A recombinant homotrimer, composed of the alpha helical neck region of human surfactant protein D and C1q B chain globular domain, is an inhibitor ofthe classical complement pathway

The first step in the activation of the classical complement pathway by imm une complexes involves the binding of the six globular heads of C1q to the Fc regions of IgG or IgM, The globular heads of C1q (gC1q domain) are locat ed C-terminal to the six triple-helical stalks present in the molecule, eac h head being composed of the C-terminal halves of one A, one B, and one C c hain. The gC1q modules are also found in a variety of noncomplement protein s, such as type VIII and X collagens, precerebellin, hibernation protein, m ultimerin, Acrp30, and saccular collagen. In several of these proteins, the chains containing these gC1q modules appear to form a homotrimeric structu re. Here, we report expression of an in-frame fusion of a trimerizing neck region of surfactant protein D with the globular head region of C1q B chain as a fusion to Escherichia coli maltose binding protein. Following cleavag e by factor Xa and removal of the maltose binding protein, the neck and glo bular region, designated ghB(3), formed a soluble, homotrimeric structure a nd could inhibit C1q-dependent hemolysis of IgG- and IgM-sensitized sheep e rythrocytes, The functional properties of ghB(3) indicate that the globular regions of C1q may adopt a modular organization in which each globular hea d of C1q may be composed of three structurally and functionally independent domains, thus retaining multivalency in the form of a heterotrimer, The fi nding that ghB(3) is an inhibitor of C1q-mediated complement activation ope ns up the possibility of blocking activation at the first step of the class ical complement pathway.