| IED ID | IndEnz0016000031 |
| Enzyme Type ID | tyrosinase000031 |
| Protein Name |
Copper-transporting ATPase 1 EC 7.2.2.8 Copper pump 1 Menkes disease-associated protein |
| Gene Name | ATP7A MC1 MNK |
| Organism | Homo sapiens (Human) |
| Taxonomic Lineage | cellular organisms Eukaryota Opisthokonta Metazoa Eumetazoa Bilateria Deuterostomia Chordata Craniata Vertebrata Gnathostomata (jawed vertebrates) Teleostomi Euteleostomi Sarcopterygii Dipnotetrapodomorpha Tetrapoda Amniota Mammalia Theria Eutheria Boreoeutheria Euarchontoglires Primates Haplorrhini Simiiformes Catarrhini Hominoidea (apes) Hominidae (great apes) Homininae Homo Homo sapiens (Human) |
| Enzyme Sequence | MDPSMGVNSVTISVEGMTCNSCVWTIEQQIGKVNGVHHIKVSLEEKNATIIYDPKLQTPKTLQEAIDDMGFDAVIHNPDPLPVLTDTLFLTVTASLTLPWDHIQSTLLKTKGVTDIKIYPQKRTVAVTIIPSIVNANQIKELVPELSLDTGTLEKKSGACEDHSMAQAGEVVLKMKVEGMTCHSCTSTIEGKIGKLQGVQRIKVSLDNQEATIVYQPHLISVEEMKKQIEAMGFPAFVKKQPKYLKLGAIDVERLKNTPVKSSEGSQQRSPSYTNDSTATFIIDGMHCKSCVSNIESTLSALQYVSSIVVSLENRSAIVKYNASSVTPESLRKAIEAVSPGLYRVSITSEVESTSNSPSSSSLQKIPLNVVSQPLTQETVINIDGMTCNSCVQSIEGVISKKPGVKSIRVSLANSNGTVEYDPLLTSPETLRGAIEDMGFDATLSDTNEPLVVIAQPSSEMPLLTSTNEFYTKGMTPVQDKEEGKNSSKCYIQVTGMTCASCVANIERNLRREEGIYSILVALMAGKAEVRYNPAVIQPPMIAEFIRELGFGATVIENADEGDGVLELVVRGMTCASCVHKIESSLTKHRGILYCSVALATNKAHIKYDPEIIGPRDIIHTIESLGFEASLVKKDRSASHLDHKREIRQWRRSFLVSLFFCIPVMGLMIYMMVMDHHFATLHHNQNMSKEEMINLHSSMFLERQILPGLSVMNLLSFLLCVPVQFFGGWYFYIQAYKALKHKTANMDVLIVLATTIAFAYSLIILLVAMYERAKVNPITFFDTPPMLFVFIALGRWLEHIAKGKTSEALAKLISLQATEATIVTLDSDNILLSEEQVDVELVQRGDIIKVVPGGKFPVDGRVIEGHSMVDESLITGEAMPVAKKPGSTVIAGSINQNGSLLICATHVGADTTLSQIVKLVEEAQTSKAPIQQFADKLSGYFVPFIVFVSIATLLVWIVIGFLNFEIVETYFPGYNRSISRTETIIRFAFQASITVLCIACPCSLGLATPTAVMVGTGVGAQNGILIKGGEPLEMAHKVKVVVFDKTGTITHGTPVVNQVKVLTESNRISHHKILAIVGTAESNSEHPLGTAITKYCKQELDTETLGTCIDFQVVPGCGISCKVTNIEGLLHKNNWNIEDNNIKNASLVQIDASNEQSSTSSSMIIDAQISNALNAQQYKVLIGNREWMIRNGLVINNDVNDFMTEHERKGRTAVLVAVDDELCGLIAIADTVKPEAELAIHILKSMGLEVVLMTGDNSKTARSIASQVGITKVFAEVLPSHKVAKVKQLQEEGKRVAMVGDGINDSPALAMANVGIAIGTGTDVAIEAADVVLIRNDLLDVVASIDLSRKTVKRIRINFVFALIYNLVGIPIAAGVFMPIGLVLQPWMGSAAMAASSVSVVLSSLFLKLYRKPTYESYELPARSQIGQKSPSEISVHVGIDDTSRNSPKLGLLDRIVNYSRASINSLLSDKRSLNSVVTSEPDKHSLLVGDFREDDDTAL |
| Enzyme Length | 1500 |
| Uniprot Accession Number | Q04656 |
| Absorption | |
| Active Site | ACT_SITE 1044; /note=4-aspartylphosphate intermediate; /evidence=ECO:0000250 |
| Activity Regulation | |
| Binding Site | BINDING 1081; /note=ATP; /evidence=ECO:0000269|PubMed:19917612 |
| Calcium Binding | |
| catalytic Activity | CATALYTIC ACTIVITY: Reaction=ATP + Cu(+)(in) + H2O = ADP + Cu(+)(out) + H(+) + phosphate; Xref=Rhea:RHEA:25792, ChEBI:CHEBI:15377, ChEBI:CHEBI:15378, ChEBI:CHEBI:30616, ChEBI:CHEBI:43474, ChEBI:CHEBI:49552, ChEBI:CHEBI:456216; EC=7.2.2.8; Evidence={ECO:0000269|PubMed:10419525};PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:25793; Evidence={ECO:0000305|PubMed:10419525, ECO:0000305|PubMed:28389643}; |
