The structure and substrate specificity of human Cdk12/Cyclin K

Christian A. Bösken, Lucas Farnung, Corinna Hintermair, Miriam Merzel Schachter, Karin Vogel-Bachmayr, Dalibor Blazek, Kanchan Anand, Robert P. Fisher, Dirk Eick and Matthias Geyer ()
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Christian A. Bösken: Group Physical Biochemistry, Center of Advanced European Studies and Research
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

Nature Communications, 2014, vol. 5, issue 1, 1-14

Abstract: 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.

Date: 2014
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DOI: 10.1038/ncomms4505

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