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

Clq 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 Clq is composed of an N-terminal triple-helical collagen-like region and a C-terminal heterotrimeric globular head domain (gClq) that is made up of individual A, B, and C chains. Recent crystallographic studies have revealed that the gClq domain, which is the main target-binding region of Clq, 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 gClq domain is the presence of a exposed Call located near the apex. We have investigated, using theoretical and experimental approaches, the role of Call in the electrostatic stability and target-binding properties of the native Clq as well as recombinant monomeric forms of the C-terminal regions of the A, B, and C chains. Here, we report that Call primarily influences the target recognition properties of Clq toward IgG, IgM, C-reactive protein, and pentraxin 3. At pH 7.4, the loss of Call 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 Clq and subsequent complement activation.