Copper-transporting ATPase 1 (ATP7A)

The protein contains 1500 amino acids for an estimated molecular weight of 163374 Da.

 

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). (updated: April 7, 2021)

Protein identification was indicated in the following studies:

  1. Goodman and co-workers. (2013) The proteomics and interactomics of human erythrocytes. Exp Biol Med (Maywood) 238(5), 509-518.
  2. Lange and co-workers. (2014) Annotating N termini for the human proteome project: N termini and Nα-acetylation status differentiate stable cleaved protein species from degradation remnants in the human erythrocyte proteome. J Proteome Res. 13(4), 2028-2044.
  3. Hegedűs and co-workers. (2015) Inconsistencies in the red blood cell membrane proteome analysis: generation of a database for research and diagnostic applications. Database (Oxford) 1-8.
  4. Wilson and co-workers. (2016) Comparison of the Proteome of Adult and Cord Erythroid Cells, and Changes in the Proteome Following Reticulocyte Maturation. Mol Cell Proteomics. 15(6), 1938-1946.
  5. Bryk and co-workers. (2017) Quantitative Analysis of Human Red Blood Cell Proteome. J Proteome Res. 16(8), 2752-2761.
  6. D'Alessandro and co-workers. (2017) Red blood cell proteomics update: is there more to discover? Blood Transfus. 15(2), 182-187.
  7. Chu and co-workers. (2018) Quantitative mass spectrometry of human reticulocytes reveal proteome-wide modifications during maturation. Br J Haematol. 180(1), 118-133.

Methods

The following articles were analysed to gather the proteome content of erythrocytes.

The gene or protein list provided in the studies were processed using the ID mapping API of Uniprot in September 2018. The number of proteins identified and mapped without ambiguity in these studies is indicated below.
Only Swiss-Prot entries (reviewed) were considered for protein evidence assignation.

PublicationIdentification 1Uniprot mapping 2Not mapped /
Obsolete
TrEMBLSwiss-Prot
Goodman (2013)2289 (gene list)227853205992269
Lange (2014)123412347281224
Hegedus (2015)2638262202352387
Wilson (2016)165815281702911068
d'Alessandro (2017)18261817201815
Bryk (2017)20902060101081942
Chu (2018)18531804553621387

1 as available in the article and/or in supplementary material
2 uniprot mapping returns all protein isoforms as one entry

The compilation of older studies can be retrieved from the Red Blood Cell Collection database.

The data and differentiation stages presented below come from the proteomic study and analysis performed by our partners of the GReX consortium, more details are available in their published work.

No sequence conservation computed yet.

This protein is annotated as membranous in Gene Ontology, is annotated as membranous in UniProt, is predicted to be membranous by TOPCONS.


Interpro domains
Total structural coverage: 50%
Model score: 0
No model available.

