ID ATP7A_MOUSE Reviewed; 1491 AA. AC Q64430; A2AG69; O35101; P97422; Q64431; DT 01-NOV-1997, integrated into UniProtKB/Swiss-Prot. DT 27-JUL-2011, sequence version 3. DT 27-MAR-2024, entry version 211. DE RecName: Full=Copper-transporting ATPase 1; DE EC=7.2.2.8 {ECO:0000250|UniProtKB:Q04656}; DE AltName: Full=Copper pump 1; DE AltName: Full=Menkes disease-associated protein homolog; GN Name=Atp7a {ECO:0000303|PubMed:25639447, ECO:0000312|MGI:MGI:99400}; GN Synonyms=Mnk; OS Mus musculus (Mouse). OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia; OC Eutheria; Euarchontoglires; Glires; Rodentia; Myomorpha; Muroidea; Muridae; OC Murinae; Mus; Mus. OX NCBI_TaxID=10090; RN [1] RP NUCLEOTIDE SEQUENCE [MRNA], INVOLVEMENT IN MOTTLED PHENOTYPES, AND TISSUE RP SPECIFICITY. RC STRAIN=BALB/cJ; TISSUE=Brain; RX PubMed=8054976; DOI=10.1038/ng0494-369; RA Levinson B., Vulpe C., Elder B., Martin C., Verley F., Packman S., RA Gitschier J.; RT "The mottled gene is the mouse homologue of the Menkes disease gene."; RL Nat. Genet. 6:369-373(1994). RN [2] RP NUCLEOTIDE SEQUENCE [MRNA], AND INVOLVEMENT IN MOTTLED PHENOTYPES. RC STRAIN=BALB/cJ, DL, and ICR X Swiss Webster; RC TISSUE=Embryo, and Kidney; RX PubMed=8054977; DOI=10.1038/ng0494-374; RA Mercer J.F.B., Grimes A., Ambrosini L., Lockhart P., Paynter J.A., RA Dierick H., Glover T.W.; RT "Mutations in the murine homologue of the Menkes gene in dappled and RT blotchy mice."; RL Nat. Genet. 6:374-378(1994). RN [3] RP NUCLEOTIDE SEQUENCE [MRNA], INVOLVEMENT IN MOTTLED PHENOTYPES, AND VARIANTS RP ARG-674 AND PRO-1381. RC STRAIN=C3H/HeJ; TISSUE=Placenta; RX PubMed=9385451; DOI=10.1080/15216549700204721; RA Ohta Y., Shiraishi N., Nishikimi M.; RT "Occurrence of two missense mutations in Cu-ATPase of the macular mouse, a RT Menkes disease model."; RL Biochem. Mol. Biol. Int. 43:913-918(1997). RN [4] RP NUCLEOTIDE SEQUENCE [MRNA], INVOLVEMENT IN MOTTLED PHENOTYPES, AND TISSUE RP SPECIFICITY. RC STRAIN=CBA X C3H; RX PubMed=9215672; DOI=10.1093/hmg/6.7.1037; RA Grimes A., Hearn C.J., Lockhart P., Newgreen D.F., Mercer J.F.B.; RT "Molecular basis of the brindled mouse mutant (Mo(br)): a murine model of RT Menkes disease."; RL Hum. Mol. Genet. 6:1037-1042(1997). RN [5] RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA]. RC STRAIN=C57BL/6J; RX PubMed=19468303; DOI=10.1371/journal.pbio.1000112; RA Church D.M., Goodstadt L., Hillier L.W., Zody M.C., Goldstein S., She X., RA Bult C.J., Agarwala R., Cherry J.L., DiCuccio M., Hlavina W., Kapustin Y., RA Meric P., Maglott D., Birtle Z., Marques A.C., Graves T., Zhou S., RA Teague B., Potamousis K., Churas C., Place M., Herschleb J., Runnheim R., RA Forrest D., Amos-Landgraf J., Schwartz D.C., Cheng Z., Lindblad-Toh K., RA Eichler E.E., Ponting C.P.; RT "Lineage-specific biology revealed by a finished genome assembly of the RT mouse."; RL PLoS Biol. 7:E1000112-E1000112(2009). RN [6] RP FUNCTION, TISSUE SPECIFICITY, AND DEVELOPMENTAL STAGE. RX PubMed=12488345; DOI=10.1210/en.2002-220716; RA Steveson T.C., Ciccotosto G.D., Ma X.M., Mueller G.P., Mains R.E., RA Eipper B.A.; RT "Menkes protein contributes to the function of peptidylglycine alpha- RT amidating monooxygenase."; RL Endocrinology 144:188-200(2003). RN [7] RP FUNCTION, AND TISSUE SPECIFICITY. RX PubMed=15634787; DOI=10.1523/jneurosci.3699-04.2005; RA Schlief M.L., Craig A.M., Gitlin J.D.; RT "NMDA receptor activation mediates copper homeostasis in hippocampal RT neurons."; RL J. Neurosci. 