Regulators of complement activity mediate inhibitory mechanisms through a common C3b-binding mode.

Area of Science:

• Immunology
• Structural Biology
• Biochemistry

Background:

• Regulators of complement activation (RCA) are crucial for preventing immune damage to host tissues.
• Understanding RCA interactions with complement component C3b is key to deciphering immune regulation and disease.

Purpose of the Study:

• To elucidate the structural basis of human RCA (MCP, DAF, CR1) and viral SPICE binding to C3b.
• To reveal how variations in RCA domains influence C3b binding and inhibitory mechanisms.

Main Methods:

• X-ray crystallography was used to determine the structures of RCA and SPICE bound to C3b.
• Comparative structural analysis was performed to identify conserved and variable binding features.

Main Results:

• Crystal structures show RCA and SPICE binding C3b via consecutive CCP domains in an extended orientation.
• Sequence variations in CCP domains lead to diverse C3b-binding patterns, with significant contacts at the third binding site.
• Rotational variations at the fourth binding site do not alter the overall binding mode.

Conclusions:

• The findings suggest a shared evolutionary origin for decay acceleration and cofactor activity in complement regulation.
• Structural data provide a framework for understanding RCA-associated mutations and viral immune evasion strategies.