Complement C1r2s2 complex (C1r2s2)

The Complement C1r2s2 complex is a calcium-dependent tetramer that serves as the enzymatic engine of the C1 complex, the initiator of the classical complement pathway (UniProt P09871, P00736). It is composed of two molecules each of the serine proteases C1r and C1s, which associate to form a catalytic unit that docks onto the C1q recognition protein (Mortensen et al., 2017). Activation occurs when C1q binds to immune complexes (IgM or IgG), triggering the auto-activation of C1r, which subsequently cleaves and activates C1s (Gaboriaud et al., 2004). Once activated, C1s cleaves complement components C4 and C2 to form the C3 convertase (C4b2a), thereby propagating the complement cascade and leading to opsonization, inflammation, and membrane attack complex formation. This tetramer is a critical therapeutic target in autoimmune conditions where the classical pathway is pathologically active, such as cold agglutinin disease (CAD) and bullous pemphigoid (Röth et al., 2021). Drugs like sutimlimab specifically inhibit the C1s subunit within this complex, effectively blocking classical pathway-mediated hemolysis while preserving the alternative and lectin pathways for host defense (FDA: Enjaymo).

Other names

C1s-C1r-C1r-C1s tetramerC1r2s2 complexC1 catalytic subunitC1r2C1s2Complement C1r/C1s tetramer

Selective inhibition of the C1s serine protease within the C1r2s2 tetramer, preventing the cleavage of C4 and C2 and thus blocking the classical complement pathway.