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Kinetic mechanism of activation of the cdk2/cyclin a complex

Academic Article
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Overview

authors

  • Morris, M. C.
  • Gondeau, C.
  • Tainer, John
  • Divita, G.

publication date

  • June 2002

journal

  • Journal of Biological Chemistry  Journal

abstract

  • Eukaryotic cell cycle progression is controlled by the ordered action of cyclin-dependent kinases, activation of which occurs through the binding of the cyclin to the Cdk followed by phosphorylation of a conserved threonine in the T-loop of the Cdk by Cdk-activating kinase (CAK). Despite our understanding of the structural changes, which occur upon Cdk/cyclin formation and activation, little is known about the dynamics of the molecular events involved. We have characterized the mechanism of Cdk2/cyclin A complex formation and activation at the molecular and dynamic level by rapid kinetics and demonstrate here that it is a two-step process. The first step involves the rapid association between the PSTAIRE helix of Cdk2 and helices 3 and 5 of the cyclin to yield an intermediate complex in which the threonine in the T-loop is not accessible for phosphorylation. Additional contacts between the C-lobe of the Cdk and the N-terminal helix of the cyclin then induce the isomerization of the Cdk into a fully mature form by promoting the exposure of the T-loop for phosphorylation by CAK and the formation of the substrate binding site. This conformational change is selective for the cyclin partner.

subject areas

  • Amino Acid Motifs
  • CDC2-CDC28 Kinases
  • Cyclin A
  • Cyclin-Dependent Kinase 2
  • Cyclin-Dependent Kinases
  • Kinetics
  • Phosphorylation
  • Protein Conformation
  • Protein-Serine-Threonine Kinases
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Identity

International Standard Serial Number (ISSN)

  • 0021-9258

Digital Object Identifier (DOI)

  • 10.1074/jbc.M107890200

PubMed ID

  • 11959850
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Additional Document Info

start page

  • 23847

end page

  • 23853

volume

  • 277

issue

  • 26

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