Modular organization of proteins containing Clq-like globular domain

The first step in the activation of the classical pathway of complement cas cade by immune complexes involves the binding of the six globular heads of C1q to the Fc regions of immunoglobulin G (IgG) or immunoglobulin M (IgM). The globular heads of C1q are located C-terminal to the six triple-helical stalks present in the molecule, each head is considered to be composed of t he C-terminal halves (3 x 135 residues) of one A-, one B- and one C-chain. It is not known if the C-terminal globular regions, present in each of the three types of chains, are independently folded modules (with each chain ha ving distinct binding properties towards immunoglobulins) or whether the di fferent binding functions of C1q are dependent upon a globular structure wh ich relies on contributions from all three chains. Recent reports of recomb inant production and characterisation of soluble globular head regions of a ll the three chains indicate that the globular regions of C1q may adopt a m odular organization, i.e., each globular head of C1q may be composed of thr ee, structurally and functionally, independent domains, thus retaining mult ivalency in the form of a heterotrimer. Modules of the same type as the C1q C-terminal module are also found in a variety of noncomplement proteins th at include the C-terminal regions of the human type VIII and type X collage ns, precerebellin, the chipmunk hibernation proteins, the human endothelial cell protein, multimerin, the serum protein, Acrp-30 which is secreted fro m mouse adipocytes, and the sunfish inner-ear specific structural protein. The C1q molecule is the only one of these proteins for which, to date, a fu nction has been ascribed to the module. The existence of a shared structura l region between C1q and certain collagens may suggest an evolutionarily co mmon ancestral precursor. Various structural and biochemical data suggest t hat these modules may be responsible for multimerisation through patches of aromatic residues within them. (C) 1999 Elsevier Science B.V. All rights r eserved.