25:239-246(2005). RN [8] RP FUNCTION, TISSUE SPECIFICITY, SUBCELLULAR LOCATION, AND INTERACTION WITH RP SOD3. RX PubMed=16371425; DOI=10.1096/fj.05-4564fje; RA Qin Z., Itoh S., Jeney V., Ushio-Fukai M., Fukai T.; RT "Essential role for the Menkes ATPase in activation of extracellular RT superoxide dismutase: implication for vascular oxidative stress."; RL FASEB J. 20:334-336(2006). RN [9] RP FUNCTION, TISSUE SPECIFICITY, SUBCELLULAR LOCATION, AND INTERACTION WITH RP TYRP1. RX PubMed=18650808; DOI=10.1038/nature07163; RA Setty S.R., Tenza D., Sviderskaya E.V., Bennett D.C., Raposo G., RA Marks M.S.; RT "Cell-specific ATP7A transport sustains copper-dependent tyrosinase RT activity in melanosomes."; RL Nature 454:1142-1146(2008). RN [10] RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-357 AND SER-1457, AND RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS]. RX PubMed=19144319; DOI=10.1016/j.immuni.2008.11.006; RA Trost M., English L., Lemieux S., Courcelles M., Desjardins M., RA Thibault P.; RT "The phagosomal proteome in interferon-gamma-activated macrophages."; RL Immunity 30:143-154(2009). RN [11] RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-357; SER-362; SER-1464; RP SER-1467 AND SER-1477, AND IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE RP ANALYSIS]. RC TISSUE=Brain, Kidney, Lung, Pancreas, and Testis; RX PubMed=21183079; DOI=10.1016/j.cell.2010.12.001; RA Huttlin E.L., Jedrychowski M.P., Elias J.E., Goswami T., Rad R., RA Beausoleil S.A., Villen J., Haas W., Sowa M.E., Gygi S.P.; RT "A tissue-specific atlas of mouse protein phosphorylation and expression."; RL Cell 143:1174-1189(2010). RN [12] RP FUNCTION, TISSUE SPECIFICITY, AND DISRUPTION PHENOTYPE. RX PubMed=25639447; DOI=10.1002/path.4511; RA Hodgkinson V.L., Dale J.M., Garcia M.L., Weisman G.A., Lee J., Gitlin J.D., RA Petris M.J.; RT "X-linked spinal muscular atrophy in mice caused by autonomous loss of RT ATP7A in the motor neuron."; RL J. Pathol. 236:241-250(2015). RN [13] RP FUNCTION, SUBCELLULAR LOCATION, DOMAIN, AND MUTAGENESIS OF RP 1443-LEU-LEU-1444; 1458-LEU-LEU-1459 AND 1478-LEU-LEU-1479. RX PubMed=27337370; DOI=10.1039/c6mt00093b; RA Zhu S., Shanbhag V., Hodgkinson V.L., Petris M.J.; RT "Multiple di-leucines in the ATP7A copper transporter are required for RT retrograde trafficking to the trans-Golgi network."; RL Metallomics 8:993-1001(2016). CC -!- FUNCTION: ATP-driven copper (Cu(+)) ion pump that plays an important CC role in intracellular copper ion homeostasis (PubMed:25639447, CC PubMed:27337370, PubMed:18650808). Within a catalytic cycle, acquires CC Cu(+) ion from donor protein on the cytoplasmic side of the membrane CC and delivers it to acceptor protein on the lumenal side. The transfer CC of Cu(+) ion across the membrane is coupled to ATP hydrolysis and is CC associated with a transient phosphorylation that shifts the pump CC conformation from inward-facing to outward-facing state (By CC similarity). Under physiological conditions, at low cytosolic copper CC concentration, it is localized at the trans-Golgi network (TGN) where CC it transfers Cu(+) ions to cuproenzymes of the secretory pathway CC (PubMed:27337370, PubMed:18650808, PubMed:16371425, PubMed:12488345). CC Upon elevated cytosolic copper concentrations, it relocalizes to the CC plasma membrane where it is responsible for the export of excess Cu(+) CC ions (By similarity). May play a dual role in neuron function and CC survival by regulating cooper efflux and neuronal transmission at the CC synapse as well as by supplying Cu(+) ions to enzymes such as PAM, TYR CC and SOD3 (PubMed:25639447, PubMed:15634787, PubMed:16371425, CC PubMed:12488345). In the melanosomes of pigmented cells, provides CC copper cofactor to TYR to form an active TYR holoenzyme for melanin CC biosynthesis (PubMed:18650808). {ECO:0000250|UniProtKB:Q04656}. CC -!- CATALYTIC ACTIVITY: CC Reaction=ATP + Cu(+)(in) + H2O = ADP + Cu(+)(out) + H(+) + phosphate; CC Xref=Rhea:RHEA:25792, ChEBI:CHEBI:15377, ChEBI:CHEBI:15378, CC ChEBI:CHEBI:30616, ChEBI:CHEBI:43474, ChEBI:CHEBI:49552, CC ChEBI:CHEBI:456216; EC=7.2.2.8; CC Evidence={ECO:0000250|UniProtKB:Q04656}; CC PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:25793; CC Evidence={ECO:0000250|UniProtKB:Q04656}; CC -!- SUBUNIT: Monomer. Interacts with PDZD11. Interacts with ATOX1 and CC COMMD1 (By similarity). Interacts with TYRP1 (PubMed:18650808). CC Directly interacts with SOD3; this interaction is copper-dependent and CC is required for SOD3 activity (PubMed:16371425). CC {ECO:0000250|UniProtKB:Q04656, ECO:0000269|PubMed:16371425, CC ECO:0000269|PubMed:18650808}. CC -!