Reviewed,
UniProtKB/Swiss-Prot Q13315 (ATM_HUMAN)
Last modified
November 25, 2008.
Version 113.
History...
Clusters with 100%,
90%,
50% identity |
Documents (6) |
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Names and origin
| Protein names | Recommended name: Serine-protein kinase ATM EC=2.7.11.1 Alternative name(s): Ataxia telangiectasia mutated Short name=A-T, mutated | ||
| Gene names |
| ||
| Organism | Homo sapiens (Human) | ||
| Taxonomic identifier | 9606 [NCBI] | ||
| Taxonomic lineage | Eukaryota › Metazoa › Chordata › Craniata › Vertebrata › Euteleostomi › Mammalia › Eutheria › Euarchontoglires › Primates › Haplorrhini › Catarrhini › Hominidae › Homo |
Protein attributes
| Sequence length | 3056 AA. |
| Sequence status | Complete. |
| Sequence processing | The displayed sequence is not processed. |
| Protein existence | Evidence at protein level. |
General annotation (Comments)
| Function | Serine/threonine protein kinase which activates checkpoint signaling upon double strand breaks (DSBs), apoptosis and genotoxic stresses such as ionizing ultraviolet A light (UVA), thereby acting as a DNA damage sensor. Recognizes the substrate consensus sequence [ST]-Q. Phosphorylates 'Ser-139' of histone variant H2AX/H2AFX at double strand breaks (DSBs), thereby regulating DNA damage response mechanism. Also involved in signal transduction and cell cycle control. May function as a tumor suppressor. Necessary for activation of ABL1 and SAPK. Phosphorylates p53/TP53, FANCD2, NFKBIA, BRCA1, CTIP, nibrin (NBN), TERF1, RAD9 and DCLRE1C. May play a role in vesicle and/or protein transport. Could play a role in T-cell development, gonad and neurological function. |
| Catalytic activity | ATP + a protein = ADP + a phosphoprotein. |
| Enzyme regulation | Inhibited by wortmannin. |
| Subunit structure | Exists in monomeric and tetrameric state. Binds DNA ends, p53/TP53, ABL1, BRCA1, NBN/nibrin and TERF1. Part of the BRCA1-associated genome surveillance complex (BASC), which contains BRCA1, MSH2, MSH6, MLH1, ATM, BLM, PMS2 and the RAD50-MRE11-NBN protein complex. This association could be a dynamic process changing throughout the cell cycle and within subnuclear domains. DNA damage promotes association with RAD17. Interacts with EEF1E1. This interaction, which takes place independently of TP53, is induced by DNA damage that may occur during genotoxic stress or cell growth. Interacts with DCLRE1C. Interacts with MYST1. Interacts with HTATIP. Interacts with OBFC2B. Interacts with ATMIN. |
| Subcellular location | Nucleus. Cytoplasmic vesicle. Note= Primarily nuclear. Found also in endocytic vesicles in association with beta-adaptin. |
| Tissue specificity | Found in pancreas, kidney, skeletal muscle, liver, lung, placenta, brain, heart, spleen, thymus, testis, ovary, small intestine, colon and leukocytes. |
| Induction | By ionizing radiation. |
| Domain | The FATC domain is required for interaction with HTATIP. |
| Post-translational modification | Phosphorylated by ARK5. Autophosphorylated on Ser-1981 upon DNA damage. Acetylated by HTATIP upon DNA damage; which is required for autophosphorylation and subsequent activation. |
| Involvement in disease | Defects in ATM are the cause of ataxia telangiectasia (AT) [MIM:208900]; also known as Louis-Bar syndrome, which includes four complementation groups: A, C, D and E. This rare recessive disorder is characterized by progressive cerebellar ataxia, dilation of the blood vessels in the conjunctiva and eyeballs, immunodeficiency, growth retardation and sexual immaturity. AT patients have a strong predisposition to cancer; about 30% of patients develop tumors, particularly lymphomas and leukemias. Cells from affected individuals are highly sensitive to damage by ionizing radiation and resistant to inhibition of DNA synthesis following irradiation. Defects in ATM contribute to T-cell acute lymphoblastic leukemia (TALL) and T-prolymphocytic leukemia (TPLL). TPLL is characterized by a