The human complement system forms an important component of the immune system that protects against microbial infections. It is composed of over 30 proteins that tag and destroy invaders. However, there are clinical situations in which activation of complement is inappropriate; including organ transplant rejection, Alzheimer's disease, asthma, restenosis and others. Thus understanding the normal functioning of the complement system is important in both basic terms and in treatment of such clinical conditions. Because of its potential for causing massive tissue damage, complement is a system that is stringently regulated. Almost half the proteins that participate in the three pathways of complement activation, the classical, alternative and lectin pathways, have regulatory functions. Most of the regulatory proteins are the products of the regulators of complement activation genetic locus and include membrane associated proteins as well as circulating proteins. The regulatory molecules exert their activity at the level of C3 and C5 convertases, that are the basis of amplification events of activation. Several viruses have evolved mechanisms that are based on viral mimics of complement regulatory components to evade destruction by complement. Vaccinia Complement Protein (VCP) was one of the first such mimics to be discovered and characterized. VCP, a small unglycosylated protein made up of four CCP modules, inhibits complement activation by binding C3b and C4b. in addition, the heparin binding activity of VCP permits the virus to persist in the host, prolonging infection. The structure of VCP has permitted us to suggest potential sites of interactions of VCP with complement components C3b and C4b and with heparin that are important for its activity. We propose X-ray crystallographic and biophysical studies on complexes of VCP with C3b, C4b, and heparin that would help us delineate the structural biology of VCP interactions with complement. This information will be of value in understanding the functioning of complement regulators and design of inhibitors of complement activation.
| Ganesh, Vannakambadi K; Muthuvel, Suresh Kumar; Smith, Scott A et al. (2005) Structural basis for antagonism by suramin of heparin binding to vaccinia complement protein. Biochemistry 44:10757-65 |
| Ganesh, Vannakambadi K; Smith, Scott A; Kotwal, Girish J et al. (2004) Structure of vaccinia complement protein in complex with heparin and potential implications for complement regulation. Proc Natl Acad Sci U S A 101:8924-9 |
