal catalytic segment C2a has been determined. The crystal structure of the N-terminal segment C2b of C2 determined to 1.8 A resolution presented here reveals the arrangement of its three CCP domains. The domains are arranged differently compared with most other CCP-domain assemblies, but their arrangement is similar to that found in the Ba part of the full-length factor B structure. The crystal structures of C2a, C2b and full-length factor B are used to generate a model for C2 and a discussion of the domain association and possible interactions with C4b during formation of the C4b-C2 complex is presented. The results of this study also suggest that upon cleavage by C1s, C2a domains undergo conformational rotation while bound to C4b and the released C2b domains may remain folded together similar to as observed in the intact protein.
authors.affiliation: Center for Biophysical Sciences and Engineering, School of Optometry, University of Alabama at Birmingham, Birmingham, AL 35294, USA.
authors.forename: Vengadesan
authors.initials: V
authors.lastname: Krishnan
authors.forename: Yuanyuan
authors.initials: Y
authors.lastname: Xu
authors.forename: Kevin
authors.initials: K
authors.lastname: Macon
authors.forename: John E
authors.initials: JE
authors.lastname: Volanakis
authors.forename: Sthanam V L
authors.initials: SV
authors.lastname: Narayana
mesh_terms: D000595:Amino Acid Sequence; D003173:Complement C1s / Q000378:metabolism; D050678:Complement C2a / Q000737:chemistry / Q000378:metabolism; D050679:Complement C2b / Q000737:chemistry* / Q000378:metabolism; D050577:Complement C3-C5 Convertases / Q000378:metabolism; D015935:Complement C4b / Q000378:metabolism; D011415:Complement Factor B / Q000737:chemistry / Q000378:metabolism; D018360:Crystallography, X-Ray; D006801:Humans; D008958:Models, Molecular; D008969:Molecular Sequence Data; D016297:Mutagenesis, Site-Directed; D017354:Point Mutation; D011485:Protein Binding; D011487:Protein Conformation; D017510:Protein Folding; D017434:Protein Structure, Tertiary; D011993:Recombinant Fusion Proteins / Q000737:chemistry / Q000378:metabolism; D016415:Sequence Alignment; D017386:Sequence Homology, Amino Acid; D013329:Structure-Activity Relationship
chemical_list: D050679:Complement C2b; D011993:Recombinant Fusion Proteins; D015935:Complement C4b; D050577:Complement C3-C5 Convertases; D003173:Complement C1s; D050678:Complement C2a; D011415:Complement Factor B