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

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 approximately 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.
Mesh Terms:
Adenosine Triphosphate, Amino Acid Sequence, Cell Extracts, Cell Nucleus, Conserved Sequence, Cyclin-Dependent Kinases, Enzyme Activation, HeLa Cells, Humans, Molecular Sequence Data, Phosphorylation, Protein Binding, Sequence Alignment, Substrate Specificity
Nat. Struct. Mol. Biol.
Date: Jan. 01, 2006
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