Structure of the Mediator Subunit Cyclin C and its Implications for CDK8 Function

Abstract

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.

Transcriptional Regulation inSaccharomyces cerevisiae: Transcription Factor Regulation and Function, Mechanisms of Initiation, and Roles of Activators and Coactivators

“…Sequence analysis predicts that many Mediator subunits are composed of proteinprotein interaction motifs connected by large inherently unstructured segments. To date, X-ray and NMR structures have been determined for five relatively small and wellordered Mediator domains Hoeppner et al 2005;Lariviere et al 2006;Koschubs et al 2009;Thakur et al 2009). …”

Crystal Structure of Human Cyclin K, a Positive Regulator of Cyclin-dependent Kinase 9

“…23 Notably, the cyclin K gene is transcriptionally activated by the tumor suppressor p53 in response to genotoxic stresses, such as adriamycin treatment, ultraviolet and γ radiation. 24 Two isoforms of CDK9 have been identified in mammalian cells, CDK9 42 and CDK9 55 , which differ in their N-terminal domains. 25,26 The association of these isoforms with cyclins K, T1, T2a, and T2b, results in the formation of eight structurally and functionally distinct P-TEFb complexes.…”

Orphan kinases turn eccentric

“…In contrast to most of the CDKs, which require phosphorylation of a conserved threonine in the T-loop, 42,50,55 CDK8 is proposed to be solely activated by interaction with its cyclin. 39 Additional mechanisms of regulation of this subclass of CDKs include autophosphorylation (CDK9, 11) 41 and activation-dependent dimerization (CDK11). 56 Another class of CDKs appears to function close to the cell membrane.…”

“…Three-dimensional structures are available for many CDK monomers (CDKs 2, 4, 5, 8 and 9) as well as cyclin/CDK dimers (cyclins A, B, C, H, T and p25/Pho80 in complex with their CDKs), [36][37][38][39][40][41][42] which provided a molecular understanding of how cyclins activate CDKs. 24,43,44 Like all kinases, cyclin-dependent kinases have a two-lobed structure.…”