Vaccinia virus complement control protein VCP structure function analysis and role in vaccinia virus pathogenesis

Abstract

The complement system is a principal component of innate immunity designed to combat a myriad of existing as well as newly emerging pathogens. Since viruses are obligatory intracellular parasites, they are continuously exposed to host complement assault and therefore, not surprisingly, have imbibed various strategies to subvert it. One of them is molecular mimicry of the host complement regulators and the examples are pox and herpesviruses, which encode proteins that are structurally and functionally similar to the human regulators of complement activation (RCA), a family of proteins that regulate complement. Vaccinia virus (VACV) is the most extensively studied member of poxviruses. It encodes a homolog of the human complement regulators named vaccinia virus complement control protein (VCP). Incidentally, it is also the most studied viral RCA molecule whose complete structure is determined. This four complement control protein domain containing secretory protein is known to inhibit complement activation by supporting the factor I-mediated inactivation of complement proteins C3b and C4b (termed cofactor activity; CFA), and by accelerating the irreversible decay of the classical and to a limited extent of the alternative pathway C3-convertases (termed decayaccelerating activity; DAA). Here, I have mapped the VCP domains important for its CFA and DAA by swapping its individual domains with those of the human decayaccelerating factor (DAF; CD55) and membrane cofactor protein (MCP; CD46). We reasoned that since DAF possesses only decay activity and is devoid of cofactor activity, while MCP possesses only cofactor activity and is devoid of decay activity, swapping of VCP domains with homologous DAF or MCP domains would allow the identification of VCP domains(s) critical for factor I interaction and decay of protease subunits from the convertases, respectively.