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Updated: Jul 15, 2025

Author Spotlight: Deciphering the Role of ATM in Ataxia-Telangiectasia and the Associated Cerebellar Degeneration
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Author Spotlight: Deciphering the Role of ATM in Ataxia-Telangiectasia and the Associated Cerebellar Degeneration

Published on: December 27, 2024

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Structural insights into the activation of ataxia-telangiectasia mutated by oxidative stress

Anna C Howes1, Olga Perisic1, Roger L Williams1

  • 1MRC Laboratory of Molecular Biology, Cambridge CB2 0QH, UK.

Science Advances
|September 27, 2023
PubMed

Insights

Ataxia-telangiectasia mutated (ATM) kinase is activated by oxidative stress through a disulfide bond, causing structural changes that optimize its catalytic activity. This study reveals the mechanism of ATM activation by reactive oxygen species.

Area of Science:

  • Biochemistry
  • Molecular Biology
  • Structural Biology

Background:

  • Ataxia-telangiectasia mutated (ATM) is crucial for DNA damage response, activated by double-strand breaks.
  • The mechanism of ATM activation by reactive oxygen species (ROS) remains poorly understood.

Purpose of the Study:

  • To elucidate the structural basis of ATM activation by oxidative stress.
  • To provide insights into how ROS triggers ATM kinase activity.

Main Methods:

  • Cryo-electron microscopy (cryo-EM) to determine the structure of H2O2-activated ATM.
  • Structural analysis of ATM conformational changes upon oxidation.

Main Results:

  • Determined the cryo-EM structure of H2O2-activated ATM, revealing an intramolecular disulfide bridge.
  • Observed protomer rotation and release of the substrate-blocking PRD region in oxidized ATM.
  • Identified N-lobe/C-lobe twisting that optimizes catalysis and enabled p53 substrate capture.

Conclusions:

  • Oxidative activation of ATM involves specific structural rearrangements, including disulfide bond formation and domain repositioning.
  • These structural changes enhance ATM's catalytic efficiency and substrate binding.
  • Provides the first structural evidence for ATM activation by oxidative stress.

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