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Clq is the subcomponent of the classical complement pathway that can interact with a range of biochemically and structurally diverse self and nonself ligands. The charged residues belonging to the apex of the global domain of Clq(gClq) heterotrimer as well as the side of the ghB are crucial for Clq binding to these ligands.

The role of Ca(super 2+) in the electrostatic stability and target-binding properties of the native Clq and the recombinant monomeric forms of the globular head domain (gClq) of human Clq are investigated using theoretical and experimental approaches. It is concluded that Ca(super 2+) primarily influences the target recognition properties of Clq and the loss of Ca(super 2+) at pH 7.4 leads to change in the direction of electric moment which is important for subsequent complement activation.

The immunoglobulin binding properties of single-residue mutants of individual globular modules of A and C chains are compared to understand the mechanism of interaction of globular C1q domain (gClq) with IgG and IgM. The results showed that residues from the apical surface of C1q are involved in the initial recognition of IgG and IgM, while [Arg.sup.B108] and [Arg.sup.B109] are able to interact during the initial recognition as well as during the final binding of immunoglobulins.

A series of substitution mutants of ghA, ghB, and ghC is generated and its interaction with IgM is examined. The comparative analysis of IgM- and IgC-binding abilities of mutants suggests that the IgG- and IgM-binding sites within the globular domain of Clq are different but may overlap.

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.