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Bösken, C.A.* ; Farnung, L.* ; Hintermair, C. ; Merzel Schachter, M.* ; Vogel-Bachmayr, K.* ; Blazek, D.* ; Anand, K.* ; Fisher, R.P.* ; Eick, D. ; Geyer, M.*

The structure and substrate specificity of human Cdk12/Cyclin K.

Nat. Commun. 5:3505 (2014)
DOI
Open Access Gold as soon as Publ. Version/Full Text is submitted to ZB.
Phosphorylation of the RNA polymerase II C-terminal domain (CTD) by cyclin-dependent kinases is important for productive transcription. Here we determine the crystal structure of Cdk12/CycK and analyse its requirements for substrate recognition. Active Cdk12/CycK is arranged in an open conformation similar to that of Cdk9/CycT but different from those of cell cycle kinases. Cdk12 contains a C-terminal extension that folds onto the N- and C-terminal lobes thereby contacting the ATP ribose. The interaction is mediated by an HE motif followed by a polybasic cluster that is conserved in transcriptional CDKs. Cdk12/CycK showed the highest activity on a CTD substrate prephosphorylated at position Ser7, whereas the common Lys7 substitution was not recognized. Flavopiridol is most potent towards Cdk12 but was still 10-fold more potent towards Cdk9. T-loop phosphorylation of Cdk12 required coexpression with a Cdk-activating kinase. These results suggest the regulation of Pol II elongation by a relay of transcriptionally active CTD kinases.
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Publication type Article: Journal article
Document type Scientific Article
Keywords Rna-polymerase-ii; C-terminal Domain; Capping Enzyme Recruitment; Cyclin-dependent Kinase-9; Ctd Code; P-tefb; Protein-kinases; Fission Yeast; Crystal-structure; In-vivo
ISSN (print) / ISBN 2041-1723
e-ISSN 2041-1723
Quellenangaben Volume: 5, Issue: , Pages: , Article Number: 3505 Supplement: ,
Publisher Nature Publishing Group
Publishing Place London
Reviewing status Peer reviewed