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The structure and substrate specificity of human Cdk12/Cyclin K

MPG-Autoren
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Geyer,  M.
Research Group Physical Biochemistry, Center of Advanced European Studies and Research (caesar), Max Planck Society;

Externe Ressourcen

http://dx.doi.org/10.1038/ncomms4505
(beliebiger Volltext)

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3973122/pdf/ncomms4505.pdf
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Zitation

Bösken, C. A., Farnung, L., Hintermair, C., Merzel Schachter, M., Vogel-Bachmayr, K., Blazek, D., et al. (2014). The structure and substrate specificity of human Cdk12/Cyclin K. Nature Communications, 5, 3505. doi:10.1038/ncomms4505.


Zitierlink: https://hdl.handle.net/11858/00-001M-0000-0028-6157-6
Zusammenfassung
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.