title: A corresponding tyrosine residue in the C2/factor B type A domain is a hot spot in the decay acceleration of the complement C3 convertases.
abstract: The cleavage of C3 by the C3 convertases (C3bBb and C4b2a) determines whether complement activation proceeds. Dissociation (decay acceleration) of these central enzymes by the regulators decay-accelerating factor (DAF), complement receptor 1 (CR1), factor H, and C4-binding protein (C4BP) controls their function. In a previous investigation, we obtained evidence implicating the alpha4/5 region of the type A domain of Bb (especially Tyr338) in decay acceleration of C3bBb and proposed this site as a potential interaction point with DAF and long homologous repeat A of CR1. Because portions of only two DAF complement control protein domains (CCPs), CCP2 and CCP3, are necessary to mediate its decay of the CP C3 convertase (as opposed to portions of at least three CCPs in all other cases, e.g. CCPs 1-3 of CR1), DAF/C4b2a provides the simplest structural model for this reaction. Therefore, we examined the importance of the C2 alpha4/5 site on decay acceleration of C4b2a. Functional C4b2a complexes made with the C2 Y327A mutant, the C2 homolog to factor B Y338A, were highly resistant to DAF, C4BP, and long homologous repeat A of CR1, whereas C2 substitutions in two nearby residues (N324A and L328A) resulted in partial resistance. Our new findings indicate that the alpha4/5 region of C2a is critical to decay acceleration mediated by DAF, C4BP, and CR1 and suggest that decay acceleration of C4b2a and C3bBb requires interaction of the convertase alpha4/5 region with a CCP2/CCP3 site of DAF or structurally homologous sites of CR1 and C4BP.
authors.affiliation: Case Western Reserve University, Institute of Pathology, Cleveland, Ohio 44106, USA.
authors.forename: Lisa A
authors.initials: LA
authors.lastname: Kuttner-Kondo
authors.forename: Megan P
authors.initials: MP
authors.lastname: Dybvig
authors.forename: Lynne M
authors.initials: LM
authors.lastname: Mitchell
authors.forename: Nasima
authors.initials: N
authors.lastname: Muqim
authors.forename: John P
authors.initials: JP
authors.lastname: Atkinson
authors.forename: M Edward
authors.initials: ME
authors.lastname: Medof
authors.forename: Dennis E
authors.initials: DE
authors.lastname: Hourcade
mesh_terms: D000595:Amino Acid Sequence; D001665:Binding Sites; D002460:Cell Line; D050577:Complement C3-C5 Convertases / Q000737:chemistry* / Q000378:metabolism; D003169:Complement Inactivator Proteins; D004305:Dose-Response Relationship, Drug; D006023:Glycoproteins / Q000737:chemistry; D006801:Humans; D008958:Models, Molecular; D008969:Molecular Sequence Data; D009154:Mutation; D011485:Protein Binding; D011487:Protein Conformation; D017434:Protein Structure, Tertiary; D017463:Receptors, Complement 3b / Q000737:chemistry; D017386:Sequence Homology, Amino Acid; D014443:Tyrosine / Q000737:chemistry*
chemical_list: D003169:Complement Inactivator Proteins; D006023:Glycoproteins; D017463:Receptors, Complement 3b; D014443:Tyrosine; D050577:Complement C3-C5 Convertases