title: Existence of different but overlapping IgG- and IgM-binding sites on the globular domain of human C1q.
abstract: C1q is the first subcomponent of the classical complement pathway that binds antigen-bound IgG or IgM and initiates complement activation via association of serine proteases C1r and C1s. The globular domain of C1q (gC1q), which is the ligand-recognition domain, is a heterotrimeric structure composed of the C-terminal regions of A (ghA), B (ghB), and C (ghC) chains. The expression and functional characterization of ghA, ghB, and ghC modules have revealed that each chain has some structural and functional autonomy. Although a number of studies have tried to identify IgG-binding sites on the gC1q domain, no such attempt has been made to localize IgM-binding site. On the basis of the information available via the gC1q crystal structure, molecular modeling, mutational studies, and bioinformatics, we have generated a series of substitution mutants of ghA, ghB, and ghC and examined their interactions with IgM. The comparative analysis of IgM- and IgG-binding abilities of the mutants suggests that the IgG- and IgM-binding sites within the gC1q domain are different but may overlap. Whereas Arg(B108), Arg (B109), and Tyr(B175) mainly constitute the IgM-binding site, the residues Arg(B114), Arg(B129), Arg(B163), and His(B117) that have been shown to be central to IgG binding are not important for the C1q-IgM interaction. Given the location of Arg(B108), Arg (B109), and Tyr(B175) in the gC1q crystal structure, it is likely that C1q interacts with IgM via the top of the gC1q domain.
authors.affiliation: Department of Biochemistry, Sofia University, St. Kliment Ohridski, 8 Dragan Tzankov Strasse, Sofia 1164, Bulgaria.
authors.forename: Alexandra S
authors.initials: AS
authors.lastname: Zlatarova
authors.forename: Marieta
authors.initials: M
authors.lastname: Rouseva
authors.forename: Lubka T
authors.initials: LT
authors.lastname: Roumenina
authors.forename: Mihaela
authors.initials: M
authors.lastname: Gadjeva
authors.forename: Martin
authors.initials: M
authors.lastname: Kolev
authors.forename: Ivan
authors.initials: I
authors.lastname: Dobrev
authors.forename: Neli
authors.initials: N
authors.lastname: Olova
authors.forename: Rohit
authors.initials: R
authors.lastname: Ghai
authors.forename: Jens Chr
authors.initials: JC
authors.lastname: Jensenius
authors.forename: Kenneth B M
authors.initials: KB
authors.lastname: Reid
authors.forename: Uday
authors.initials: U
authors.lastname: Kishore
authors.forename: Mihaela S
authors.initials: MS
authors.lastname: Kojouharova
mesh_terms: D001120:Arginine / Q000235:genetics; D001665:Binding Sites; D015922:Complement C1q / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D019295:Computational Biology; D018360:Crystallography, X-Ray; D006801:Humans; D006863:Hydrogen-Ion Concentration; D007074:Immunoglobulin G / Q000378:metabolism*; D007075:Immunoglobulin M / Q000378:metabolism*; D008024:Ligands; D008958:Models, Molecular; D017354:Point Mutation; D017510:Protein Folding; D021122:Protein Subunits / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D011994:Recombinant Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D014443:Tyrosine / Q000235:genetics
chemical_list: D007074:Immunoglobulin G; D007075:Immunoglobulin M; D008024:Ligands; D021122:Protein Subunits; D011994:Recombinant Proteins; D014443:Tyrosine; D015922:Complement C1q; D001120:Arginine