high white blood cell count, with a predominance of prolymphocytes, marked splenomegaly, lymphadenopathy, skin lesions and serous effusion. The clinical course is highly aggressive, with poor response to chemotherapy and short survival time. TPLL occurs both in adults as a sporadic disease and in younger AT patients. Defects in ATM contribute to B-cell non-Hodgkin lymphomas (BNHL), including mantle cell lymphoma (MCL). Defects in ATM contribute to B-cell chronic lymphocytic leukemia (BCLL). BCLL is the commonest form of leukemia in the elderly. It is characterized by the accumulation of mature CD5+ B lymphocytes, lymphadenopathy, immunodeficiency and bone marrow failure. |
| Sequence similarities | Belongs to the PI3/PI4-kinase family. ATM subfamily. Contains 1 FAT domain. Contains 1 FATC domain. Contains 1 PI3K/PI4K domain. |
Ontologies
Binary interactions
With | Entry | #Exp. | IntAct | Notes |
|---|---|---|---|---|
| AATF | Q9NY61 | 2 | EBI-495465,EBI-372428 | |
| ABL1 | P00519 | 1 | EBI-495465,EBI-375543 | |
| MDC1 | Q14676 | 1 | EBI-495465,EBI-495644 | |
| PPP1CA | P62136 | 1 | EBI-495465,EBI-357253 | |
| PPP1CC | P36873-1 | 1 | EBI-495465,EBI-356289 | |
| SMC1A | Q14683 | 1 | EBI-495465,EBI-80690 | |
| TELO2 | Q9Y4R8 | 1 | EBI-495465,EBI-1043674 | |
| TERF1 | P54274 | 1 | EBI-495465,EBI-710997 | |
| TERF1 | P54274-1 | 1 | EBI-495465,EBI-711014 | |
| TERF1 | P54274-2 | 4 | EBI-495465,EBI-711018 | |
| Tp53 | P02340 | 1 | EBI-495465,EBI-474016 | From a different organism. |
Sequence annotation (Features)
| Feature key | Position(s) | Length | Description | Graphical view | Feature identifier | ||||
Molecule processing | |||||||||
|---|---|---|---|---|---|---|---|---|---|
| Chain | 1 – 3056 | 3056 | Serine-protein kinase ATM | PRO_0000088840 | |||||
Regions | |||||||||
| Domain | 1960 – 2566 | 607 | FAT | ||||||
| Domain | 2712 – 2962 | 251 | PI3K/PI4K | ||||||
| Domain | 3024 – 3056 | 33 | FATC | ||||||
| Region | 1373 – 1382 | 10 | Interaction with ABL1 | ||||||
Amino acid modifications | |||||||||
| Modified residue | 72 | 1 | Phosphothreonine | ||||||
| Modified residue | 85 | 1 | Phosphoserine | ||||||
| Modified residue | 86 | 1 | Phosphothreonine | ||||||
| Modified residue | 367 | 1 | Phosphoserine | ||||||
| Modified residue | 373 | 1 | Phosphothreonine | ||||||
| Modified residue | 1981 | 1 | Phosphoserine; by autocatalysis | ||||||
| Modified residue | 1985 | 1 | Phosphothreonine | ||||||
Natural variations | |||||||||
| Natural variant | 23 | 1 | R → Q in a colorectal adenocarcinoma sample; somatic mutation. | VAR_041545 | |||||
| Natural variant | 49 | 1 | S → C: dbSNP rs1800054. | VAR_010798 | |||||
| Natural variant | 126 | 1 | D → E | VAR_010799 | |||||
| Natural variant | 140 | 1 | D → H | VAR_041546 | |||||
| Natural variant | 182 | 1 | V → L | VAR_010800 | |||||
| Natural variant | 224 | 1 | K → E in AT. | VAR_010801 | |||||
| Natural variant | 250 | 1 | R → Q | VAR_041547 | |||||
| Natural variant | 292 | 1 | P → L in AT; associated with lymphoma. | VAR_010802 | |||||
| Natural variant | 323 | 1 | I → V in AT. | VAR_010803 | |||||
| Natural variant | 332 | 1 | Y → C in B-cell chronic lymphocytic leukemia. | VAR_010804 | |||||
| Natural variant | 333 | 1 | S → F | VAR_041548 | |||||
| Natural variant | 337 | 1 | R → C in a colorectal adenocarcinoma sample; somatic mutation. | VAR_041549 | |||||
| Natural variant | 337 | 1 | R → H in a colorectal adenocarcinoma sample; somatic mutation. | VAR_041550 | |||||
| Natural variant | 350 | 1 | A → T in B-cell chronic lymphocytic leukemia. | VAR_010805 | |||||
| Natural variant | 352 | 1 | I → T in B-cell chronic lymphocytic leukemia. | VAR_010806 | |||||
| Natural variant | 410 | 1 | V → A | VAR_041551 | |||||
| Natural variant | 504 | 1 | N → S | VAR_041552 | |||||
| Natural variant | 514 | 1 | G → D | VAR_010807 | |||||
| Natural variant | 540 | 1 | C → Y in a colorectal adenocarcinoma sample; somatic mutation. | VAR_041553 | |||||