- SUBCELLULAR LOCATION: Golgi apparatus, trans-Golgi network membrane CC {ECO:0000269|PubMed:16371425, ECO:0000269|PubMed:18650808, CC ECO:0000269|PubMed:27337370}; Multi-pass membrane protein CC {ECO:0000255}. Cell membrane {ECO:0000269|PubMed:27337370}; Multi-pass CC membrane protein {ECO:0000255}. Melanosome membrane CC {ECO:0000269|PubMed:18650808}; Multi-pass membrane protein CC {ECO:0000255}. Early endosome membrane {ECO:0000269|PubMed:27337370}; CC Multi-pass membrane protein {ECO:0000255}. Cell projection, axon CC {ECO:0000250|UniProtKB:P70705}. Cell projection, dendrite CC {ECO:0000250|UniProtKB:P70705}. Postsynaptic density CC {ECO:0000250|UniProtKB:P70705}. Note=Cycles constitutively between the CC TGN and the plasma membrane. Predominantly found in the TGN and CC relocalized to the plasma membrane in response to elevated copper CC levels (PubMed:27337370). Targeting into melanosomes is regulated by CC BLOC-1 complex (PubMed:18650808). In response to glutamate translocates CC to neuron processes with a minor fraction at extrasynaptic sites (By CC similarity). {ECO:0000250|UniProtKB:P70705, CC ECO:0000269|PubMed:18650808, ECO:0000269|PubMed:27337370}. CC -!- TISSUE SPECIFICITY: Widely expressed (PubMed:25639447, PubMed:8054976, CC PubMed:12488345). Highly expressed in pituitary endocrine cells CC (PubMed:12488345). Expressed in melanocytes (at protein level) CC (PubMed:18650808). Expressed in motor neuron (at protein level) CC (PubMed:25639447). Expressed in hippocampal neuron (at protein level) CC (PubMed:15634787). In the kidney, it is detected in the proximal and CC distal tubules (at protein level) (PubMed:9215672). Expressed in aorta CC (at protein level) (PubMed:16371425). {ECO:0000269|PubMed:12488345, CC ECO:0000269|PubMed:15634787, ECO:0000269|PubMed:16371425, CC ECO:0000269|PubMed:18650808, ECO:0000269|PubMed:25639447, CC ECO:0000269|PubMed:8054976, ECO:0000269|PubMed:9215672}. CC -!- DEVELOPMENTAL STAGE: Detected 10 days after birth in pituitary and CC adrenal endocrine tissues and at a lower level in hypothalamus and CC atrium (at protein level). {ECO:0000269|PubMed:12488345}. CC -!- DOMAIN: The ATP binding site comprises residues located in alpha-1 and CC alpha-2 helices and beta-2 and beta-3 strands, which are involved in CC van der Waal's interactions, and Glu-1072 which forms an hydrogen bond CC with the adenine ring. {ECO:0000250|UniProtKB:Q04656}. CC -!- DOMAIN: The heavy-metal-associated domain (HMA) coordinates a Cu(+) ion CC via the cysteine residues within the CXXC motif. The transfer of Cu(+) CC ion from ATOX1 to ATP7A involves the formation of a three-coordinate CC Cu(+)-bridged heterodimer where the metal is shared between the two CC metal binding sites of ATOX1 and ATP7A. The Cu(+) ion appears to switch CC between two coordination modes, forming two links with one protein and CC one with the other. Cisplatin, a chemotherapeutic drug, can bind the CC CXXC motif and hinder the release of Cu(+) ion. CC {ECO:0000250|UniProtKB:Q04656}. CC -!- DOMAIN: Contains three di-leucine motifs in the C-terminus which are CC required for recycling from the plasma membrane to the TGN. The di- CC leucine 1478-Leu-Leu-1479 motif mediates endocytosis at the plasma CC membrane, whereas the di-leucine 1458-Leu-Leu-1459 motif is a sorting CC signal for retrograde trafficking to TGN via early endosomes. CC {ECO:0000269|PubMed:27337370}. CC -!- DISEASE: Note=Defects in Atp7a are associated with mottled, an X-linked CC recessive condition characterized by mottled pigmentation of the coat, CC defects in connective tissue and neonatal or fetal death. It is due to CC a defect in absorption and transport of copper. The mottled mutants CC exhibit a diversity of phenotypes. Two of these mutants are called CC brindled and blotchy and their phenotypes resemble classical Menkes CC disease (MD) and occipital horn syndrome (OHS) in humans, respectively. CC Other mutants are called dappled, mosaic, tortoiseshell, pewter, etc. CC {ECO:0000269|PubMed:8054976, ECO:0000269|PubMed:8054977, CC ECO:0000269|PubMed:9215672, ECO:0000269|PubMed:9385451}. CC -!