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C1q is the target recognition protein of the classical complement pathway and a major connecting link between innate and acquired immunity. As a charge pattern recognition molecule of innate immunity, C1q can engage a broad range of self and non-self ligands via its heterotrimeric globular (gC1q) domain and thus trigger the classical pathway. The trimeric gC1q signature domain has been identified in a variety of non-complement proteins that can be grouped together as a C1q family. The X-ray crystal structures of the gC1q domain of a few members of the C1q family reveal a compact jelly-roll beta-sandwich fold similar to that of the multifunctional tumor necrosis factor (TNF) ligand family, hence the C1q and TNF superfamily. This review is an update on the structural and functional aspects of the gC1q domain of human C1q. We also mention the diverse range of proteins that utilize a gC1q domain in order to reflect on its importance as a versatile scaffold to support a variety of functions.

The first step in the activation of the classical pathway of complement cascade by immune complexes involves the binding of the C-terminal globular head regions of C1q to the Fc regions of IgG or IgM, each globular head being composed of the C-terminal halves of one A-, one B- and one C-chain. Recent studies using recombinant forms of globular region appear to suggest that each globular head of C1q may be composed of three, structurally and functionally, independent domains/modules. The heterotrimeric organisation thus could offer functional flexibility and versatility to the whole C1q molecule. The crystal structure of an adipocyte-specific serum protein, Acrp-30, has revealed the existence of a structural fold shared by members of a new C1q/tumor necrosis factor (TNF) superfamily, characterized by a distinctive globular domain. The protein members seem to be active as self-assembling noncovalent trimers, whose individual chains fold as compact 'jellyroll' beta sandwiches. The recognition of a C1q/TNF superfamily, which has wide-ranging functions, highlights the possibility that the globular regions of C1q may fulfill more binding functions than previously envisaged.