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VariantDescription
MNK
OHS
dbSNP:rs2234935
dbSNP:rs2234936
MNK
MNK
dbSNP:rs2227291
MNK
MNK
MNK; decreased protein abundance; impaired copper transport activity
MNK
MNK; subcellular location restricted to post-TGN compartments; impaired copper transport activity
MNK; loss of protein expression
OHS; has no effect on copper-dependent trafficking; impaired copper transport activity
DSMAX3
MNK; decreased protein abundance; increased protein degradation; does not affect interaction with ATOX1; does not affect interaction with COMMD1; subc
MNK
MNK; impaired copper-dependent trafficking from TGN to post-TGN compartments; subcellular location restricted to TGN; impaired copper transport activi
MNK; subcellular location restricted to post-TGN compartments; impaired copper transport activity
MNK
MNK; impaired copper-dependent trafficking from TGN to post-TGN compartments; subcellular location restricted to TGN; impaired copper transport activi
MNK
MNK
MNK
MNK
MNK; impaired copper-dependent trafficking from TGN to post-TGN compartments; subcellular location restricted to TGN; impaired copper transport activi
MNK; impaired copper-dependent trafficking from TGN to post-TGN compartments; subcellular location restricted to TGN; impaired copper transport activi
MNK
MNK; impaired copper-dependent trafficking from TGN to post-TGN compartments; subcellular location restricted to TGN; impaired copper transport activi
MNK; impaired copper-dependent trafficking from TGN to post-TGN compartments; subcellular location restricted to TGN; impaired copper transport activi
OHS
MNK; impaired copper-dependent trafficking from TGN to post-TGN compartments; subcellular location restricted to TGN; impaired copper transport activi
MNK
MNK; subcellular location restricted to post-TGN compartments; impaired copper transport activity
MNK
MNK
MNK; decreased protein abundance; increased protein degradation; does not affect interaction with ATOX1; does not affect interaction with COMMD1; subc
MNK; loss of protein expression
DSMAX3
MNK; impaired copper-dependent trafficking from TGN to post-TGN compartments; subcellular location restricted to TGN; impaired copper transport activi
dbSNP:rs2234938
dbSNP:rs4826245
MNK; loss of protein expression
MNK; loss of protein expression
MNK; impaired copper-dependent trafficking from TGN to post-TGN compartments; subcellular location restricted to TGN; impaired copper transport activi
MNK
MNK
MNK; has no effect on copper-dependent trafficking from TGN to post-TGN compartments; impaired copper transport activity
MNK; loss of protein expression
MNK
MNK; loss of protein expression
MNK
MNK; impaired copper-dependent trafficking from TGN to post-TGN compartments; subcellular location restricted to TGN; impaired copper transport activi
MNK; impaired copper-dependent trafficking from TGN to post-TGN compartments; subcellular location restricted to TGN; impaired copper transport activi
MNK; impaired copper-dependent trafficking from TGN to post-TGN compartments; subcellular location restricted to TGN; impaired copper transport activi
MNK; loss of protein expression
MNK; impaired copper-dependent trafficking from TGN to post-TGN compartments; subcellular location restricted to TGN; impaired copper transport activi

Biological Process

Antimicrobial humoral response GO Logo
ATP metabolic process GO Logo
Blood vessel development GO Logo
Blood vessel remodeling GO Logo
Cartilage development GO Logo
Catecholamine metabolic process GO Logo
Cellular copper ion homeostasis GO Logo
Cellular response to amino acid stimulus GO Logo
Cellular response to antibiotic GO Logo
Cellular response to cadmium ion GO Logo
Cellular response to cobalt ion GO Logo
Cellular response to copper ion GO Logo
Cellular response to hypoxia GO Logo
Cellular response to iron ion GO Logo
Cellular response to lead ion GO Logo
Cellular response to platelet-derived growth factor stimulus GO Logo
Central nervous system neuron development GO Logo
Cerebellar Purkinje cell differentiation GO Logo
Collagen fibril organization GO Logo
Copper ion export GO Logo
Copper ion import GO Logo
Copper ion transport GO Logo
Dendrite morphogenesis GO Logo
Detoxification of copper ion GO Logo
Dopamine metabolic process GO Logo
Elastic fiber assembly GO Logo
Elastin biosynthetic process GO Logo
Epinephrine metabolic process GO Logo
Extracellular matrix organization GO Logo
Female pregnancy GO Logo
Hair follicle morphogenesis GO Logo
In utero embryonic development GO Logo
Ion transmembrane transport GO Logo
Lactation GO Logo
Liver development GO Logo
Locomotory behavior GO Logo
Lung alveolus development GO Logo
Mitochondrion organization GO Logo
Negative regulation of catalytic activity GO Logo
Negative regulation of iron ion transmembrane transport GO Logo
Negative regulation of neuron apoptotic process GO Logo
Neuron projection morphogenesis GO Logo
Norepinephrine biosynthetic process GO Logo
Norepinephrine metabolic process GO Logo
Peptidyl-lysine modification GO Logo
Pigmentation GO Logo
Plasma membrane copper ion transport GO Logo
Positive regulation of catalytic activity GO Logo
Positive regulation of cell size GO Logo
Positive regulation of epithelial cell proliferation GO Logo
Positive regulation of lamellipodium assembly GO Logo
Positive regulation of melanin biosynthetic process GO Logo
Positive regulation of monophenol monooxygenase activity GO Logo
Positive regulation of oxidoreductase activity GO Logo
Positive regulation of response to wounding GO Logo
Positive regulation of vascular associated smooth muscle cell migration GO Logo
Pyramidal neuron development GO Logo
Regulation of cytochrome-c oxidase activity GO Logo
Regulation of gene expression GO Logo
Regulation of oxidative phosphorylation GO Logo
Release of cytochrome c from mitochondria GO Logo
Removal of superoxide radicals GO Logo
Response to iron(III) ion GO Logo
Response to manganese ion GO Logo
Response to reactive oxygen species GO Logo
Response to zinc ion GO Logo
Serotonin metabolic process GO Logo
Skin development GO Logo
T-helper cell differentiation GO Logo
Transmembrane transport GO Logo
Tryptophan metabolic process GO Logo
Tyrosine metabolic process GO Logo