- DISRUPTION PHENOTYPE: Cell-specific silencing in motor neurons is CC associated with loss of motor neuron cell bodies and progressive CC denervation of the neuromuscular junctions with aging, consistent with CC the clinical features of human distal spinal muscular atrophy X-linked CC disease, 3 (DSMAX3). {ECO:0000269|PubMed:25639447}. CC -!- SIMILARITY: Belongs to the cation transport ATPase (P-type) (TC 3.A.3) CC family. Type IB subfamily. {ECO:0000305}. CC -!- WEB RESOURCE: Name=Protein Spotlight; Note=Heavy metal - Issue 79 of CC February 2007; CC URL="https://web.expasy.org/spotlight/back_issues/079"; CC --------------------------------------------------------------------------- CC Copyrighted by the UniProt Consortium, see https://www.uniprot.org/terms CC Distributed under the Creative Commons Attribution (CC BY 4.0) License CC --------------------------------------------------------------------------- DR EMBL; U03434; AAA57445.1; -; mRNA. DR EMBL; U03736; AAB08487.1; -; mRNA. DR EMBL; AB007134; BAA22369.1; -; mRNA. DR EMBL; U71091; AAB37301.1; -; mRNA. DR EMBL; AL672288; -; NOT_ANNOTATED_CDS; Genomic_DNA. DR CCDS; CCDS41097.1; -. DR PIR; S43793; S43793. DR RefSeq; NP_033856.3; NM_009726.5. DR AlphaFoldDB; Q64430; -. DR SMR; Q64430; -. DR BioGRID; 198268; 30. DR CORUM; Q64430; -. DR IntAct; Q64430; 27. DR STRING; 10090.ENSMUSP00000058840; -. DR GlyCosmos; Q64430; 2 sites, No reported glycans. DR GlyGen; Q64430; 2 sites. DR iPTMnet; Q64430; -. DR PhosphoSitePlus; Q64430; -. DR SwissPalm; Q64430; -. DR jPOST; Q64430; -. DR MaxQB; Q64430; -. DR PaxDb; 10090-ENSMUSP00000058840; -. DR ProteomicsDB; 277131; -. DR Pumba; Q64430; -. DR ABCD; Q64430; 1 sequenced antibody. DR Antibodypedia; 536; 474 antibodies from 35 providers. DR DNASU; 11977; -. DR Ensembl; ENSMUST00000113557.8; ENSMUSP00000109186.2; ENSMUSG00000033792.13. DR GeneID; 11977; -. DR KEGG; mmu:11977; -. DR UCSC; uc012hnn.2; mouse. DR AGR; MGI:99400; -. DR CTD; 538; -. DR MGI; MGI:99400; Atp7a. DR VEuPathDB; HostDB:ENSMUSG00000033792; -. DR eggNOG; KOG0207; Eukaryota. DR GeneTree; ENSGT00940000159568; -. DR HOGENOM; CLU_001771_0_1_1; -. DR InParanoid; Q64430; -. DR OrthoDB; 5480493at2759; -. DR BRENDA; 7.2.2.8; 3474. DR BRENDA; 7.2.2.9; 3474. DR Reactome; R-MMU-6803544; Ion influx/efflux at host-pathogen interface. DR Reactome; R-MMU-936837; Ion transport by P-type ATPases. DR BioGRID-ORCS; 11977; 4 hits in 80 CRISPR screens. DR ChiTaRS; Atp7a; mouse. DR PRO; PR:Q64430; -. DR Proteomes; UP000000589; Chromosome X. DR RNAct; Q64430; Protein. DR Bgee; ENSMUSG00000033792; Expressed in choroid plexus epithelium and 257 other cell types or tissues. DR ExpressionAtlas; Q64430; baseline and differential. DR GO; GO:0016324; C:apical plasma membrane; ISO:MGI. DR GO; GO:0030424; C:axon; ISS:UniProtKB. DR GO; GO:0016323; C:basolateral plasma membrane; ISO:MGI. DR GO; GO:0031526; C:brush border membrane; ISO:MGI. DR GO; GO:0031252; C:cell leading edge; ISO:MGI. DR GO; GO:0031410; C:cytoplasmic vesicle; IDA:MGI. DR GO; GO:0030425; C:dendrite; ISS:UniProtKB. DR GO; GO:0031901; C:early endosome membrane; IDA:UniProtKB. DR GO; GO:0005783; C:endoplasmic reticulum; ISO:MGI. DR GO; GO:0005794; C:Golgi apparatus; IDA:MGI. DR GO; GO:0005770; C:late endosome; ISO:MGI. DR GO; GO:0033162; C:melanosome membrane; IDA:UniProtKB. DR GO; GO:0016020; C:membrane; IDA:MGI. DR GO; GO:0005902; C:microvillus; ISO:MGI. DR GO; GO:0043005; C:neuron projection; IDA:MGI. DR GO; GO:0043025; C:neuronal cell body; IDA:MGI. DR GO; GO:0043204; C:perikaryon; ISO:MGI. DR GO; GO:0048471; C:perinuclear region of cytoplasm; ISO:MGI. DR GO; GO:0005886; C:plasma membrane; IDA:UniProtKB. DR GO; GO:0014069; C:postsynaptic density; IEA:UniProtKB-SubCell. DR GO; GO:0030141; C:secretory granule; ISO:MGI. DR GO; GO:0005802; C:trans-Golgi network; IDA:MGI. DR GO; GO:0032588; C:trans-Golgi network membrane; IDA:UniProtKB. DR GO; GO:0030140; C:trans-Golgi network transport vesicle; ISS:HGNC-UCL. DR GO; GO:0005524; F:ATP binding; ISS:UniProtKB. DR