Structural and Functional Analysis of the Cdk13/Cyclin K Complex

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Authors

GREIFENBERG Ann Katrin HÖNIG Dana PILAŘOVÁ Květa DÜSTER Robert BARTHOLOMEEUSEN Koen BOSKEN Christian A. ANAND Kanchan BLAŽEK Dalibor GEYER Matthias

Year of publication 2016
Type Article in Periodical
Magazine / Source Cell Reports
MU Faculty or unit

Central European Institute of Technology

Citation
Web http://www.sciencedirect.com/science/article/pii/S2211124715014382
Doi http://dx.doi.org/10.1016/j.celrep.2015.12.025
Field Genetics and molecular biology
Keywords RNA-POLYMERASE-II; P-TEFB; TRANSCRIPTION CYCLE; OVARIAN-CARCINOMA; MESSENGER-RNA; PHOSPHORYLATION; KINASE; CTD; ELONGATION; CDK12
Description Cyclin-dependent kinases regulate the cell cycle and transcription in higher eukaryotes. We have determined the crystal structure of the transcription kinase Cdk13 and its Cyclin K subunit at 2.0 angstrom resolution. Cdk13 contains a C-terminal extension helix composed of a polybasic cluster and a DCHEL motif that interacts with the bound ATP. Cdk13/CycK phosphorylates both Ser5 and Ser2 of the RNA polymerase II C-terminal domain (CTD) with a preference for Ser7 pre-phosphorylations at a C-terminal position. The peptidyl-prolyl isomerase Pin1 does not change the phosphorylation specificities of Cdk9, Cdk12, and Cdk13 but interacts with the phosphorylated CTD through its WW domain. Using recombinant proteins, we find that flavopiridol inhibits Cdk7 more potently than it does Cdk13. Gene expression changes after knockdown of Cdk13 or Cdk12 are markedly different, with enrichment of growth signaling pathways for Cdk13-dependent genes. Together, our results provide insights into the structure, function, and activity of human Cdk13/CycK.
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