| DNA Binding | |
| EC Number | 7.2.2.8 |
| Enzyme Function | FUNCTION: ATP-driven copper (Cu(+)) ion pump that plays an important role in intracellular copper ion homeostasis (PubMed:10419525, PubMed:11092760, PubMed:28389643). Within a catalytic cycle, acquires Cu(+) ion from donor protein on the cytoplasmic side of the membrane and delivers it to acceptor protein on the lumenal side. The transfer of Cu(+) ion across the membrane is coupled to ATP hydrolysis and is associated with a transient phosphorylation that shifts the pump conformation from inward-facing to outward-facing state (PubMed:10419525, PubMed:19453293, PubMed:19917612, PubMed:31283225, PubMed:28389643). Under physiological conditions, at low cytosolic copper concentration, it is localized at the trans-Golgi network (TGN) where it transfers Cu(+) ions to cuproenzymes of the secretory pathway (PubMed:28389643, PubMed:11092760). Upon elevated cytosolic copper concentrations, it relocalizes to the plasma membrane where it is responsible for the export of excess Cu(+) ions (PubMed:10419525, PubMed:28389643). May play a dual role in neuron function and survival by regulating cooper efflux and neuronal transmission at the synapse as well as by supplying Cu(+) ions to enzymes such as PAM, TYR and SOD3 (PubMed:28389643) (By similarity). In the melanosomes of pigmented cells, provides copper cofactor to TYR to form an active TYR holoenzyme for melanin biosynthesis (By similarity). {ECO:0000250|UniProtKB:Q64430, ECO:0000269|PubMed:10419525, ECO:0000269|PubMed:11092760, ECO:0000269|PubMed:19453293, ECO:0000269|PubMed:19917612, ECO:0000269|PubMed:28389643, ECO:0000269|PubMed:31283225}. |
| Temperature Dependency | |
| PH Dependency | |
| Pathway | |
| nucleotide Binding | |
| Features | Active site (1); Alternative sequence (7); Beta strand (47); Binding site (1); Chain (1); Domain (7); Glycosylation (2); Helix (24); Metal binding (15); Modified residue (17); Motif (2); Mutagenesis (3); Natural variant (57); Region (1); Sequence conflict (22); Topological domain (9); Transmembrane (8); Turn (27) |
| Keywords | 3D-structure;ATP-binding;Alternative splicing;Cell junction;Cell membrane;Cell projection;Copper;Copper transport;Cytoplasm;Disease variant;Endoplasmic reticulum;Endosome;Glycoprotein;Golgi apparatus;Ion transport;Magnesium;Membrane;Metal-binding;Neurodegeneration;Nucleotide-binding;Phosphoprotein;Reference proteome;Repeat;Synapse;Translocase;Transmembrane;Transmembrane helix;Transport |
| Interact With | P09172; Q5EBL8 |
| Induction | |
