C1rs

C1rs refers to the C1r and C1s subcomponents of the C1 complex, a key protease assembly in the classical pathway of the complement system. In humans, the genes C1R and C1S encode these two serine proteases and are located as adjacent genes on chromosome 12p13.31. The C1 complex comprises C1q, two C1r molecules, and two C1s molecules, functioning together to initiate complement cascade activation.

C1r and C1s are secreted serine proteases that exist as zymogens within the C1 complex. Their polypeptides contain modular domains, including CUB and EGF-like regions, and a C-terminal serine protease domain responsible for proteolytic activity. Activation occurs when C1q binds to antibodies on a target surface, inducing conformational changes that lead to autoactivation of C1r, which then cleaves and activates C1s. Active C1s subsequently cleaves C4 and C2, generating the C4b2a C3 convertase and propagating the classical complement pathway.

Regulation of C1rs activity is tightly controlled; the C1 inhibitor and other regulatory proteins limit protease activity to prevent inappropriate complement activation. Deficiencies or mutations in C1R or C1S can impair classical pathway function and may predispose individuals to certain infections, while genetic variation in these genes has been explored for associations with immune-mediated diseases. The C1r–C1s pair thus plays a central role in the initiation and regulation of the complement system’s classical pathway.