Cryo-EM Structure of Nucleotide-Bound Tel1ATM Unravels the Molecular Basis of Inhibition and Structural Rationale for Disease-Associated Mutations

Luke A. Yates, Rhys M. Williams, Sarem Hailemariam, Rafael Ayala, Peter Burgers, Xiaodong Zhang

Research output: Contribution to journalArticlepeer-review

21 Scopus citations

Abstract

Yeast Tel1 and its highly conserved human ortholog ataxia-telangiectasia mutated (ATM) are large protein kinases central to the maintenance of genome integrity. Mutations in ATM are found in ataxia-telangiectasia (A-T) patients and ATM is one of the most frequently mutated genes in many cancers. Using cryoelectron microscopy, we present the structure of Tel1 in a nucleotide-bound state. Our structure reveals molecular details of key residues surrounding the nucleotide binding site and provides a structural and molecular basis for its intrinsically low basal activity. We show that the catalytic residues are in a productive conformation for catalysis, but the phosphatidylinositol 3-kinase-related kinase (PIKK) regulatory domain insert restricts peptide substrate access and the N-lobe is in an open conformation, thus explaining the requirement for Tel1 activation. Structural comparisons with other PIKKs suggest a conserved and common allosteric activation mechanism. Our work also provides a structural rationale for many mutations found in A-T and cancer. Yates et al. describe the cryo-EM structure of Tel1 kinase in a nucleotide-bound state. The 3.7 Å structure provides a structural basis for its intrinsically low basal activity and a potential allosteric activation mechanism, and further provides insight into the occurrence of many disease-associated mutations of its human ortholog ATM.

Original languageEnglish
Pages (from-to)96-104.e3
JournalStructure
Volume28
Issue number1
DOIs
StatePublished - Jan 7 2020

Keywords

  • Ataxia Telangiectasia
  • DNA damage response
  • DNA double-strand break repair
  • Serine/Threonine kinase
  • cryo-EM
  • genome integrity
  • phosphatidylinositol-3-kinase-like kinase
  • phosphorylation
  • telomere maintenance

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