Role of Ca2+ in the electrostatic stability and the functional activity of the globular domain of human C1q

Lubka T. Roumenina, Alexandar A. Kantardjiev, Boris P. Atanasov, Patrick Waters, Mihaela Gadjeva, Kenneth B M Reid, Alberto Mantovani, Uday Kishore, Mihaela S. Kojouharova

Research output: Contribution to journalArticle

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 Ca2+ 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 Ca2+ primarily influences the target recognition properties of C1q toward IgG, IgM, C-reactive protein, and pentraxin 3. At pH 7.4, the loss of Ca2+ 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.

Original languageEnglish
Pages (from-to)14097-14109
Number of pages13
JournalBiochemistry
Volume44
Issue number43
DOIs
Publication statusPublished - Nov 1 2005

ASJC Scopus subject areas

  • Biochemistry

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    Roumenina, L. T., Kantardjiev, A. A., Atanasov, B. P., Waters, P., Gadjeva, M., Reid, K. B. M., Mantovani, A., Kishore, U., & Kojouharova, M. S. (2005). Role of Ca2+ in the electrostatic stability and the functional activity of the globular domain of human C1q. Biochemistry, 44(43), 14097-14109. https://doi.org/10.1021/bi051186n