C1R

C1r is a calcium-dependent serine protease component of the C1 complex, the initiator of the classical pathway of the complement system. In humans, C1r circulates as a zymogen attached to C1q and, together with C1s, forms the C1 complex. Activation begins when C1q binds to antibodies in immune complexes or to certain microbial surfaces, bringing C1r into proximity to enable autoactivation. Autocatalytic cleavage converts C1r into an active enzyme, comprising two chains linked by a disulfide bond. Active C1r then proteolytically activates the closely associated protease C1s, which subsequently cleaves the complement components C4 and C2 to form the C4b2a C3 convertase and propagate the cascade.

Structurally, C1r is a multidomain protein with domains that mediate assembly with C1q, and a C-terminal serine protease domain responsible for its catalytic activity. The protein’s activity is modulated by calcium ions and is tightly regulated by inhibitors such as C1-inhibitor to prevent unintended proteolysis.

Functionally, C1r acts as the initiating protease of the classical complement pathway. Its activation and interaction with C1q and C1s ensure that complement activation occurs prominently at sites of immune complex formation or pathogenic encounter, contributing to opsonization, inflammation, and lysis of targets through downstream proteolytic events.

Defects or dysregulation of C1r or the C1 complex can impair classical pathway activation, potentially affecting immune complex clearance and host defense. Research and clinical interest continue in understanding C1r’s structure, regulation, and role in disease.

See also: classical pathway, C1 complex, C1s, C1q.