Structure of the mediator subunit cyclin C and its implications for CDK8 function.
Cyclin C binds the cyclin-dependent kinases CDK8 and CDK3, which regulate mRNA transcription and the cell cycle, respectively. The crystal structure of cyclin C reveals two canonical five-helix repeats and a specific N-terminal helix. In contrast to other cyclins, the N-terminal helix is short, mobile, and in an exposed position that allows for interactions with proteins other than the CDKs. A model of the CDK8/cyclin C pair reveals two regions in the interface with apparently distinct roles. A conserved region explains promiscuous binding of cyclin C to CDK8 and CDK3, and a non-conserved region may be responsible for discrimination of CDK8 against other CDKs involved in transcription. A conserved and cyclin C-specific surface groove may recruit substrates near the CDK8 active site. Activation of CDKs generally involves phosphorylation of a loop at a threonine residue. In CDK8, this loop is longer and the threonine is absent, suggesting an alternative mechanism of activation that we discuss based on a CDK8-cyclin C model.
Gene Center, University of Munich (LMU), Department of Chemistry and Biochemistry, Feodor-Lynen-Str. 25, 81377 Munich, Germany.
Sabine
S
Hoeppner
Sonja
S
Baumli
Patrick
P
Cramer
D000595:Amino Acid Sequence; D001665:Binding Sites; D018360:Crystallography, X-Ray; D056850:Cyclin-Dependent Kinase 8; D018844:Cyclin-Dependent Kinases / Q000737:chemistry* / Q000378:metabolism / Q000502:physiology; D016213:Cyclins / Q000737:chemistry* / Q000378:metabolism / Q000502:physiology; D011485:Protein Binding; D011487:Protein Conformation; D012568:Schizosaccharomyces / Q000737:chemistry*; D029702:Schizosaccharomyces pombe Proteins / Q000737:chemistry* / Q000378:metabolism / Q000502:physiology; D016415:Sequence Alignment
D016213:Cyclins; D029702:Schizosaccharomyces pombe Proteins; D056850:Cyclin-Dependent Kinase 8; D018844:Cyclin-Dependent Kinases; C112462:srb10 protein, S pombe