GO; GO:0016887; F:ATP hydrolysis activity; IEA:InterPro. DR GO; GO:0005507; F:copper ion binding; ISS:HGNC. DR GO; GO:0005375; F:copper ion transmembrane transporter activity; IMP:MGI. DR GO; GO:0032767; F:copper-dependent protein binding; ISS:UniProtKB. DR GO; GO:1903136; F:cuprous ion binding; ISS:UniProtKB. DR GO; GO:0043682; F:P-type divalent copper transporter activity; IDA:MGI. DR GO; GO:0140581; F:P-type monovalent copper transporter activity; ISS:UniProtKB. DR GO; GO:0051087; F:protein-folding chaperone binding; ISO:MGI. DR GO; GO:0031267; F:small GTPase binding; ISO:MGI. DR GO; GO:0016532; F:superoxide dismutase copper chaperone activity; IDA:MGI. DR GO; GO:0046034; P:ATP metabolic process; IMP:MGI. DR GO; GO:0001568; P:blood vessel development; IMP:MGI. DR GO; GO:0001974; P:blood vessel remodeling; IMP:MGI. DR GO; GO:0051216; P:cartilage development; IMP:MGI. DR GO; GO:0006584; P:catecholamine metabolic process; IMP:MGI. DR GO; GO:0071230; P:cellular response to amino acid stimulus; ISO:MGI. DR GO; GO:0071280; P:cellular response to copper ion; ISO:MGI. DR GO; GO:0036120; P:cellular response to platelet-derived growth factor stimulus; ISO:MGI. DR GO; GO:0021954; P:central nervous system neuron development; IMP:MGI. DR GO; GO:0021702; P:cerebellar Purkinje cell differentiation; IMP:MGI. DR GO; GO:0030199; P:collagen fibril organization; IMP:MGI. DR GO; GO:0060003; P:copper ion export; IMP:UniProtKB. DR GO; GO:0055070; P:copper ion homeostasis; IBA:GO_Central. DR GO; GO:0015677; P:copper ion import; IMP:MGI. DR GO; GO:0006825; P:copper ion transport; IDA:MGI. DR GO; GO:0048813; P:dendrite morphogenesis; IMP:MGI. DR GO; GO:0010273; P:detoxification of copper ion; IMP:MGI. DR GO; GO:0042417; P:dopamine metabolic process; IMP:MGI. DR GO; GO:0048251; P:elastic fiber assembly; IMP:MGI. DR GO; GO:0051542; P:elastin biosynthetic process; IMP:MGI. DR GO; GO:0042414; P:epinephrine metabolic process; IMP:MGI. DR GO; GO:0051649; P:establishment of localization in cell; IMP:MGI. DR GO; GO:0030198; P:extracellular matrix organization; IMP:MGI. DR GO; GO:0031069; P:hair follicle morphogenesis; IMP:MGI. DR GO; GO:0006878; P:intracellular copper ion homeostasis; IMP:UniProtKB. DR GO; GO:0007626; P:locomotory behavior; IMP:MGI. DR GO; GO:0048286; P:lung alveolus development; IMP:MGI. DR GO; GO:0007005; P:mitochondrion organization; IMP:MGI. DR GO; GO:0045914; P:negative regulation of catecholamine metabolic process; IMP:MGI. DR GO; GO:0034760; P:negative regulation of iron ion transmembrane transport; ISO:MGI. DR GO; GO:0043524; P:negative regulation of neuron apoptotic process; IMP:MGI. DR GO; GO:0051402; P:neuron apoptotic process; IMP:MGI. DR GO; GO:0070050; P:neuron cellular homeostasis; IMP:MGI. DR GO; GO:0048812; P:neuron projection morphogenesis; IMP:MGI. DR GO; GO:0042421; P:norepinephrine biosynthetic process; IMP:MGI. DR GO; GO:0042415; P:norepinephrine metabolic process; IMP:MGI. DR GO; GO:0043473; P:pigmentation; IMP:MGI. DR GO; GO:0045793; P:positive regulation of cell size; ISO:MGI. DR GO; GO:0050679; P:positive regulation of epithelial cell proliferation; ISO:MGI. DR GO; GO:0010592; P:positive regulation of lamellipodium assembly; ISO:MGI. DR GO; GO:0048023; P:positive regulation of melanin biosynthetic process; ISS:UniProtKB. DR GO; GO:1903036; P:positive regulation of response to wounding; ISO:MGI. DR GO; GO:0032773; P:positive regulation of tyrosinase activity; ISS:UniProtKB. DR GO; GO:1904754; P:positive regulation of vascular associated smooth muscle cell migration; ISO:MGI. DR GO; GO:0021860; P:pyramidal neuron development; IMP:MGI. DR GO; GO:0010468; P:regulation of gene expression; IMP:MGI. DR GO; GO:0002082; P:regulation of oxidative phosphorylation; IMP:MGI. DR GO; GO:0001836; P:release of cytochrome c from mitochondria; IMP:MGI. DR GO; GO:0019430; P:removal of superoxide radicals; IMP:MGI. DR GO; GO:0046688; P:response to copper ion; ISO:MGI. DR GO; GO:0010042; P:response to manganese ion; ISO:MGI. DR GO; GO:0042428; P:serotonin metabolic process; IMP:MGI. DR