C1r Enzyme

Background

It is well known that C1 is a crucial initiator of the classical complement pathway, while the C1r enzyme (C1R) is an integral part of C1. C1R, also known as complement C1r, EDSPD1, and EDS8, is a vital member of the S1 family of peptidases. C1r enzyme is known to be the activated form of C1r zymogen and is inactive before C1 is activated.

Its Gene ID: 715, UniProtKB ID: P00736, and OMIM ID: 613785.

Description of C1r Enzyme

The C1 complex is composed of one C1q molecule, two C1r molecules, and two C1s molecules. Generally, when C1q binds to the immune complex, a specific stimulation signal is generated. This signal promotes the conversion of the C1r proenzyme into the C1r enzyme. Subsequently, the generated C1r enzyme can stimulate and activate C1s, converting C1s proenzyme into C1s enzyme, thereby initiating the classical complement pathway.

Fig.1 Structure of the catalytic region of active C1r.¹

Properties of C1r Enzyme

The C1r zymogen is reportedly highly susceptible to external factors, which allows for its spontaneous activation under normal conditions. Once activated, C1r zymogen transforms into the C1r enzyme, characterized by a distinctive double-stranded structure. Furthermore, this enzyme comprises two distinct domains, namely the C-terminal catalytic domain and the N-terminal domain, each serving different functions. Specifically, the C-terminal domain primarily facilitates C1r activation and the proteolysis of C1s, while the N-terminal domain is involved in the formation of the C1 complex.

Functions

The C1r enzyme plays a crucial role in activating the C1s proenzyme. The C1r enzyme facilitates the activation of two C1s proenzymes to generate C1s enzymes. Subsequently, two C1r enzyme molecules bind to the two C1s molecules to form a complex. Finally, this complex binds to C1q to produce a fully active C1 molecule. In the presence of activating factors, the C1 molecule initiates the complement cascade by activating other complement factors.

C1r Enzyme Assays

Typically, C1r enzyme activity can be characterized by monitoring the ability of the C1r enzyme to covalently bind to a C1 esterase inhibitor.

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Reference

1. Gál, Péter, et al. "Early complement proteases: C1r, C1s and MASPs. A structural insight into activation and functions." Molecular immunology 46.14 (2009): 2745-2752.