| Subcellular Location | SUBCELLULAR LOCATION: Golgi apparatus, trans-Golgi network membrane {ECO:0000269|PubMed:10484781, ECO:0000269|PubMed:28389643, ECO:0000269|PubMed:9147644, ECO:0000269|PubMed:9467005}; Multi-pass membrane protein {ECO:0000255}. Cell membrane {ECO:0000269|PubMed:10484781, ECO:0000269|PubMed:28389643, ECO:0000269|PubMed:9147644}; Multi-pass membrane protein {ECO:0000255}. Melanosome membrane {ECO:0000250|UniProtKB:Q64430}; Multi-pass membrane protein {ECO:0000255}. Early endosome membrane {ECO:0000250|UniProtKB:Q64430}; Multi-pass membrane protein {ECO:0000255}. Cell projection, axon {ECO:0000250|UniProtKB:P70705}. Cell projection, dendrite {ECO:0000250|UniProtKB:P70705}. Cell junction, synapse, postsynaptic density {ECO:0000250|UniProtKB:P70705}. Note=Cycles constitutively between the TGN and the plasma membrane (PubMed:9147644). Predominantly found in the TGN and relocalized to the plasma membrane in response to elevated copper levels. Targeting into melanosomes is regulated by BLOC-1 complex (By similarity). In response to glutamate, translocates to neuron processes with a minor fraction at extrasynaptic sites (By similarity). {ECO:0000250|UniProtKB:P70705, ECO:0000250|UniProtKB:Q64430, ECO:0000269|PubMed:9147644}.; SUBCELLULAR LOCATION: [Isoform 3]: Cytoplasm, cytosol {ECO:0000305}.; SUBCELLULAR LOCATION: [Isoform 5]: Endoplasmic reticulum {ECO:0000269|PubMed:9467005}. |
| Modified Residue | MOD_RES 152; /note="Phosphothreonine"; /evidence="ECO:0007744|PubMed:23186163"; MOD_RES 270; /note="Phosphoserine"; /evidence="ECO:0007744|PubMed:23186163"; MOD_RES 327; /note="Phosphothreonine"; /evidence="ECO:0007744|PubMed:23186163"; MOD_RES 339; /note="Phosphoserine"; /evidence="ECO:0007744|PubMed:20068231, ECO:0007744|PubMed:23186163"; MOD_RES 353; /note="Phosphoserine"; /evidence="ECO:0000250|UniProtKB:P70705"; MOD_RES 357; /note="Phosphoserine"; /evidence="ECO:0007744|PubMed:23186163"; MOD_RES 362; /note="Phosphoserine"; /evidence="ECO:0000250|UniProtKB:Q64430"; MOD_RES 1212; /note="Phosphothreonine"; /evidence="ECO:0000250|UniProtKB:P70705"; MOD_RES 1430; /note="Phosphoserine"; /evidence="ECO:0007744|PubMed:24275569"; MOD_RES 1432; /note="Phosphoserine"; /evidence="ECO:0007744|PubMed:24275569"; MOD_RES 1460; /note="Phosphoserine"; /evidence="ECO:0007744|PubMed:23186163"; MOD_RES 1463; /note="Phosphoserine"; /evidence="ECO:0007744|PubMed:23186163"; MOD_RES 1466; /note="Phosphoserine"; /evidence="ECO:0007744|PubMed:23186163"; MOD_RES 1469; /note="Phosphoserine"; /evidence="ECO:0007744|PubMed:23186163"; MOD_RES 1473; /note="Phosphoserine"; /evidence="ECO:0007744|PubMed:23186163"; MOD_RES 1476; /note="Phosphoserine"; /evidence="ECO:0000250|UniProtKB:Q64430"; MOD_RES 1486; /note="Phosphoserine"; /evidence="ECO:0000250|UniProtKB:Q64430" |
| Post Translational Modification | |
| Signal Peptide | |
| Structure 3D | X-ray crystallography (2); NMR spectroscopy (20) |
| Cross Reference PDB | 1AW0; 1KVI; 1KVJ; 1Q8L; 1S6O; 1S6U; 1Y3J; 1Y3K; 1YJR; 1YJT; 1YJU; 1YJV; 2AW0; 2G9O; 2GA7; 2K1R; 2KIJ; 2KMV; 2KMX; 3CJK; 5T7L; 7LU8; |
