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A Guide to Production, Crystallization, and Structure Determination of Human IKK1/α
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A Guide to Production, Crystallization, and Structure Determination of Human IKK1/α

Published on: November 2, 2018

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Structure of the human dimeric ATM kinase

Wilson C Y Lau1,2, Yinyin Li3, Zhe Liu4

  • 1a School of Biomedical Sciences, The University of Hong Kong , Hong Kong.

Cell Cycle (Georgetown, Tex.)
|April 21, 2016
PubMed

Insights

The ataxia-telangiectasia mutated (ATM) protein kinase, crucial for DNA damage response, remains inactive as a dimer. Its structure reveals buried active sites, explaining how ATM is inhibited in its resting state.

Area of Science:

  • Biochemistry
  • Molecular Biology
  • Structural Biology

Background:

  • DNA double-strand breaks (DSBs) trigger cellular responses.
  • The serine/threonine protein kinase ataxia-telangiectasia mutated (ATM) is central to DNA damage signal transduction.
  • ATM activation involves autophosphorylation and dissociation of inactive dimers into active monomers.

Purpose of the Study:

  • To determine the structure of dimeric ATM in its resting state using single-particle electron microscopy (EM).
  • To understand the mechanism of ATM inhibition based on its structural organization.

Main Methods:

  • Single-particle electron microscopy (EM) to visualize dimeric ATM.
  • Integration of crystal structure data of N-terminal truncated mammalian target of rapamycin (mTOR) to localize ATM domains.

Main Results:

  • The structure of dimeric ATM in its resting state was determined.
  • The EM map allowed localization of N- and C-terminal regions of ATM by accommodating the mTOR crystal structure.
  • The dimeric ATM structure revealed that active sites are buried, restricting substrate access.

Conclusions:

  • The unanticipated domain organization of dimeric ATM explains its inhibited state.
  • This structural insight provides a foundation for understanding ATM regulation in DNA damage response.
Keywords:
ATM kinaseDNA damageDNA damage responsePIKKataxia telangiectasiaelectron microscopy (EM)post-translational modification (PTM)

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