GO; GO:0043588; P:skin development; IMP:MGI. DR GO; GO:0042093; P:T-helper cell differentiation; IMP:MGI. DR GO; GO:0006568; P:tryptophan metabolic process; IMP:MGI. DR GO; GO:0006570; P:tyrosine metabolic process; IMP:MGI. DR CDD; cd00371; HMA; 6. DR CDD; cd02094; P-type_ATPase_Cu-like; 1. DR Gene3D; 3.30.70.100; -; 6. DR Gene3D; 3.40.1110.10; Calcium-transporting ATPase, cytoplasmic domain N; 1. DR Gene3D; 2.70.150.10; Calcium-transporting ATPase, cytoplasmic transduction domain A; 1. DR Gene3D; 3.40.50.1000; HAD superfamily/HAD-like; 1. DR InterPro; IPR023299; ATPase_P-typ_cyto_dom_N. DR InterPro; IPR018303; ATPase_P-typ_P_site. DR InterPro; IPR023298; ATPase_P-typ_TM_dom_sf. DR InterPro; IPR008250; ATPase_P-typ_transduc_dom_A_sf. DR InterPro; IPR036412; HAD-like_sf. DR InterPro; IPR023214; HAD_sf. DR InterPro; IPR017969; Heavy-metal-associated_CS. DR InterPro; IPR006122; HMA_Cu_ion-bd. DR InterPro; IPR006121; HMA_dom. DR InterPro; IPR036163; HMA_dom_sf. DR InterPro; IPR027256; P-typ_ATPase_IB. DR InterPro; IPR001757; P_typ_ATPase. DR InterPro; IPR044492; P_typ_ATPase_HD_dom. DR NCBIfam; TIGR01525; ATPase-IB_hvy; 1. DR NCBIfam; TIGR01494; ATPase_P-type; 2. DR NCBIfam; TIGR00003; copper ion binding protein; 6. DR PANTHER; PTHR46594; P-TYPE CATION-TRANSPORTING ATPASE; 1. DR PANTHER; PTHR46594:SF4; P-TYPE CATION-TRANSPORTING ATPASE; 1. DR Pfam; PF00122; E1-E2_ATPase; 1. DR Pfam; PF00403; HMA; 6. DR Pfam; PF00702; Hydrolase; 1. DR PRINTS; PR00119; CATATPASE. DR PRINTS; PR00942; CUATPASEI. DR SFLD; SFLDS00003; Haloacid_Dehalogenase; 1. DR SFLD; SFLDF00027; p-type_atpase; 1. DR SUPFAM; SSF81653; Calcium ATPase, transduction domain A; 1. DR SUPFAM; SSF81665; Calcium ATPase, transmembrane domain M; 1. DR SUPFAM; SSF56784; HAD-like; 1. DR SUPFAM; SSF55008; HMA, heavy metal-associated domain; 6. DR PROSITE; PS00154; ATPASE_E1_E2; 1. DR PROSITE; PS01047; HMA_1; 6. DR PROSITE; PS50846; HMA_2; 7. DR Genevisible; Q64430; MM. PE 1: Evidence at protein level; KW ATP-binding; Cell membrane; Cell projection; Copper; Copper transport; KW Disease variant; Endosome; Glycoprotein; Golgi apparatus; Ion transport; KW Magnesium; Membrane; Metal-binding; Nucleotide-binding; Phosphoprotein; KW Reference proteome; Repeat; Synapse; Translocase; Transmembrane; KW Transmembrane helix; Transport. FT CHAIN 1..1491 FT /note="Copper-transporting ATPase 1" FT /id="PRO_0000046312" FT TOPO_DOM 1..644 FT /note="Cytoplasmic" FT /evidence="ECO:0000255" FT TRANSMEM 645..666 FT /note="Helical" FT /evidence="ECO:0000255" FT TOPO_DOM 667..705 FT /note="Extracellular" FT /evidence="ECO:0000255" FT TRANSMEM 706..725 FT /note="Helical" FT /evidence="ECO:0000255" FT TOPO_DOM 726..732 FT /note="Cytoplasmic" FT /evidence="ECO:0000255" FT TRANSMEM 733..753 FT /note="Helical" FT /evidence="ECO:0000255" FT TOPO_DOM 754..772 FT /note="Extracellular" FT /evidence="ECO:0000255" FT TRANSMEM 773..793 FT /note="Helical" FT /evidence="ECO:0000255" FT TOPO_DOM 794..926 FT /note="Cytoplasmic" FT /evidence="ECO:0000255" FT TRANSMEM 927..950 FT /note="Helical" FT /evidence="ECO:0000255" FT TOPO_DOM 951..980 FT /note="Extracellular" FT /evidence="ECO:0000255" FT TRANSMEM 981..1002 FT /note="Helical" FT /evidence="ECO:0000255" FT TOPO_DOM 1003..1347 FT /note="Cytoplasmic" FT /evidence="ECO:0000255" FT TRANSMEM 1348..1365 FT /note="Helical" FT /evidence="ECO:0000255" FT TOPO_DOM 1366..1376 FT /note="Extracellular" FT /evidence="ECO:0000255" FT TRANSMEM 1377..1396 FT /note="Helical" FT /evidence="ECO:0000255" FT TOPO_DOM 1397..1491 FT /note="Cytoplasmic" FT /evidence="ECO:0000255" FT DOMAIN 8..74 FT /note="HMA 1" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00280" FT DOMAIN 85..151 FT /note="HMA 2" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00280" FT DOMAIN 171..237 FT /note="HMA 3" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00280" FT DOMAIN 277..343 FT /note="HMA 4" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00280" FT DOMAIN 377..443 FT /note="HMA 5" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00280" FT DOMAIN 479..545 