Author
Listed:
- Christian A. Bösken
(Group Physical Biochemistry, Center of Advanced European Studies and Research
Max Planck Institute of Molecular Physiology)
- Lucas Farnung
(Max Planck Institute of Molecular Physiology)
- Corinna Hintermair
(Helmholtz Center Munich, Center for Integrated Protein Science (CIPSM))
- Miriam Merzel Schachter
(Icahn School of Medicine at Mount Sinai)
- Karin Vogel-Bachmayr
(Max Planck Institute of Molecular Physiology)
- Dalibor Blazek
(Central European Institute of Technology (CEITEC), Masaryk University)
- Kanchan Anand
(Group Physical Biochemistry, Center of Advanced European Studies and Research)
- Robert P. Fisher
(Icahn School of Medicine at Mount Sinai)
- Dirk Eick
(Helmholtz Center Munich, Center for Integrated Protein Science (CIPSM))
- Matthias Geyer
(Group Physical Biochemistry, Center of Advanced European Studies and Research
Max Planck Institute of Molecular Physiology)
Abstract
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.
Suggested Citation
Christian A. Bösken & Lucas Farnung & Corinna Hintermair & Miriam Merzel Schachter & Karin Vogel-Bachmayr & Dalibor Blazek & Kanchan Anand & Robert P. Fisher & Dirk Eick & Matthias Geyer, 2014.
"The structure and substrate specificity of human Cdk12/Cyclin K,"
Nature Communications, Nature, vol. 5(1), pages 1-14, May.
Handle:
RePEc:nat:natcom:v:5:y:2014:i:1:d:10.1038_ncomms4505
DOI: 10.1038/ncomms4505
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