Dichotomous but stringent substrate selection by the dual-function Cdk7 complex revealed by chemical genetics

Stéphane Larochelle, Jasmin Batliner, Matthew J. Gamble, Nora M. Barboza, Brian C. Kraybill, Justin D. Blethrow, Kevan M. Shokat, Robert P. Fisher

Research output: Contribution to journalArticle

71 Scopus citations

Abstract

Cdk7 performs two essential but distinct functions as a CDK-activating kinase (CAK) required for cell-cycle progression and as the RNA polymerase II (Pol II) CTD kinase of general transcription factor IIH. To investigate the substrate specificity underlying this dual function, we created an analog-sensitive (AS) Cdk7 able to use bulky ATP derivatives. Cdk7-AS-cyclin H-Mat1 phosphorylates ∼10-15 endogenous polypeptides in nuclear extracts. We identify seven of these as known and previously unknown Cdk7 substrates that define two classes: proteins such as Pol II and transcription elongation factor Spt5, recognized efficiently only by the fully activated Cdk7 complex, through sequences surrounding the site of phosphorylation; and CDKs, targeted equivalently by all active forms of Cdk7, dependent on substrate motifs remote from the phosphoacceptor residue. Thus, Cdk7 accomplishes dual functions in cell-cycle control and transcription not through promiscuity but through distinct, stringent modes of substrate recognition.

Original languageEnglish (US)
Pages (from-to)55-62
Number of pages8
JournalNature Structural and Molecular Biology
Volume13
Issue number1
DOIs
StatePublished - Jan 1 2006
Externally publishedYes

ASJC Scopus subject areas

  • Structural Biology
  • Molecular Biology

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    Larochelle, S., Batliner, J., Gamble, M. J., Barboza, N. M., Kraybill, B. C., Blethrow, J. D., Shokat, K. M., & Fisher, R. P. (2006). Dichotomous but stringent substrate selection by the dual-function Cdk7 complex revealed by chemical genetics. Nature Structural and Molecular Biology, 13(1), 55-62. https://doi.org/10.1038/nsmb1028