CRYSTALLOGRAPHIC STUDIES OF VIRAL CYCLINS AND CDK6

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In recent years, key enzymes that regulate cell cycle progression have been identified and characterized extensively. The major transition of the eucaryotic cell cycle are controlled by cyclin-dependent protein kinases (CDKs) that exert their regulatory function by phosphorylation of key proteins involved in cell cycle transitions. To ensure proper timing and coordination of cell cycle events, CDK kinase activity is tightly controlled by various mechanisms, such as activation of the apoenzyme by complex formation with cyclins, activating and inhibiting phosphorylations, and complex formation with inhibitory proteins. Not surprisingly from their key role in cell cycle control, mutations and overexpression of cyclins and CDKs have been reported to be oncogenic events. The recent discovery of two proteins from oncogenic herpes viruses that show close homology with human D-type cyclins supports these observations. V-cyclin from herpesvirus saimiri (HVS) and k- cyclin from Kaposi's sarcoma associated herpesvirus (KSHV) show 24 percent and 31 percent identity with human cyclin D1 and D3, respectively. They associate with CDK4 and CDK6, resulting in strong kinase activity toward retinoblastoma protein and histone H1. This high level of unlicensed kinase activity most likely induces deregulation of cell proliferation inherent to HVS and KSHV diseases. The sequence homologies between viral cyclins and D-type cyclins and the similarities in CDK activation make viral cyclins a good system to study activation mechanisms of CDK4 and CDK6, that might lead to oncogenic events if not properly controlled. Futhermore, KSHV is implicated in the development of Kaposi's sarcoma, especially in AIDS patients. Hence, studies of the two homologous viral cylclins may contribute to understanding the pathogenesis and treatment of this disease. The short term goal is to determine the three-dimensional structure of v-cyclin. The long-term goal is to determine the structures of k- cyclin, and CDK6 by x-ray crystallography and to study complexes of CDK6 with viral cyclins with the final aim of structure determination as well. This information will help to understand the activation mechanism of host cell CDKs by proteins from viruses that cause various diseases including cancer.