| Mapped Pubmed ID | 11936860; 12221109; 12485192; 12539960; 12539963; 12565888; 12679332; 12812980; 14572476; 14635105; 14644159; 14977365; 15035611; 15135234; 15670166; 15761197; 16083905; 16172131; 16211579; 16317117; 16397091; 16826513; 16873374; 16884690; 17109627; 17158254; 17496194; 17531189; 17545667; 17562324; 17717039; 17987894; 17989919; 18030470; 18272047; 18515074; 18565219; 18688737; 18752978; 18768397; 18977292; 19046832; 19127267; 19194885; 19645496; 19679821; 20045993; 20566629; 20671235; 21115196; 21117320; 21208200; 21242307; 21494555; 21646353; 22074552; 22130675; 22210628; 22304828; 22389498; 22710939; 23028306; 23281160; 23345593; 23596324; 23751120; 23963605; 24002164; 24100245; 24150977; 24403508; 24614111; 24735419; 24754450; 24882692; 24927440; 25172213; 25355947; 25574028; 26055706; 26437801; 26638075; 26879543; 27112899; 27226607; 27293072; 27307295; 27462781; 27806319; 27896900; 28164426; 28178522; 28271598; 28355134; 28451781; 28737129; 29394468; 29579719; 30230404; 30530920; 30809870; 30842251; 31932435; 31959876; 32293788; 33359139; 33565059; 34461106; 34747666; |
| Motif | MOTIF 1467..1468; /note=Endocytosis signal; /evidence=ECO:0000250|UniProtKB:Q64430; MOTIF 1487..1488; /note=Endocytosis signal; /evidence=ECO:0000250|UniProtKB:Q64430 |
| Gene Encoded By | |
| Mass | 163,373 |
| Kinetics | BIOPHYSICOCHEMICAL PROPERTIES: Kinetic parameters: KM=4 uM for Cu(+) ion {ECO:0000269|PubMed:10419525}; Vmax=1.15 nmol/min/mg enzyme toward Cu(+) ion {ECO:0000269|PubMed:10419525}; |
| Metal Binding | METAL 18; /note="Cu(+) 1"; /evidence="ECO:0000269|PubMed:31283225, ECO:0007744|PDB:5T7L"; METAL 19; /note="Cu(+) 1; via amino nitrogen"; /evidence="ECO:0000255|PROSITE-ProRule:PRU00280, ECO:0000269|PubMed:31283225, ECO:0007744|PDB:5T7L"; METAL 22; /note="Cu(+) 1"; /evidence="ECO:0000255|PROSITE-ProRule:PRU00280, ECO:0000269|PubMed:31283225, ECO:0007744|PDB:5T7L"; METAL 182; /note="Cu(+) 2"; /evidence="ECO:0000255|PROSITE-ProRule:PRU00280"; METAL 185; /note="Cu(+) 2"; /evidence="ECO:0000255|PROSITE-ProRule:PRU00280"; METAL 288; /note="Cu(+) 3"; /evidence="ECO:0000255|PROSITE-ProRule:PRU00280"; METAL 291; /note="Cu(+) 3"; /evidence="ECO:0000255|PROSITE-ProRule:PRU00280"; METAL 388; /note="Cu(+) 4"; /evidence="ECO:0000255|PROSITE-ProRule:PRU00280"; METAL 391; /note="Cu(+) 4"; /evidence="ECO:0000255|PROSITE-ProRule:PRU00280"; METAL 499; /note="Cu(+) 5"; /evidence="ECO:0000255|PROSITE-ProRule:PRU00280"; METAL 502; /note="Cu(+) 5"; /evidence="ECO:0000255|PROSITE-ProRule:PRU00280"; METAL 575; /note="Cu(+) 6"; /evidence="ECO:0000255|PROSITE-ProRule:PRU00280"; METAL 578; /note="Cu(+) 6"; /evidence="ECO:0000255|PROSITE-ProRule:PRU00280"; METAL 1301; /note="Magnesium"; METAL 1305; /note="Magnesium" |
| Rhea ID | RHEA:25792; RHEA:25793 |
| Cross Reference Brenda | 7.2.2.8;7.2.2.9; |