InnateDB: Systems Biology of the Innate Immune Response

Homo sapiens Protein: ATM

Summary

InnateDB Protein

IDBP-382900.5

Last Modified

2014-10-13 [Report errors or provide feedback]

Gene Symbol

ATM

Protein Name

ataxia telangiectasia mutated

Synonyms

AT1; ATA; ATC; ATD; ATDC; ATE; TEL1; TELO1;

Species

Homo sapiens

Ensembl Protein

ENSP00000388058

InnateDB Gene

IDBG-70193 (ATM)

Protein Structure

UniProt Annotation

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 plays a role in pre-B cell allelic exclusion, a process leading to expression of a single immunoglobulin heavy chain allele to enforce clonality and monospecific recognition by the B-cell antigen receptor (BCR) expressed on individual B-lymphocytes. After the introduction of DNA breaks by the RAG complex on one immunoglobulin allele, acts by mediating a repositioning of the second allele to pericentromeric heterochromatin, preventing accessibility to the RAG complex and recombination of the second allele. Also involved in signal transduction and cell cycle control. May function as a tumor suppressor. Necessary for activation of ABL1 and SAPK. Phosphorylates DYRK2, CHEK2, 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. Plays a role in replication-dependent histone mRNA degradation. Binds DNA ends. Phosphorylation of DYRK2 in nucleus in response to genotoxic stress prevents its MDM2-mediated ubiquitination and subsequent proteasome degradation. Phosphorylates ATF2 which stimulates its function in DNA damage response. {ECO:0000269PubMed:10973490, ECO:0000269PubMed:12556884, ECO:0000269PubMed:14871926, ECO:0000269PubMed:15916964, ECO:0000269PubMed:16086026, ECO:0000269PubMed:16858402, ECO:0000269PubMed:17923702, ECO:0000269PubMed:19965871}.

Subcellular Localization

Nucleus. Cytoplasmic vesicle. Note=Primarily nuclear. Found also in endocytic vesicles in association with beta-adaptin.

Disease Associations

Ataxia telangiectasia (AT) [MIM:208900]: A rare recessive disorder characterized by progressive cerebellar ataxia, dilation of the blood vessels in the conjunctiva and eyeballs, immunodeficiency, growth retardation and sexual immaturity. 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. {ECO:0000269PubMed:10234507, ECO:0000269PubMed:10425038, ECO:0000269PubMed:10817650, ECO:0000269PubMed:10873394, ECO:0000269PubMed:7792600, ECO:0000269PubMed:8698354, ECO:0000269PubMed:8755918, ECO:0000269PubMed:8789452, ECO:0000269PubMed:8797579, ECO:0000269PubMed:8808599, ECO:0000269PubMed:8845835, ECO:0000269PubMed:9043869, ECO:0000269PubMed:9150358, ECO:0000269PubMed:9443866, ECO:0000269PubMed:9450874, ECO:0000269PubMed:9463314, ECO:0000269PubMed:9497252, ECO:0000269PubMed:9521587, ECO:0000269PubMed:9711876, ECO:0000269PubMed:9792409, ECO:0000269PubMed:9792410, ECO:0000269PubMed:9872980, ECO:0000269PubMed:9887333}. Note=The disease is caused by mutations affecting the gene represented in this entry.Note=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.Note=Defects in ATM contribute to B-cell non-Hodgkin lymphomas (BNHL), including mantle cell lymphoma (MCL).Note=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.

Tissue Specificity

Found in pancreas, kidney, skeletal muscle, liver, lung, placenta, brain, heart, spleen, thymus, testis, ovary, small intestine, colon and leukocytes.

Comments

Interactions

Number of Interactions

This gene and/or its encoded proteins are associated with 221 experimentally validated interaction(s) in this database.
They are also associated with 7 interaction(s) predicted by orthology.

Experimentally validated
Total	221 [view]
Protein-Protein	210 [view]
Protein-DNA	8 [view]
Protein-RNA	1 [view]
DNA-DNA	2 [view]
RNA-RNA	0
DNA-RNA	0

Predicted by orthology
Total	7 [view]

Gene Ontology

Molecular Function

Accession	GO Term
GO:0003677	DNA binding
GO:0004674	protein serine/threonine kinase activity
GO:0004677	DNA-dependent protein kinase activity
GO:0005488	binding
GO:0005515	protein binding
GO:0005524	ATP binding
GO:0016303	1-phosphatidylinositol-3-kinase activity
GO:0016772	transferase activity, transferring phosphorus-containing groups
GO:0016773	phosphotransferase activity, alcohol group as acceptor
GO:0032403	protein complex binding
GO:0046983	protein dimerization activity
GO:0047485	protein N-terminus binding

Biological Process

GO:0000723	telomere maintenance
GO:0000724	double-strand break repair via homologous recombination
GO:0002331	pre-B cell allelic exclusion
GO:0006281	DNA repair
GO:0006302	double-strand break repair
GO:0006468	protein phosphorylation
GO:0006974	cellular response to DNA damage stimulus
GO:0006975	DNA damage induced protein phosphorylation
GO:0006977	DNA damage response, signal transduction by p53 class mediator resulting in cell cycle arrest
GO:0007050	cell cycle arrest
GO:0007094	mitotic spindle assembly checkpoint
GO:0007131	reciprocal meiotic recombination
GO:0007165	signal transduction
GO:0010212	response to ionizing radiation
GO:0018105	peptidyl-serine phosphorylation
GO:0030889	negative regulation of B cell proliferation
GO:0036092	phosphatidylinositol-3-phosphate biosynthetic process
GO:0043065	positive regulation of apoptotic process
GO:0043517	positive regulation of DNA damage response, signal transduction by p53 class mediator
GO:0046777	protein autophosphorylation
GO:0071044	histone mRNA catabolic process
GO:0071480	cellular response to gamma radiation
GO:0072434	signal transduction involved in mitotic G2 DNA damage checkpoint
GO:0090399	replicative senescence

Cellular Component

GO:0000781	chromosome, telomeric region
GO:0005654	nucleoplasm
GO:0016023	cytoplasmic membrane-bounded vesicle

Protein Structure and Domains

PDB ID

InterPro

IPR000403 Phosphatidylinositol 3-/4-kinase, catalytic domain
IPR003151 PIK-related kinase, FAT
IPR003152 PIK-related kinase, FATC
IPR011009 Protein kinase-like domain
IPR014009 PIK-related kinase
IPR016024 Armadillo-type fold
IPR021668 Telomere-length maintenance and DNA damage repair

PFAM

PF00454
PF02259
PF02260
PF11640

PRINTS

PIRSF

SMART

SM00146

TIGRFAMs

Post-translational Modifications

Modification

Cross-References

SwissProt

Q13315