Project Details
Projekt
Regulatory interaction between cellular cyclins and the cyclin-dependent protein kinase ortholog pUL97 of human cytomegalovirus
Subject Area
Virology
Biochemistry
Cell Biology
Biochemistry
Cell Biology
Term
from 2015 to 2019
Project identifier
Deutsche Forschungsgemeinschaft (DFG) - Project number 280194832
Replication of human cytomegalovirus (HCMV) is characterized by a tight virus-host cell interaction. In particular, cyclin-dependent protein kinases (CDKs) are functionally integrated into viral gene expression and protein modification. The HCMV-encoded protein kinase pUL97 acts as a CDK ortholog showing structural and functional similarities. Recently, we reported an interaction between pUL97 kinase with a subset of host cyclins, in particular with cyclin T1. The sequence domain of pUL97 responsible for the interaction with cyclin T1 was identified in the amino acid region 231-280 lying outside the conserved kinase domain. In our ongoing preliminary work, we describe an even more pronounced interaction of pUL97 with cyclin B1. The finding is surprising and important regarding that this is the only example of a herpesviral kinase-cyclin interaction identified so far that may illustrate a cross-talk between cyclins representing regulatory effectors of the cell cycle and viral replication. Importantly, we were able to demonstrate that the HCMV-encoded kinase pUL97 does not exclusively bind to one cyclin but undergoes interactions with several types of cyclins, which is reminiscent to the variable combinations of CDK-cyclin interactions. As a striking feature, the interaction between pUL97 and cyclin B1 (but not cyclin T1) seems to be dependent on pUL97 activity, i.e. our preliminary data suggest a block of cyclin B1 interaction by treatment with pUL97 inhibitors. Thus, the mechanism of interaction is scientifically challenging and will be studied by a combination of bioinformatics and biochemical analyses. Especially, the role of the pUL97-cyclin interaction, in regard of phosphorylation-dependent regulatory activities of pUL97, will be investigated in detail. Combined, it will be fundamental to ascertain the importance of pUL97-cyclin interaction in the context of viral replication possessing a putative impact on viral pathogenesis.
DFG Programme
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