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From Proteopedia
Structure of nucleotide-bound Tel1/ATM
Structural highlights
FunctionATM_YEAST Serine/threonine protein kinase which activates checkpoint signaling upon genotoxic stresses such as ionizing radiation (IR), ultraviolet light (UV), or DNA replication stalling, thereby acting as a DNA damage sensor. Recognizes the substrate consensus sequence [ST]-Q. Recruited by the MRX-complex to sites of DNA lesions immediately after damage to initiate non-homologous end-joining (NHEJ). Subsequently displaced by the RPA complex in a reaction probably involving the SAE2 protein. Phosphorylates MRE11 and XRS2, 2 subunits of the MRX-complex. The phosphorylation of MRE11 is a feedback response from the checkpoint signaling pathway. Phosphorylates RAD9, CHK1 and RAD53, leading to the activation of the CHK1 and RAD23 kinases involved in the DNA damage response cascade. Phosphorylates histone H2A to form H2AS128ph (gamma-H2A) at sites of DNA damage, also involved in the regulation of DNA damage response mechanism. Phosphorylates also SLX4 and RTT107 which are involved in genome stability. Required for the control of telomere length and genome stability.[1] [2] [3] [4] [5] [6] [7] [8] [9] [10] [11] [12] [13] Publication Abstract from PubMedYeast 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. Cryo-EM Structure of Nucleotide-Bound Tel1(ATM) Unravels the Molecular Basis of Inhibition and Structural Rationale for Disease-Associated Mutations.,Yates LA, Williams RM, Hailemariam S, Ayala R, Burgers P, Zhang X Structure. 2019 Nov 4. pii: S0969-2126(19)30353-3. doi:, 10.1016/j.str.2019.10.012. PMID:31740029[14] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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