The conformation of subcomponent C1q of the first component of human complement

Abstract

The complement system in the blood of vertebrates^1,2 has a vital role in the defence of the body against invading foreign material. Although it can be triggered before immunity has developed, it is usually activated following an initial intervention by antibodies, and about 20 serum proteins are involved. Some of these act as controlling inhibitors while others form nine components which, if following the classical activation pathway, all take part in bringing about membrane damage and cell lysis. The first component C1 consists of three subcomponents, C1q, C1r and C1s. C1q binds to antibody–antigen complexes as the first stage of fixation³ and as it shows no enzymatic activity by itself, conformational changes on binding have been proposed as the driving mechanism of the subsequent reactions. Since structural investigation by electron microscopy^4–7 leaves doubt as to whether unnatural constraints were applied in the preparation and treatment of specimens, techniques such as X-ray or neutron small-angle scattering, which investigate the equilibrium state in dilute solution, provide valuable complementary evidence for both its findings and those of other physicochemical methods⁸. We have already carried out neutron work on the conformation of immunoglobulin and the influence of hapten binding (to be published) and are now studying the conformation of C1q as a preliminary to investigating the composite structures resulting from their mutual interaction. As evidence of the structure of this molecule has accumulated, the question has arisen of whether it maintains a compact closed conformation in its native state or a more open one in readiness for interaction with other proteins. The neutron small angle scattering curve is sensitive to conformational changes and although our measurements are not yet complete, model calculations suggest that the structural arrangement is indeed open.