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Cryo-EM structure of nucleotide-bound Tel1ATM unravels the molecular basis of inhibition and structural rationale for disease-associated mutations

DOI: 10.1016/j.str.2019.10.012 DOI Help

Authors: Luke A. Yates (Imperial College London) , Rhys M. Williams (Imperial College London) , Sarem Hailemariam (Washington University School of Medicine) , Rafael Ayala (Imperial College London) , Peter Burgers (Washington University School of Medicine) , Xiaodong Zhang (Imperial College London)
Co-authored by industrial partner: No

Type: Journal Paper
Journal: Structure

State: Published (Approved)
Published: November 2019
Diamond Proposal Number(s): 19865

Open Access Open Access

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.

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

Subject Areas: Biology and Bio-materials

Diamond Offline Facilities: Electron Bio-Imaging Centre (eBIC)
Instruments: Krios III-Titan Krios III at Diamond

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