Reviewed, UniProtKB/Swiss-Prot Q13315 (ATM_HUMAN)

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

Name:

ATM

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

Keywords
Biological process	Cell cycle DNA damage DNA repair
Cellular component	Cytoplasmic vesicle Nucleus
Coding sequence diversity	Polymorphism
Disease	Disease mutation Neurodegeneration
Ligand	DNA-binding
Molecular function	Anti-oncogene Kinase Serine/threonine-protein kinase Transferase
PTM	Phosphoprotein
Gene Ontology (GO)
Biological process	DNA repair Ref.18 Traceable author statement. Source: ProtInc mitotic cell cycle spindle assembly checkpoint Inferred from mutant phenotype. Source: UniProtKB negative regulation of cell cycle Inferred from electronic annotation. Source: UniProtKB-KW reciprocal meiotic recombination Ref.7 Traceable author statement. Source: ProtInc response to ionizing radiation Ref.26 Inferred from direct assay. Source: UniProtKB
Cellular component	cytoplasmic vesicle Inferred from electronic annotation. Source: UniProtKB-KW nucleoplasm Ref.20 Inferred from Experiment. Source: Reactome
Molecular function	1-phosphatidylinositol-3-kinase activity Ref.26 Inferred from mutant phenotype. Source: UniProtKB DNA binding Inferred from electronic annotation. Source: UniProtKB-KW protein N-terminus binding Ref.26 Inferred from direct assay. Source: UniProtKB protein serine/threonine kinase activity Ref.18 Ref.26 Inferred from direct assay. Source: UniProtKB
Complete GO annotation...

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.