C1r2

C1r2 refers to the dimeric form of the C1r protease components that are part of the C1 complex of the classical complement pathway. In humans, the C1 complex comprises six C1q subunits, two C1r proteases and two C1s proteases. C1r and C1s are circulating as zymogens that bind to the collagen-like tails of C1q.

C1r structure: C1r is a calcium-dependent serine protease containing N-terminal CUB and EGF-like domains followed by two CCP repeats and a C-terminal serine protease domain. Two C1r molecules associate with C1q to form the functional C1r2 dimer in the complex.

Activation: When C1q binds to immune complexes or on surfaces, conformational changes promote activation of the C1r zymogens through autoactivation. Activated C1r then cleaves and activates C1s, another C1 protease, which in turn cleaves C4 and C2 to generate the C4b2a C3 convertase, propagating the classical pathway.

Genetics and clinical significance: The C1R gene encodes C1r; deficiencies or dysregulation of C1r-containing complexes can impair classical pathway activation and are associated with dysregulated immune responses and susceptibility to immune complex–mediated diseases. Recently, mutations affecting C1R or its partner C1S have been linked to autoinflammatory and periodontal conditions, highlighting the functional importance of the C1r2 subcomplex within the C1 complex.

See also: complement system, C1q, C1s, classical pathway.