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Chk2 oligomerization studied by phosphopeptide ligation: implications for regulation and phosphodependent

Jiejin Li1, Ian A Taylor, Janette Lloyd

  • 1Division of Molecular Structure, MRC National Institute for Medical Research, The Ridgeway, London NW7 1AA, United Kingdom.

The Journal of Biological Chemistry
|October 25, 2008
PubMed

Insights

DNA damage kinase Chk2 (CHEK2) activation involves dimerization. Thr-68 phosphorylation stabilizes Chk2 dimers, which are then dissociated by Ser-140 autophosphorylation, revealing a novel activation mechanism.

Area of Science:

  • Molecular Biology
  • Biochemistry
  • Cell Signaling

Background:

  • Checkpoint kinase 2 (Chk2) is a key serine-threonine kinase in DNA damage signal transduction.
  • Activation of Chk2 by ataxia telangiectasia-mutated kinase (ATM) involves phosphorylation and self-association.

Purpose of the Study:

  • To investigate the structural and functional role of Chk2 N-terminal regulatory region dimerization in kinase activation.
  • To elucidate the mechanism of Chk2 dimer dissociation following activation.

Main Methods:

  • Expressed protein ligation to generate the Chk2 N-terminal regulatory region.
  • Hydrodynamic analysis to study protein interactions.
  • Biochemical assays to investigate phosphorylation-dependent interactions.

Main Results:

  • Phosphorylation of Thr-68 stabilizes Chk2 N-terminal regulatory region into a high-affinity dimer.
  • Dimerization modulates phosphodependent interactions with effector proteins and substrates.
  • Intra-dimer autophosphorylation at Ser-140 releases the dimer-occluded pThr-68 motif, leading to dimer dissociation.

Conclusions:

  • Chk2 dimerization, regulated by Thr-68 phosphorylation, is a prerequisite for activation.
  • Ser-140 autophosphorylation triggers Chk2 dimer dissociation, providing a mechanism for kinase domain activation and signal termination.

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