telomere maintenance via telomere trimming / chromosomal region / telomeric 3' overhang formation / Mre11 complex / positive regulation of DNA catabolic process / establishment of RNA localization to telomere / positive regulation of telomerase catalytic core complex assembly / blastocyst growth / positive regulation of DNA damage response, signal transduction by p53 class mediator / cellular response to nitrosative stress ...telomere maintenance via telomere trimming / chromosomal region / telomeric 3' overhang formation / Mre11 complex / positive regulation of DNA catabolic process / establishment of RNA localization to telomere / positive regulation of telomerase catalytic core complex assembly / blastocyst growth / positive regulation of DNA damage response, signal transduction by p53 class mediator / cellular response to nitrosative stress / establishment of protein-containing complex localization to telomere / regulation of microglial cell activation / negative regulation of telomere capping / protection from non-homologous end joining at telomere / Sensing of DNA Double Strand Breaks / BRCA1-C complex / positive regulation of telomere maintenance via telomere lengthening / telomere maintenance in response to DNA damage / R-loop processing / meiotic telomere clustering / phosphorylation-dependent protein binding / t-circle formation / DNA-dependent protein kinase activity / histone H2AXS139 kinase activity / male meiotic nuclear division / histone mRNA catabolic process / pre-B cell allelic exclusion / female meiotic nuclear division / chromatin-protein adaptor activity / pexophagy / DNA strand resection involved in replication fork processing / DNA double-strand break processing / cellular response to X-ray / regulation of telomere maintenance via telomerase / homologous recombination / nuclear inclusion body / peptidyl-serine autophosphorylation / lipoprotein catabolic process / V(D)J recombination / positive regulation of telomere maintenance / oocyte development / isotype switching / Impaired BRCA2 binding to PALB2 / protein localization to site of double-strand break / HDR through MMEJ (alt-NHEJ) / mitotic G2/M transition checkpoint / positive regulation of kinase activity / reciprocal meiotic recombination / DNA repair complex / Defective homologous recombination repair (HRR) due to BRCA1 loss of function / Defective HDR through Homologous Recombination Repair (HRR) due to PALB2 loss of BRCA1 binding function / Defective HDR through Homologous Recombination Repair (HRR) due to PALB2 loss of BRCA2/RAD51/RAD51C binding function / Homologous DNA Pairing and Strand Exchange / Resolution of D-loop Structures through Synthesis-Dependent Strand Annealing (SDSA) / regulation of DNA-templated DNA replication initiation / DNA duplex unwinding / Resolution of D-loop Structures through Holliday Junction Intermediates / HDR through Single Strand Annealing (SSA) / Impaired BRCA2 binding to RAD51 / 1-phosphatidylinositol-3-kinase activity / response to ionizing radiation / mitotic spindle assembly checkpoint signaling / double-strand break repair via alternative nonhomologous end joining / TP53 Regulates Transcription of Caspase Activators and Caspases / negative regulation of B cell proliferation / mitotic G2 DNA damage checkpoint signaling / Presynaptic phase of homologous DNA pairing and strand exchange / TP53 Regulates Transcription of Genes Involved in Cytochrome C Release / peroxisomal matrix / protein K63-linked ubiquitination / neuromuscular process controlling balance / positive regulation of cell adhesion / positive regulation of double-strand break repair via homologous recombination / DNA damage response, signal transduction by p53 class mediator / replicative senescence / Regulation of HSF1-mediated heat shock response / neuroblast proliferation / signal transduction in response to DNA damage / somitogenesis / regulation of cellular response to heat / cellular response to retinoic acid / ovarian follicle development / positive regulation of protein autophosphorylation / negative regulation of TORC1 signaling / positive regulation of telomere maintenance via telomerase / DNA damage response, signal transduction by p53 class mediator resulting in cell cycle arrest / Pexophagy / telomere maintenance / protein serine/threonine kinase activator activity / intrinsic apoptotic signaling pathway / post-embryonic development / thymus development / meiotic cell cycle / regulation of signal transduction by p53 class mediator / replication fork / DNA damage checkpoint signaling / regulation of autophagy / determination of adult lifespan / TP53 Regulates Transcription of DNA Repair Genes / Nonhomologous End-Joining (NHEJ) 類似検索 - 分子機能
