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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)
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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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Publikationstyp Artikel: Journalartikel
Dokumenttyp Wissenschaftlicher Artikel
Schlagwörter 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
Sprache englisch
Veröffentlichungsjahr 2014
HGF-Berichtsjahr 2014
ISSN (print) / ISBN 2041-1723
e-ISSN 2041-1723
Zeitschrift Nature Communications
Quellenangaben Band: 5, Heft: , Seiten: , Artikelnummer: 3505 Supplement: ,
Verlag Nature Publishing Group
Verlagsort London
Begutachtungsstatus Peer reviewed
Institut(e) Institute of Clinical Molecular Biology and Tumor Genetics (K.MOLBI)
POF Topic(s) 30504 - Mechanisms of Genetic and Environmental Influences on Health and Disease
Forschungsfeld(er) Immune Response and Infection
PSP-Element(e) G-501490-001
PubMed ID 24662513
DOI 10.1038/ncomms4505
WOS ID WOS:000334302000008
Erfassungsdatum 2014-03-26
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