Structural highlights
Publication Abstract from PubMed
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.
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[1]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
References
- ↑ Yates LA, Williams RM, Hailemariam S, Ayala R, Burgers P, Zhang X. Cryo-EM Structure of Nucleotide-Bound Tel1(ATM) Unravels the Molecular Basis of Inhibition and Structural Rationale for Disease-Associated Mutations. Structure. 2019 Nov 4. pii: S0969-2126(19)30353-3. doi:, 10.1016/j.str.2019.10.012. PMID:31740029 doi:http://dx.doi.org/10.1016/j.str.2019.10.012