FT /note="HMA 6" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00280" FT DOMAIN 555..621 FT /note="HMA 7" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00280" FT REGION 1477..1491 FT /note="PDZD11-binding" FT /evidence="ECO:0000250" FT MOTIF 1458..1459 FT /note="Endocytosis signal" FT /evidence="ECO:0000269|PubMed:27337370" FT MOTIF 1478..1479 FT /note="Endocytosis signal" FT /evidence="ECO:0000269|PubMed:27337370" FT ACT_SITE 1035 FT /note="4-aspartylphosphate intermediate" FT /evidence="ECO:0000305" FT BINDING 18 FT /ligand="Cu(+)" FT /ligand_id="ChEBI:CHEBI:49552" FT /ligand_label="1" FT /evidence="ECO:0000250|UniProtKB:Q04656" FT BINDING 19 FT /ligand="Cu(+)" FT /ligand_id="ChEBI:CHEBI:49552" FT /ligand_label="1" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00280" FT BINDING 22 FT /ligand="Cu(+)" FT /ligand_id="ChEBI:CHEBI:49552" FT /ligand_label="1" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00280" FT BINDING 182 FT /ligand="Cu(+)" FT /ligand_id="ChEBI:CHEBI:49552" FT /ligand_label="2" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00280" FT BINDING 185 FT /ligand="Cu(+)" FT /ligand_id="ChEBI:CHEBI:49552" FT /ligand_label="2" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00280" FT BINDING 288 FT /ligand="Cu(+)" FT /ligand_id="ChEBI:CHEBI:49552" FT /ligand_label="3" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00280" FT BINDING 291 FT /ligand="Cu(+)" FT /ligand_id="ChEBI:CHEBI:49552" FT /ligand_label="3" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00280" FT BINDING 388 FT /ligand="Cu(+)" FT /ligand_id="ChEBI:CHEBI:49552" FT /ligand_label="4" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00280" FT BINDING 391 FT /ligand="Cu(+)" FT /ligand_id="ChEBI:CHEBI:49552" FT /ligand_label="4" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00280" FT BINDING 490 FT /ligand="Cu(+)" FT /ligand_id="ChEBI:CHEBI:49552" FT /ligand_label="5" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00280" FT BINDING 493 FT /ligand="Cu(+)" FT /ligand_id="ChEBI:CHEBI:49552" FT /ligand_label="5" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00280" FT BINDING 566 FT /ligand="Cu(+)" FT /ligand_id="ChEBI:CHEBI:49552" FT /ligand_label="6" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00280" FT BINDING 569 FT /ligand="Cu(+)" FT /ligand_id="ChEBI:CHEBI:49552" FT /ligand_label="6" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00280" FT BINDING 1072 FT /ligand="ATP" FT /ligand_id="ChEBI:CHEBI:30616" FT /evidence="ECO:0000250|UniProtKB:Q04656" FT BINDING 1292 FT /ligand="Mg(2+)" FT /ligand_id="ChEBI:CHEBI:18420" FT BINDING 1296 FT /ligand="Mg(2+)" FT /ligand_id="ChEBI:CHEBI:18420" FT MOD_RES 152 FT /note="Phosphothreonine" FT /evidence="ECO:0000250|UniProtKB:Q04656" FT MOD_RES 270 FT /note="Phosphoserine" FT /evidence="ECO:0000250|UniProtKB:Q04656" FT MOD_RES 327 FT /note="Phosphothreonine" FT /evidence="ECO:0000250|UniProtKB:Q04656" FT MOD_RES 339 FT /note="Phosphoserine" FT /evidence="ECO:0000250|UniProtKB:Q04656" FT MOD_RES 353 FT /note="Phosphoserine" FT /evidence="ECO:0000250|UniProtKB:P70705" FT MOD_RES 357 FT /note="Phosphoserine" FT /evidence="ECO:0007744|PubMed:19144319, FT ECO:0007744|PubMed:21183079" FT MOD_RES 362 FT /note="Phosphoserine" FT /evidence="ECO:0007744|PubMed:21183079" FT MOD_RES 1203 FT /note="Phosphothreonine" FT /evidence="ECO:0000250|UniProtKB:P70705" FT MOD_RES 1421 FT /note="Phosphoserine" FT /evidence="ECO:0000250|UniProtKB:Q04656" FT MOD_RES 1423 FT /note="Phosphoserine" FT /evidence="ECO:0000250|UniProtKB:Q04656" FT MOD_RES 1451 FT /note="Phosphoserine" FT /evidence="ECO:0000250|UniProtKB:Q04656" FT MOD_RES 1454 FT /note="Phosphoserine" FT /evidence="ECO:0000250|UniProtKB:Q04656" FT MOD_RES 1457 FT /note="Phosphoserine" FT /evidence="ECO:0007744|PubMed:19144319" FT MOD_RES 1460 FT /note="Phosphoserine" FT /evidence="ECO:0000250|UniProtKB:Q04656" FT MOD_RES 1464 FT /note="Phosphoserine" FT /evidence="ECO:0007744|PubMed:21183079" FT MOD_RES 1467 FT /note="Phosphoserine" FT /evidence="ECO:0007744|PubMed:21183079" FT