C1q is the first subcomponent of the classical pathway of the complement system and a major connecting link between innate and acquired immunity. As a versatile charge pattern recognition molecule, C1q is capable of engaging a broad range of ligands via its heterotrimeric globular domain (gC1q) which is composed of the C-terminal regions of its A (ghA), B (ghB) and C (ghC) chains. Recent studies using recombinant forms of ghA, ghB and ghC have suggested that the gC1q domain has a modular organization and each chain can have differential ligand specificity. The crystal structure of the gC1q, molecular modeling and protein engineering studies have combined to illustrate how modular organization, charge distribution and the spatial orientation of the heterotrimeric assembly offer versatility of ligand recognition to C1q. Although the biochemical and structural studies have provided novel insights into the structure-function relationships within the gC1q domain, they have also raised many unexpected issues for debate.

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C1q is the first subcomponent of the classical complement pathway that can interact with a range of biochemically and structurally diverse self and nonself ligands. The globular domain of C1q (gC1q), which is the ligand-recognition domain, is a heterotrimeric structure composed of the Cterminal 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 specific and differential binding properties toward C1q ligands. It is largely considered that C1q-ligand interactions are ionic in nature; however, the complementary ligand-binding sites on C1q and the mechanisms of interactions are still unclear. To identify the residues on the gC1q domain that are likely to be involved in ligand recognition, we have generated a number of substitution mutants of ghA, ghB, and ghC modules and examined their interactions with three selected ligands: IgG1, Creactive protein (CRP), and pentraxin 3 (PTX3). Our results suggest that charged residues belonging to the apex of the gC1q heterotrimer (with participation of all three chains) as well as the side of the ghB are crucial for C1q binding to these ligands, and their contribution to each interaction is different. It is likely that a set of charged residues from the gC1q surface participate † This study was supported by the National Science Foundation of Bulgaria, Grant MY-K-1303 to L.T.R. and L-1000 to M.S.K. R.G.is sponsored by the Deutsche Forschungsgemeinschaft through the Graduiertenkolleg GK370. U.K. is funded by the European Commission, University of Oxford, and the Alexander von Humboldt Foundation. A.M. and B.B. are funded by TELETHON, MIUR (FIRB Fund), the European Commission, and AIRC.© 2006 American Chemical Society * Corresponding author. Phone: +44-1865+44- -222325. Fax: +44-1865 +49-641-9941259. ukishore@hotmail.comu.kishore@rediffmail.com. NIH Public Access Author ManuscriptBiochemistry. Author manuscript; available in PMC 2013 December 29. NIH-PA Author ManuscriptNIH-PA Author Manuscript NIH-PA Author Manuscript via different ionic and hydrogen bonds with corresponding residues from the ligand, instead of forming separate binding sites. Thus, a recently proposed model suggesting the rotation of the gC1q domain upon ligand recognition may be extended to C1q interaction with CRP and PTX3 in addition to IgG1.C1q is the first subcomponent of the classical complement pathway and its binding to IgGor IgM-containing immune complexes leads to the autoactivation of C1r, which in turn, activates C1s. C1r and C1s, the two serine protease proenzymes, together with C1q constitute C1, the first component of the classical pathway. The activation of the C1 complex (C1q + C1r2 + C1s2) subsequently leads to the activation of the C2−C9 components of the classical pathway and the formation of the terminal-membrane-attack complex (MAC) (1, 2). C1q is a versatile innate immune molecule that can bind a diverse range of self and nonself ligands, ranging from proteins to lipids ...