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ATM protein (Ataxia Telangiectasia mutated)

Protein product of gene mutated in ataxia telangiectasia Function: - serine/threonine protein kinas - activates checkpoint signaling upon double strand breaks), apoptosis & genotoxic stresses, including ionizing ultraviolet light, thus acting as a DNA damage sensor - role in cell-cycle control at G1->S & G2->M boundaries - phosphorylates many proteins in response to DNA damage - recognizes substrate consensus sequence [ST]-Q - phosphorylates Ser-139 of histone variant H2AX/H2AFX at double strand breaks (DSBs), thereby regulating DNA damage response mechanism - role in signal transduction & cell cycle control - may function as a tumor suppressor - necessary for activation of ABL1 & SAPK - phosphorylates p53/TP53, FANCD2, NFKBIA, BRCA1, CTIP, nibrin, TERF1, RAD9 & DCLRE1C - phosphorylated by ARK5 - autophosphorylated on Ser-1981 upon DNA damage - acetylated by HTATIP upon DNA damage, required for autophosphorylation & subsequent activation - role in vesicle &/or protein transport - role in T-cell development, gonad & neurological function - binds DNA ends, p53/TP53, ABL1, BRCA1, NBN/nibrin & TERF1 - component of BRCA1-associated genome surveillance complex (BASC) - association could be a dynamic process changing throughout cell cycle & within subnuclear domains - DNA damage promotes association with RAD17 - interaction with EEF1E1, independent of TP53, induced by DNA damage - interacts with DCLRE1C - interacts with MYST1 - HTATIP. - unlike p53-deficient cells, ATM-deficient cells show no impairment of DNA damage-induced apoptosis ATP + a protein = ADP + a phosphoprotein Inhibited by wortmannin Structure: - monomeric & tetrameric states - belongs to the PI3/PI4-kinase family, ATM subfamily - contains 1 FAT domain - contains 1 FATC domain, required for interaction with HTATIP - contains 1 PI3K/PI4K domain - C-terminal region is homologous to PI-3-kinase p110 subunit, thus the assignment as a kinase Compartment: - nucleus, cytoplasmic vesicle - primarily nuclear - found also in endocytic vesicles in association with beta-adaptin Expression: - expressed in pancreas, kidney, skeletal muscle, liver, lung, placenta, brain, heart, spleen, thymus, testis, ovary, small intestine, colon, leukocytes - induced by ionizing radiation Pathology: - defects in ATM are the cause of ataxia telangiectasia - defects in ATM contribute to T-cell ALL & T cell prolymphocytic leukemia - defects in ATM contribute to B-cell non-Hodgkin lymphomas including mantle cell lymphoma - defects in ATM may contribute to B-cell CLL

Interactions

molecular events

Related

ataxia telangiectasia; Louis-Bar syndrome ATM gene (Ataxia Telangiectasia mutated) ATM gene mutation

General

anti-oncoprotein (tumor suppressor protein) serine/threonine kinase

Properties

SIZE: entity length = 3056 aa COMPARTMENT: cytoplasm cell nucleus MOTIF: Thr phosphorylation site {T72} Ser phosphorylation site {S85} Thr phosphorylation site {T86} Ser phosphorylation site {S367} Thr phosphorylation site {T373} interaction with ABL1 {1373-1382} FAT domain NAME: FAT domain SITE: 1960-2566 MOTIF: Tyr phosphorylation site binding site FOR-BINDING-OF: Paxillin Ser phosphorylation site {S1981} Thr phosphorylation site {T1985} PI3K/PI4K {2712-2962} FATC {3024-3056} STATE: active state

References

  1. Lavin MF, Khanna KK, Beamish H, Spring K, Watters D, Shiloh Y. Relationship of the ataxia-telangiectasia protein ATM to phosphoinositide 3-kinase. Trends Biochem Sci. 1995 Oct;20(10):382-3. Review. PMID: 8533147
  2. Entrez Gene :accession 472
  3. Uniprot :accession
  4. Ataxia talangiectasia mutation db http://benaroyaresearch.org/investigators/concannon_patrick/atm.htm
  5. Atlas of Genetics and Cytogenetics in Oncology and Haematology http://atlasgeneticsoncology.org/Genes/ATM123.html
  6. GeneReviews https://www.genecards.org/cgi-bin/carddisp.pl?gene=ATM
  7. Wikipedia ataxia telangiectasia mutated entry http://en.wikipedia.org/wiki/Ataxia_telangiectasia_mutated

Component-of

BRCA1-associated genome surveillance complex (BASC)

Databases & Figures

OMIM correlations MORBIDMAP 607585 UniProt Q13315 PFAM correlations Entrez Gene 472 KEGG correlations Figures/diagrams/slides/tables related to ATM protein