Dissecting sites important for complement regulatory activity in membrane cofactor protein (MCP; CD46).

Area of Science:

• Immunology
• Molecular Biology
• Structural Biology

Background:

• Membrane cofactor protein (MCP; CD46) is a key regulator of complement activation.
• MCP acts as a cofactor for factor I-mediated degradation of C3b and C4b on host cells.
• MCP contains four extracellular complement control protein (CCP) modules crucial for its inhibitory function.

Purpose of the Study:

• To delineate functional sites within the four CCP modules of MCP.
• To understand the specific roles of MCP residues in C3b and C4b interactions and cofactor activity.

Main Methods:

• Site-directed mutagenesis to alter specific residues within MCP CCP modules.
• Epitope mapping to identify regions involved in protein interactions.
• Comparative analysis with primate MCP sequences.
• Computational modeling based on existing crystal structures.

Main Results:

• Functional sites were identified in all four CCP modules of MCP.
• Specific residues were found to be critical for C3b and/or C4b binding and cofactor activity.
• Some MCP mutants exhibited reduced cofactor activity despite retained ligand binding.
• MCP regions involved in C4b regulation overlapped with measles virus binding sites.
• Identified MCP regulatory regions showed homology to functionally critical sites in other CCP-containing proteins.

Conclusions:

• MCP's four CCP modules contain distinct and overlapping functional sites for complement regulation.
• The interaction of measles virus hemagglutinin with MCP highlights a convergence of viral evasion and complement inhibition strategies.
• Structural and functional insights into MCP provide a basis for understanding its role in host defense and disease.