The structure and substrate specificity of human Cdk12/Cyclin K

J 2014

The structure and substrate specificity of human Cdk12/Cyclin K

BÖSKEN, Christian A.; Lucas FARNUNG; Corinna HINTERMAIR; Miriam Merzel SCHACHTER; Karin VOGEL- BACHMAYR et. al.

Basic information

Original name

The structure and substrate specificity of human Cdk12/Cyclin K

Authors

BÖSKEN, Christian A. (276 Germany); Lucas FARNUNG (276 Germany); Corinna HINTERMAIR (276 Germany); Miriam Merzel SCHACHTER (840 United States of America); Karin VOGEL- BACHMAYR (840 United States of America); Dalibor BLAŽEK (203 Czech Republic, guarantor, belonging to the institution); Kanchan ANAND (276 Germany); Robert P. FISHER (840 United States of America); Dirk EICK (276 Germany) and Matthias GEYER (276 Germany)

Edition

NATURE COMMUNICATIONS, London, Nature Publishing Group, 2014, 2041-1723

Other information

Language

English

Type of outcome

Article in a journal

Field of Study

10600 1.6 Biological sciences

Country of publisher

United Kingdom of Great Britain and Northern Ireland

Confidentiality degree

is not subject to a state or trade secret

References:

URL

Impact factor

Impact factor: 11.470

RIV identification code

RIV/00216224:14740/14:00073691

Organization unit

Central European Institute of Technology

DOI

http://dx.doi.org/10.1038/ncomms4505

UT WoS

000334302000008

EID Scopus

2-s2.0-84904343427

Keywords in English

RNA-POLYMERASE-II; C-TERMINAL DOMAIN; CAPPING ENZYME RECRUITMENT; CYCLIN-DEPENDENT KINASE-9; CTD CODE; P-TEFB; PROTEIN-KINASES; FISSION YEAST; CRYSTAL-STRUCTURE; IN-VIVO

Abstract

In the original language

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.

Links

ED1.1.00/02.0068, research and development project

Name: CEITEC - central european institute of technology

GA14-09979S, research and development project

Name: Role Cdk12 a C-terminální domény RNA polymerázy II v transkripcně regulovaném procesu genomové nestability

Investor: Czech Science Foundation

Cite

BÖSKEN, Christian A.; Lucas FARNUNG; Corinna HINTERMAIR; Miriam Merzel SCHACHTER; Karin VOGEL- BACHMAYR; Dalibor BLAŽEK; Kanchan ANAND; Robert P. FISHER; Dirk EICK and Matthias GEYER. The structure and substrate specificity of human Cdk12/Cyclin K. NATURE COMMUNICATIONS. London: Nature Publishing Group, 2014, vol. 5, No 3505, p. "nestránkováno", 14 pp. ISSN 2041-1723. Available from: https://dx.doi.org/10.1038/ncomms4505.

@article{1186174,
   author = {Bösken, Christian A. and Farnung, Lucas and Hintermair, Corinna and Schachter, Miriam Merzel and Vogeland Bachmayr, Karin and Blažek, Dalibor and Anand, Kanchan and Fisher, Robert P. and Eick, Dirk and Geyer, Matthias},
   article_location = {London},
   article_number = {3505},
   doi = {http://dx.doi.org/10.1038/ncomms4505},
   keywords = {RNA-POLYMERASE-II; C-TERMINAL DOMAIN; CAPPING ENZYME RECRUITMENT; CYCLIN-DEPENDENT KINASE-9; CTD CODE; P-TEFB; PROTEIN-KINASES; FISSION YEAST; CRYSTAL-STRUCTURE; IN-VIVO},
   language = {eng},
   issn = {2041-1723},
   journal = {NATURE COMMUNICATIONS},
   title = {The structure and substrate specificity of human Cdk12/Cyclin K},
   url = {http://www.nature.com/ncomms/2014/140324/ncomms4505/pdf/ncomms4505.pdf},
   volume = {5},
   year = {2014}
}

TY  - JOUR
ID  - 1186174
AU  - Bösken, Christian A. - Farnung, Lucas - Hintermair, Corinna - Schachter, Miriam Merzel - Vogel- Bachmayr, Karin - Blažek, Dalibor - Anand, Kanchan - Fisher, Robert P. - Eick, Dirk - Geyer, Matthias
PY  - 2014
TI  - The structure and substrate specificity of human Cdk12/Cyclin K
JF  - NATURE COMMUNICATIONS
VL  - 5
IS  - 3505
SP  - "nestránkováno"
EP  - "nestránkováno"
PB  - Nature Publishing Group
SN  - 20411723
KW  - RNA-POLYMERASE-II
KW  - C-TERMINAL DOMAIN
KW  - CAPPING ENZYME RECRUITMENT
KW  - CYCLIN-DEPENDENT KINASE-9
KW  - CTD CODE
KW  - P-TEFB
KW  - PROTEIN-KINASES
KW  - FISSION YEAST
KW  - CRYSTAL-STRUCTURE
KW  - IN-VIVO
UR  - http://www.nature.com/ncomms/2014/140324/ncomms4505/pdf/ncomms4505.pdf
L2  - http://www.nature.com/ncomms/2014/140324/ncomms4505/pdf/ncomms4505.pdf
N2  - 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.
ER  -

BÖSKEN, Christian A.; Lucas FARNUNG; Corinna HINTERMAIR; Miriam Merzel SCHACHTER; Karin VOGEL- BACHMAYR; Dalibor BLAŽEK; Kanchan ANAND; Robert P. FISHER; Dirk EICK and Matthias GEYER. The structure and substrate specificity of human Cdk12/Cyclin K. \textit{NATURE COMMUNICATIONS}. London: Nature Publishing Group, 2014, vol.~5, No~3505, p.~''nestránkováno'', 14 pp. ISSN~2041-1723. Available from: https://dx.doi.org/10.1038/ncomms4505.

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