The first enzymic event in the cascade of the classical pathway of complement is the activation of its first component, C1. C1 is a multimolecular complex consisting of two loosely interacting entities: C1q, the recognition subunit, and C1r2-C1s2, the catalytic one. C1r2-C1s2 is a tetrameric Ca2+-dependent complex of C1r and C1s, two serine-proteinase zymogens. These zymogens are activated in sequence during the C1 activation: first, the dimeric form of C1r autoactivates by proteolysis of a single Arg-Ile bond in each monomer; C1r2 then cleaves an Arg-Ile bond in each molecule of C1s, leading to C1s, which is able to proteolytically attack its substrates C4 and C2.
C1r plays a key role in these series of events, due to its autoactivation potential. It acts by transforming the activation signal (the fixation of C1q on activating reagents, e.g. immune complexes) into an enzymic activity. Up to now, most biochemical studies on human C1r have been performed on the protein purified from plasma pools. Its complete sequence has been determined since the present studies were initiated. Intracellular and secreted C1r have been studied by using cultured Hep G2 hepatoma cells. These cells synthesize low amounts of C1r. Nevertheless, it has been possible to observe that the protein secreted by Hep G2 cells does not autoactivate, although it is synthesized in its dimeric form and is activated by exogeneous C1r.
1. Journet A, et al. (1986). Cloning and sequencing of full-length cDNA encoding the precursor of human complement component C1r. Biochemical Journal, 240(3), 783-787.
2. Ziccardi R J, et al. (1976). Physicochemical and functional characterization of the C1r subunit of the first complement component. The Journal of Immunology, 116(2), 496-503.