The reference OMIM entry for this protein is 300011

Atpase, cu(2+)-transporting, alpha polypeptide; atp7a

DESCRIPTION

The ATP7A gene encodes a transmembrane copper-transporting P-type ATPase (summary by Vulpe et al., 1993).

CLONING

The ATP7A gene was cloned as a candidate for the site of mutations causing Menkes disease (MNK; 309400) by 3 independent groups (Vulpe et al., 1993; Chelly et al., 1993; Mercer et al., 1993). By a database search of the predicted sequence, Vulpe et al. (1993) found strong homology to P-type ATPases, a family of integral membrane proteins that use an aspartylphosphate intermediate to transport cations across membranes. The 1,500-residue protein was found to have the characteristics of a copper-binding protein. It has 6 N-terminal copper binding sites and a catalytic transduction core with several functional domains. Northern blot analysis showed that the mRNA of the gene, which was symbolized 'MNK' before its precise nature was known, is present in a variety of cell types and tissues, except liver, in which expression is reduced or absent. The findings were consistent with the clinical observation that the liver is largely unaffected in Menkes disease and fails to accumulate excess copper. Levinson et al. (1994) and Mercer et al. (1994) isolated the mouse homolog of the Menkes disease gene. The mouse protein shows 89% identity to the human protein, and both proteins contain 8 transmembrane domains.

GENE STRUCTURE

Tumer et al. (1995) determined that the ATP7A gene spans about 150 kb of genomic DNA and contains 23 exons. The ATG start codon is in the second exon. The ATP7A and ATP7B (606882) genes showed strikingly similar exonic structures, with almost identical structures starting from the fifth metal-binding domain, suggesting the presence of a common ancestor encoding 1, and possibly 2, metal-binding domains in addition to the ATPase 'core.' Dierick et al. (1995) showed that the ATP7A gene contains 23 exons distributed over approximately 140 kb of genomic DNA. The authors showed that exon 10 is alternatively spliced. They found that the structures of the ATP7A and ATP7B genes are similar in the 3-prime two-thirds region, consistent with their common evolutionary ancestry.

GENE FUNCTION

Kuo et al. (1997) determined the gene expression patterns during mouse embryonic development for the Atp7a and Atp7b genes by RNA in situ hybridization. Atp7a expression was widespread throughout development whereas Atp7b expression was more delimited. Kuo et al. (1997) suggested that Atp7a functions primarily in the homeostatic maintenance of cell copper levels, whereas Atp7b may be involved specifically in the biosynthesis of distinct cuproproteins in different tissues. Studies in cultured cells localized the MNK protein to the final compartment of the Golgi apparatus, the trans-Golgi network (TGN). At this location, MNK is predicted to supply copper to the copper-dependent enzymes as they migrate through the secretory pathway. However, under conditions of elevated extracellular copper, the MNK protein undergoes a rapid relocalization to the plasma membrane where it functions in the efflux of copper from cells. By in vitro mutagenesis of the human ATP7A cDNA and immunofluorescence detection of mutant forms of the MNK protein expressed in cultured cells, Petris et al. (1998) demonstrated that the dileucine, L1487L1488, was essential for localization of MNK within the TGN, but not for copper efflux. They suggested that this dileucine motif is a putative endocytic targeting motif necessar ... More on the omim web site

Subscribe to this protein entry history

April 10, 2021: Protein entry updated
Automatic update: Entry updated from uniprot information.

Feb. 2, 2018: Protein entry updated
Automatic update: Uniprot description updated

Dec. 19, 2017: Protein entry updated
Automatic update: Uniprot description updated

Nov. 23, 2017: Protein entry updated
Automatic update: Uniprot description updated

March 16, 2016: Protein entry updated
Automatic update: OMIM entry 300011 was added.