MOD_RES 1477 FT /note="Phosphoserine" FT /evidence="ECO:0007744|PubMed:21183079" FT CARBOHYD 677 FT /note="N-linked (GlcNAc...) asparagine" FT /evidence="ECO:0000255" FT CARBOHYD 966 FT /note="N-linked (GlcNAc...) asparagine" FT /evidence="ECO:0000255" FT VARIANT 674 FT /note="H -> R (in MD)" FT /evidence="ECO:0000269|PubMed:9385451" FT VARIANT 1381 FT /note="S -> P (in MD)" FT /evidence="ECO:0000269|PubMed:9385451" FT MUTAGEN 1443..1444 FT /note="LL->AA: Impaired trafficking from endosome to TGN." FT /evidence="ECO:0000269|PubMed:27337370" FT MUTAGEN 1443..1444 FT /note="LL->VV: Has no effect on trafficking from endosome FT to TGN." FT /evidence="ECO:0000269|PubMed:27337370" FT MUTAGEN 1458..1459 FT /note="LL->AA,VV: Impaired trafficking from endosome to FT TGN." FT /evidence="ECO:0000269|PubMed:27337370" FT MUTAGEN 1478..1479 FT /note="LL->AA,VV: Impaired endocytosis associated with FT retention at the plasma membrane." FT /evidence="ECO:0000269|PubMed:27337370" FT CONFLICT 44 FT /note="E -> D (in Ref. 1; AAA57445 and 4; AAB37301)" FT /evidence="ECO:0000305" FT CONFLICT 103 FT /note="I -> V (in Ref. 1; AAA57445 and 4; AAB37301)" FT /evidence="ECO:0000305" FT CONFLICT 172 FT /note="M -> R (in Ref. 1; AAA57445 and 4; AAB37301)" FT /evidence="ECO:0000305" FT CONFLICT 245..246 FT /note="LK -> PI (in Ref. 2; AAB08487)" FT /evidence="ECO:0000305" FT CONFLICT 445 FT /note="P -> PA (in Ref. 2; AAB08487 and 4; AAB37301)" FT /evidence="ECO:0000305" FT CONFLICT 470 FT /note="L -> P (in Ref. 2; AAB08487, 3; BAA22369 and 4; FT AAB37301)" FT /evidence="ECO:0000305" FT CONFLICT 515 FT /note="M -> T (in Ref. 1; AAA57445 and 4; AAB37301)" FT /evidence="ECO:0000305" FT CONFLICT 717 FT /note="C -> F (in Ref. 2; AAB08487)" FT /evidence="ECO:0000305" FT CONFLICT 770 FT /note="T -> A (in Ref. 2; AAB08487)" FT /evidence="ECO:0000305" FT CONFLICT 775 FT /note="P -> S (in Ref. 2; AAB08487)" FT /evidence="ECO:0000305" FT CONFLICT 885 FT /note="I -> T (in Ref. 2; AAB08487)" FT /evidence="ECO:0000305" FT CONFLICT 1169 FT /note="Y -> H (in Ref. 2; AAB08487)" FT /evidence="ECO:0000305" FT CONFLICT 1204 FT /note="A -> P (in Ref. 2; AAB08487 and 4; AAB37301)" FT /evidence="ECO:0000305" FT CONFLICT 1217 FT /note="I -> M (in Ref. 1; AAA57445)" FT /evidence="ECO:0000305" FT CONFLICT 1253 FT /note="R -> Q (in Ref. 1; AAA57445)" FT /evidence="ECO:0000305" SQ SEQUENCE 1491 AA; 161959 MW; 2FADCC6806994CA5 CRC64; MEPSVDANSI TITVEGMTCI SCVRTIEQQI GKVNGVHHIK VSLEEKSATI IYDPKLQTPK TLQEAIDDMG FDALLHNANP LPVLTNTVFL TVTAPLTLPW DHIQSTLLKT KGVTGVKISP QQRSAVVTII PSVVSASQIV ELVPDLSLDM GTQEKKSGAC EEHSTPQAGE VMLKMKVEGM TCHSCTSTIE GKVGKLQGVQ RIKVSLDNQE ATIVFQPHLI TAEEIKKQIE AVGFPAFIKK QPKYLKLGAI DVERLKNTPV KSSEGSQQKS PSYPSDSTTM FTIEGMHCKS CVSNIESALS TLQYVSSIVV SLENRSAIVK YNASLVTPEM LRKAIEAISP GQYRVSIASE VESTASSPSS SSLQKMPLNI VSQPLTQEAV ININGMTCNS CVQSIEGVIS KKPGVKSIHV SLANSTGTIE FDPLLTSPET LREAIEDMGF DAALPDMKEP LVVIAQPSLE TPLLPSSNEL ENVMTSVQNK CYIQVSGMTC ASCVANIERN LRREEGIYSV LVALMAGKAE VRYNPAVIQP RVIAEFIREL GFGAMVMENA GEGNGILELV VRGMTCASCV HKIESTLTKH KGIFYCSVAL ATNKAHIKYD PEIIGPRDII HTIGSLGFEA SLVKKDRSAN HLDHKREIKQ WRGSFLVSLF FCIPVMGLMV YMMVMDHHLA TLHHNQNMSN EEMINMHSAM FLERQILPGL SIMNLLSLLL CLPVQFCGGW YFYIQAYKAL KHKTANMDVL IVLATTIAFA YSLVILLVAM FERAKVNPIT FFDTPPMLFV FIALGRWLEH IAKGKTSEAL AKLISLQATE ATIVTLNSEN LLLSEEQVDV ELVQRGDIIK VVPGGKFPVD GRVIEGHSMV DESLITGEAM PVAKKPGSTV IAGSINQNGS LLIRATHVGA DTTLSQIVKL VEEAQTSKAP IQQFADKLSG YFVPFIVLVS IVTLLVWIII GFQNFEIVET YFPGYNRSIS RTETIIRFAF QASITVLCIA CPCSLGLATP TAVMVGTGVG AQNGILIKGG EPLEMAHKVK VVVFDKTGTI THGTPVVNQV KVLVESNKIS RNKILAIVGT AESNSEHPLG AAVTKYCKKE LDTETLGTCT DFQVVPGCGI SCKVTNIEGL LHKSNLKIEE NNIKNASLVQ IDAINEQSST SSSMIIDAHL SNAVNTQQYK VLIGNREWMI RNGLVISNDV DESMIEHERR GRTAVLVTID DELCGLIAIA DTVKPEAELA VHILKSMGLE VVLMTGDNSK TARSIASQVG ITKVFAEVLP SHKVAKVKQL QEEGKRVAMV GDGINDSPAL AMANVGIAIG TGTDVAIEAA DVVLIRNDLL DVVASIDLSR KTVKRIRINF VFALIYNLVG IPIAAGVFLP IGLVLQPWMG SAAMAASSVS VVLSSLFLKL YRKPTYDNYE LHPRSHTGQR SPSEISVHVG IDDTSRNSPR LGLLDRIVNY SRASINSLLS DKRSLNSVVT SEPDKHSLLV GDFREDDDTT L //