Nibrin, C-terminal / Nibrin / DNA damage repair protein Nbs1 / DNA damage repair protein Nbs1 / Nibrin, second BRCT domain / Nibrin, second BRCT domain superfamily / Second BRCT domain on Nijmegen syndrome breakage protein / Nibrin-related / Telomere-length maintenance and DNA damage repair / Serine/threonine-protein kinase ATM, plant ...Nibrin, C-terminal / Nibrin / DNA damage repair protein Nbs1 / DNA damage repair protein Nbs1 / Nibrin, second BRCT domain / Nibrin, second BRCT domain superfamily / Second BRCT domain on Nijmegen syndrome breakage protein / Nibrin-related / Telomere-length maintenance and DNA damage repair / Serine/threonine-protein kinase ATM, plant / ATM, catalytic domain / Telomere-length maintenance and DNA damage repair / Telomere-length maintenance and DNA damage repair / FATC domain / PIK-related kinase, FAT / FAT domain / Forkhead associated domain / FATC / Forkhead-associated (FHA) domain profile. / FATC domain / PIK-related kinase / FAT domain profile. / FATC domain profile. / FHA domain / Forkhead-associated (FHA) domain / SMAD/FHA domain superfamily / BRCA1 C Terminus (BRCT) domain / Phosphatidylinositol 3- and 4-kinases signature 1. / Phosphatidylinositol 3/4-kinase, conserved site / Phosphatidylinositol 3- and 4-kinases signature 2. / Phosphatidylinositol 3-/4-kinase, catalytic domain superfamily / Phosphoinositide 3-kinase, catalytic domain / Phosphatidylinositol 3- and 4-kinase / Phosphatidylinositol 3- and 4-kinases catalytic domain profile. / Phosphatidylinositol 3-/4-kinase, catalytic domain / BRCT domain / BRCT domain superfamily / Armadillo-type fold / Protein kinase-like domain superfamily 類似検索 - ドメイン・相同性
National Institutes of Health/National Cancer Institute (NIH/NCI)
5F32CA247320
米国
National Institutes of Health/Eunice Kennedy Shriver National Institute of Child Health & Human Development (NIH/NICHD)
CA008748
米国
引用
ジャーナル: Elife / 年: 2022 タイトル: Structure of the human ATM kinase and mechanism of Nbs1 binding. 著者: Christopher Warren / Nikola P Pavletich / 要旨: DNA double-strand breaks (DSBs) can lead to mutations, chromosomal rearrangements, genome instability, and cancer. Central to the sensing of DSBs is the ATM (Ataxia-telangiectasia mutated) kinase, ...DNA double-strand breaks (DSBs) can lead to mutations, chromosomal rearrangements, genome instability, and cancer. Central to the sensing of DSBs is the ATM (Ataxia-telangiectasia mutated) kinase, which belongs to the phosphatidylinositol 3-kinase-related protein kinase (PIKK) family. In response to DSBs, ATM is activated by the MRN (Mre11-Rad50-Nbs1) protein complex through a poorly understood process that also requires double-stranded DNA. Previous studies indicate that the FxF/Y motif of Nbs1 directly binds to ATM, and is required to retain active ATM at sites of DNA damage. Here, we report the 2.5 Å resolution cryo-EM structures of human ATM and its complex with the Nbs1 FxF/Y motif. In keeping with previous structures of ATM and its yeast homolog Tel1, the dimeric human ATM kinase adopts a symmetric, butterfly-shaped structure. The conformation of the ATM kinase domain is most similar to the inactive states of other PIKKs, suggesting that activation may involve an analogous realigning of the N and C lobes along with relieving the blockage of the substrate-binding site. We also show that the Nbs1 FxF/Y motif binds to a conserved hydrophobic cleft within the Spiral domain of ATM, suggesting an allosteric mechanism of activation. We evaluate the importance of these structural findings with mutagenesis and biochemical assays.
履歴
登録
2021年10月13日
登録サイト: RCSB / 処理サイト: RCSB
改定 1.0
2022年2月2日
Provider: repository / タイプ: Initial release
改定 1.1
2024年6月5日
Group: Data collection / カテゴリ: chem_comp_atom / chem_comp_bond