title: Role of Ca2+ in the electrostatic stability and the functional activity of the globular domain of human C1q.
abstract: C1q is the recognition subunit of the classical pathway of the complement system and a major connecting link between classical pathway-driven innate immunity and IgG- or IgM-mediated acquired immunity. The basic structural subunit of C1q is composed of an N-terminal triple-helical collagen-like region and a C-terminal heterotrimeric globular head domain (gC1q) that is made up of individual A, B, and C chains. Recent crystallographic studies have revealed that the gC1q domain, which is the main target-binding region of C1q, has a compact and spherical heterotrimeric assembly, held together by both electrostatic and nonpolar interactions, with quasi-3-fold symmetry. A characteristic feature of the gC1q domain is the presence of a exposed Ca(2+) located near the apex. We have investigated, using theoretical and experimental approaches, the role of Ca(2+) in the electrostatic stability and target-binding properties of the native C1q as well as recombinant monomeric forms of the C-terminal regions of the A, B, and C chains. Here, we report that Ca(2+) primarily influences the target recognition properties of C1q toward IgG, IgM, C-reactive protein, and pentraxin 3. At pH 7.4, the loss of Ca(2+) leads to changes in the direction of electric moment from coaxial (where the putative C-reactive protein-binding site is located) to perpendicular to the molecular axis (toward the most likely IgG-binding site), which appears important for target recognition by C1q and subsequent complement activation.
authors.affiliation: Department of Biochemistry, Sofia University, St. Kliment Ohridski, 8 Dragan Tsankov Street, Sofia 1164, Bulgaria.
authors.forename: Lubka T
authors.initials: LT
authors.lastname: Roumenina
authors.forename: Alexandar A
authors.initials: AA
authors.lastname: Kantardjiev
authors.forename: Boris P
authors.initials: BP
authors.lastname: Atanasov
authors.forename: Patrick
authors.initials: P
authors.lastname: Waters
authors.forename: Mihaela
authors.initials: M
authors.lastname: Gadjeva
authors.forename: Kenneth B M
authors.initials: KB
authors.lastname: Reid
authors.forename: Alberto
authors.initials: A
authors.lastname: Mantovani
authors.forename: Uday
authors.initials: U
authors.lastname: Kishore
authors.forename: Mihaela S
authors.initials: MS
authors.lastname: Kojouharova
mesh_terms: D002118:Calcium / Q000737:chemistry / Q000378:metabolism*; D002413:Cations, Divalent; D015922:Complement C1q / Q000737:chemistry* / Q000378:metabolism; D004797:Enzyme-Linked Immunosorbent Assay; D006801:Humans; D006863:Hydrogen-Ion Concentration; D007074:Immunoglobulin G / Q000737:chemistry / Q000378:metabolism; D007075:Immunoglobulin M / Q000737:chemistry / Q000378:metabolism; D007136:Immunoglobulins / Q000737:chemistry* / Q000378:metabolism; D011485:Protein Binding; D011487:Protein Conformation; D055672:Static Electricity
chemical_list: D002413:Cations, Divalent; D007074:Immunoglobulin G; D007075:Immunoglobulin M; D007136:Immunoglobulins; D015922:Complement C1q; D002118:Calcium