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Nat Chem Biol. 2008 Jan;4(1):25-32. Epub 2007 Nov 25.

Molecular basis of cyclin-CDK-CKI regulation by reversible binding of an inositol pyrophosphate.

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  • 1Howard Hughes Medical Institute, Harvard University, Department of Molecular and Cellular Biology, Faculty of Arts and Sciences Center for Systems Biology, 7 Divinity Avenue, Cambridge, Massachusetts 02138, USA.

Abstract

When Saccharomyces cerevisiae cells are starved of inorganic phosphate, the Pho80-Pho85 cyclin-cyclin-dependent kinase (CDK) is inactivated by the Pho81 CDK inhibitor (CKI). The regulation of Pho80-Pho85 is distinct from previously characterized mechanisms of CDK regulation: the Pho81 CKI is constitutively associated with Pho80-Pho85, and a small-molecule ligand, inositol heptakisphosphate (IP7), is required for kinase inactivation. We investigated the molecular basis of the IP7- and Pho81-dependent Pho80-Pho85 inactivation using electrophoretic mobility shift assays, enzyme kinetics and fluorescence spectroscopy. We found that IP7 interacts noncovalently with Pho80-Pho85-Pho81 and induces additional interactions between Pho81 and Pho80-Pho85 that prevent substrates from accessing the kinase active site. Using synthetic peptides corresponding to Pho81, we define regions of Pho81 responsible for constitutive Pho80-Pho85 binding and IP7-regulated interaction and inhibition. These findings expand our understanding of the mechanisms of cyclin-CDK regulation and of the biochemical mechanisms of IP7 action.

Comment in

  • IP7 guards the CDK gate. [Nat Chem Biol. 2008]
PMID:
18059263
[PubMed - indexed for MEDLINE]
PMCID:
PMC2367112
Free PMC Article

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