| Natural variant | 546 | 1 | L → V | VAR_041554 | |||||
| Natural variant | 570 | 1 | F → S in AT. | VAR_010808 | |||||
| Natural variant | 582 | 1 | F → L | VAR_041555 | |||||
| Natural variant | 705 – 707 | 3 | YSS → FIP in AT; might be associated with susceptibility to cancer. | VAR_010809 | |||||
| Natural variant | 707 | 1 | S → P | VAR_010810 | |||||
| Natural variant | 750 | 1 | N → K in mantle cell lymphoma. | VAR_010811 | |||||
| Natural variant | 768 | 1 | N → D in AT. | VAR_010812 | |||||
| Natural variant | 785 | 1 | R → C in AT. | VAR_010813 | |||||
| Natural variant | 848 | 1 | E → Q in a lung adenocarcinoma sample; somatic mutation. | VAR_041556 | |||||
| Natural variant | 858 | 1 | F → L Rare polymorphism. dbSNP rs1800056. | VAR_010814 | |||||
| Natural variant | 872 | 1 | P → S | VAR_041557 | |||||
| Natural variant | 924 | 1 | R → W | VAR_041558 | |||||
| Natural variant | 935 | 1 | T → A | VAR_041559 | |||||
| Natural variant | 950 | 1 | L → R in AT. | VAR_010815 | |||||
| Natural variant | 1001 | 1 | L → Q in AT; associated with T-cell acute lymphoblastic leukemia. | VAR_010816 | |||||
| Natural variant | 1040 | 1 | M → V in B-cell non-Hodgkin lymphoma. | VAR_010817 | |||||
| Natural variant | 1054 | 1 | P → R: dbSNP rs1800057. | VAR_010818 | |||||
| Natural variant | 1082 | 1 | H → L in AT. | VAR_010819 | |||||
| Natural variant | 1091 | 1 | E → D in AT. | VAR_010820 | |||||
| Natural variant | 1179 | 1 | S → F in a gastric adenocarcinoma sample; somatic mutation. | VAR_041560 | |||||
| Natural variant | 1321 | 1 | M → I | VAR_041561 | |||||
| Natural variant | 1380 | 1 | H → Y | VAR_041562 | |||||
| Natural variant | 1382 | 1 | P → S | VAR_041563 | |||||
| Natural variant | 1407 | 1 | I → T in T-prolymphocytic leukemia. | VAR_010821 | |||||
| Natural variant | 1420 | 1 | L → F Rare polymorphism. dbSNP rs1800058. | VAR_010822 | |||||
| Natural variant | 1420 | 1 | L → P in AT. | VAR_010823 | |||||
| Natural variant | 1454 | 1 | K → N | VAR_010824 | |||||
| Natural variant | 1463 | 1 | F → S in B-cell non-Hodgkin lymphoma. | VAR_010825 | |||||
| Natural variant | 1465 | 1 | L → P in AT. | VAR_010826 | |||||
| Natural variant | 1469 | 1 | I → M in a renal papillary cancer sample; somatic mutation. | VAR_041564 | |||||
| Natural variant | 1475 | 1 | Y → C | VAR_041565 | |||||
| Natural variant | 1566 | 1 | P → R in AT. | VAR_010827 | |||||
| Natural variant | 1570 | 1 | V → A | VAR_010828 | |||||
| Natural variant | 1650 | 1 | N → S | VAR_041566 | |||||
| Natural variant | 1682 | 1 | D → H in T-prolymphocytic leukemia. | VAR_010829 | |||||
| Natural variant | 1691 | 1 | S → R in AT and B-cell chronic lymphocytic leukemia; could be a rare polymorphism. dbSNP rs1800059. | VAR_010830 | |||||
| Natural variant | 1739 | 1 | N → T in a colorectal adenocarcinoma sample; somatic mutation. | VAR_041567 | |||||
| Natural variant | 1743 | 1 | T → I in AT; associated with preleukemic T-cell proliferation. | VAR_010831 | |||||
| Natural variant | 1812 – 1813 | 2 | AF → V in AT. | VAR_010832 | |||||
| Natural variant | 1853 | 1 | D → N Common polymorphism. dbSNP rs1801516. | VAR_010833 | |||||
| Natural variant | 1853 | 1 | D → V Might contribute to B-cell chronic lymphocytic leukemia. dbSNP rs1801673. | VAR_010834 | |||||
| Natural variant | 1910 | 1 | L → H in T-prolymphocytic leukemia. | VAR_010835 | |||||
| Natural variant | 1913 | 1 | V → G in AT. | VAR_010836 | |||||
| Natural variant | 1916 | 1 | M → I in a breast pleomorphic lobular carcinoma sample; somatic mutation. | VAR_041568 | |||||
| Natural variant | 1945 | 1 | A → T in a colorectal adenocarcinoma sample; somatic mutation. | VAR_041569 | |||||
| Natural variant | 1953 | 1 | T → R in B-cell chronic lymphocytic leukemia. | VAR_010837 | |||||
| Natural variant | 1961 | 1 | Y → C | VAR_041570 | |||||
| Natural variant | 1983 | 1 | S → N | VAR_041571 | |||||
| Natural variant | 1991 | 1 | E → D in a renal clear cell carcinoma sample; somatic mutation. | ||||||

Clusters with