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The structure and substrate specificity of human Cdk12/Cyclin K
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...
Autores principales: | , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Nature Pub. Group
2014
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3973122/ https://www.ncbi.nlm.nih.gov/pubmed/24662513 http://dx.doi.org/10.1038/ncomms4505 |
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author | Bösken, Christian A. Farnung, Lucas Hintermair, Corinna Merzel Schachter, Miriam Vogel-Bachmayr, Karin Blazek, Dalibor Anand, Kanchan Fisher, Robert P. Eick, Dirk Geyer, Matthias |
author_facet | Bösken, Christian A. Farnung, Lucas Hintermair, Corinna Merzel Schachter, Miriam Vogel-Bachmayr, Karin Blazek, Dalibor Anand, Kanchan Fisher, Robert P. Eick, Dirk Geyer, Matthias |
author_sort | Bösken, Christian A. |
collection | PubMed |
description | 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. |
format | Online Article Text |
id | pubmed-3973122 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2014 |
publisher | Nature Pub. Group |
record_format | MEDLINE/PubMed |
spelling | pubmed-39731222014-04-03 The structure and substrate specificity of human Cdk12/Cyclin K Bösken, Christian A. Farnung, Lucas Hintermair, Corinna Merzel Schachter, Miriam Vogel-Bachmayr, Karin Blazek, Dalibor Anand, Kanchan Fisher, Robert P. Eick, Dirk Geyer, Matthias Nat Commun Article 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. Nature Pub. Group 2014-03-24 /pmc/articles/PMC3973122/ /pubmed/24662513 http://dx.doi.org/10.1038/ncomms4505 Text en Copyright © 2014, Nature Publishing Group, a division of Macmillan Publishers Limited. All Rights Reserved. http://creativecommons.org/licenses/by-nc-by/3.0/ This work is licensed under a Creative Commons Attribution 3.0 Unported License. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in the credit line; if the material is not included under the Creative Commons license, users will need to obtain permission from the license holder to reproduce the material. To view a copy of this license, visit http://creativecommons.org/licenses/by/3.0/ |
spellingShingle | Article Bösken, Christian A. Farnung, Lucas Hintermair, Corinna Merzel Schachter, Miriam Vogel-Bachmayr, Karin Blazek, Dalibor Anand, Kanchan Fisher, Robert P. Eick, Dirk Geyer, Matthias The structure and substrate specificity of human Cdk12/Cyclin K |
title | The structure and substrate specificity of human Cdk12/Cyclin K |
title_full | The structure and substrate specificity of human Cdk12/Cyclin K |
title_fullStr | The structure and substrate specificity of human Cdk12/Cyclin K |
title_full_unstemmed | The structure and substrate specificity of human Cdk12/Cyclin K |
title_short | The structure and substrate specificity of human Cdk12/Cyclin K |
title_sort | structure and substrate specificity of human cdk12/cyclin k |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3973122/ https://www.ncbi.nlm.nih.gov/pubmed/24662513 http://dx.doi.org/10.1038/ncomms4505 |
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