| Structural highlights
4nst is a 4 chain structure with sequence from Human. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
| | Ligands: | , , ,
| | NonStd Res: | |
| Gene: | CDK12, CRK7, CRKRS, KIAA0904 (HUMAN), CCNK, CPR4 (HUMAN) |
| Resources: | FirstGlance, OCA, RCSB, PDBsum |
Disease
[CDK12_HUMAN] Chromosomal aberrations involving CDK12 may be a cause gastric cancer. Deletions within 17q12 region producing fusion transcripts with ERBB2, leading to CDK12-ERBB2 fusion leading to trunctated CDK12 protein not in-frame with ERBB2.
Function
[CDK12_HUMAN] Cyclin-dependent kinase which displays CTD kinase activity and is required for RNA splicing. Has CTD kinase activity by hyperphosphorylating the C-terminal heptapeptide repeat domain (CTD) of the largest RNA polymerase II subunit RPB1, thereby acting as a key regulator of transcription elongation. Required for RNA splicing, possibly by phosphorylating SRSF1/SF2. Involved in regulation of MAP kinase activity, possibly leading to affect the response to estrogn inhibitors.[1] [2] [3] [CCNK_HUMAN] May play a role in transcriptional regulation. In vitro, is associated with a kinase activity toward both RNA polymerase II C-terminal domain and CDK2 (CAK).[4]
Publication Abstract from PubMed
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.
The structure and substrate specificity of human Cdk12/Cyclin K.,Bosken CA, Farnung L, Hintermair C, Merzel Schachter M, Vogel-Bachmayr K, Blazek D, Anand K, Fisher RP, Eick D, Geyer M Nat Commun. 2014 Mar 24;5:3505. doi: 10.1038/ncomms4505. PMID:24662513[5]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
See Also
References
- ↑ Ko TK, Kelly E, Pines J. CrkRS: a novel conserved Cdc2-related protein kinase that colocalises with SC35 speckles. J Cell Sci. 2001 Jul;114(Pt 14):2591-603. PMID:11683387
- ↑ Iorns E, Martens-de Kemp SR, Lord CJ, Ashworth A. CRK7 modifies the MAPK pathway and influences the response to endocrine therapy. Carcinogenesis. 2009 Oct;30(10):1696-701. doi: 10.1093/carcin/bgp187. Epub 2009, Aug 3. PMID:19651820 doi:http://dx.doi.org/10.1093/carcin/bgp187
- ↑ Bartkowiak B, Liu P, Phatnani HP, Fuda NJ, Cooper JJ, Price DH, Adelman K, Lis JT, Greenleaf AL. CDK12 is a transcription elongation-associated CTD kinase, the metazoan ortholog of yeast Ctk1. Genes Dev. 2010 Oct 15;24(20):2303-16. doi: 10.1101/gad.1968210. PMID:20952539 doi:http://dx.doi.org/10.1101/gad.1968210
- ↑ Fu TJ, Peng J, Lee G, Price DH, Flores O. Cyclin K functions as a CDK9 regulatory subunit and participates in RNA polymerase II transcription. J Biol Chem. 1999 Dec 3;274(49):34527-30. PMID:10574912
- ↑ Bosken CA, Farnung L, Hintermair C, Merzel Schachter M, Vogel-Bachmayr K, Blazek D, Anand K, Fisher RP, Eick D, Geyer M. The structure and substrate specificity of human Cdk12/Cyclin K. Nat Commun. 2014 Mar 24;5:3505. doi: 10.1038/ncomms4505. PMID:24662513 doi:http://dx.doi.org/10.1038/ncomms4505
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