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3.A.3.5.6
Cu+-ATPase, ATP7A (MNK or Mc1) (efflux from the cytosol into the secretory pathway) (Menkes disease protein, α-chain) (Tümer 2013). It plays a role in systemic copper absorption in the gut and copper reabsorption in the kidney. In nonpolarized cells, the metal binding sites in the amino-terminal domain of MNK are required for copper-regulated trafficking from the Golgi to the plasma membrane (Greenough et al. 2004). It is expressed in Purkinje cells early in development and later in Bergmann glia. In melanocytes, it delivers Cu2+ to tyrosinase (Barnes et al., 2005). ATP7A has dual functions: 1) it incorporates copper into copper-dependent enzymes; and 2) it maintains intracellular copper levels by removing excess copper from the cytosol. To accomplish both functions, the protein traffics between different cellular locations, depending on copper levels (Bertini and Rosato, 2008). The lumenal loop Met672-Pro707 of ATP7A binds metals and facilitates copper release from the intramembrane sites (Barry et al., 2011).  Modeling suggests that Cu+-binding sites HMBDs 5 and 6 are most important for function (Gourdon et al. 2012).  In addition to X-linked recessive Menkes disease, mutations cause occipital horn syndrome and adult-onset distal motor neuropathy (Yi and Kaler 2014). p97/VCP interacts with ATP7A playing a role in motor neuron degeneration (Yi and Kaler 2018). 55 different mutations were located around the six copper binding sites and the ATP binding site. 76.7% of the mothers were carriers. Approximately half of the male siblings of patients with MNK were diagnosed with MNK (Fujisawa et al. 2019). It may play a role in melanosome (melanocyte) function (Wiriyasermkul et al. 2020).  Cu+ is predominately sequestered in lysosomes via the Cu+ transporter ATP7A in oyster hemocytes to reduce the toxic effects of intracellular Cu+ (Luo et al. 2024).

Accession Number:Q04656
Protein Name:ATP7A aka MNK aka MC1
Length:1500
Molecular Weight:163374.00
Species:Homo sapiens (Human) [9606]
Number of TMSs:9
Location1 / Topology2 / Orientation3: Endoplasmic reticulum1
Substrate copper(2+), copper(1+)

Cross database links:

RefSeq: NP_000043.3   
Entrez Gene ID: 538   
Pfam: PF00122    PF00403    PF00702   
OMIM: 300011  gene
304150  phenotype
309400  phenotype
KEGG: hsa:538   

Gene Ontology

GO:0016323 C:basolateral plasma membrane
GO:0005829 C:cytosol
GO:0005783 C:endoplasmic reticulum
GO:0016021 C:integral to membrane
GO:0005770 C:late endosome
GO:0043005 C:neuron projection
GO:0043025 C:neuronal cell body
GO:0048471 C:perinuclear region of cytoplasm
GO:0005802 C:trans-Golgi network
GO:0030140 C:trans-Golgi network transport vesicle
GO:0005524 F:ATP binding
GO:0032767 F:copper-dependent protein binding
GO:0004008 F:copper-exporting ATPase activity
GO:0016532 F:superoxide dismutase copper chaperone activity
GO:0006754 P:ATP biosynthetic process
GO:0001974 P:blood vessel remodeling
GO:0051216 P:cartilage development
GO:0006878 P:cellular copper ion homeostasis
GO:0021702 P:cerebellar Purkinje cell differentiation
GO:0030199 P:collagen fibril organization
GO:0060003 P:copper ion export
GO:0015677 P:copper ion import
GO:0010273 P:detoxification of copper ion
GO:0042417 P:dopamine metabolic process
GO:0048251 P:elastic fiber assembly
GO:0051542 P:elastin biosynthetic process
GO:0042414 P:epinephrine metabolic process
GO:0031069 P:hair follicle morphogenesis
GO:0007626 P:locomotory behavior
GO:0048286 P:lung alveolus development
GO:0007005 P:mitochondrion organization
GO:0048553 P:negative regulation of metalloenzyme activity
GO:0048812 P:neuron projection morphogenesis
GO:0043526 P:neuroprotection
GO:0042415 P:norepinephrine metabolic process
GO:0018205 P:peptidyl-lysine modification
GO:0043473 P:pigmentation
GO:0048554 P:positive regulation of metalloenzyme activity
GO:0051353 P:positive regulation of oxidoreductase activity
GO:0021860 P:pyramidal neuron development
GO:0002082 P:regulation of oxidative phosphorylation
GO:0019430 P:removal of superoxide radicals
GO:0042428 P:serotonin metabolic process
GO:0043588 P:skin development
GO:0042093 P:T-helper cell differentiation
GO:0006568 P:tryptophan metabolic process

References (24)

[1] “Isolation of a candidate gene for Menkes disease and evidence that it encodes a copper-transporting ATPase.”  Vulpe C.D.et.al.   8490659
[2] “Characterization of the exon structure of the Menkes disease gene using vectorette PCR.”  Tuemer Z.et.al.   7607665
[3] “Multiple transcripts coding for the menkes gene: evidence for alternative splicing of Menkes mRNA.”  Reddy M.C.et.al.   9693104
[4] “Multiple forms of the Menkes Cu-ATPase.”  Harris E.D.et.al.   10079814
[5] “The DNA sequence of the human X chromosome.”  Ross M.T.et.al.   15772651
[6] “Molecular structure of the Menkes disease gene (ATP7A).”  Dierick H.A.et.al.   7490081
[7] “Isolation of a candidate gene for Menkes disease that encodes a potential heavy metal binding protein.”  Chelly J.et.al.   8490646
[8] “Isolation of a partial candidate gene for Menkes disease by positional cloning.”  Mercer J.F.B.et.al.   8490647
[9] “Molecular phylogenetics and the origins of placental mammals.”  Murphy W.J.et.al.   11214319
[10] “Constitutive skipping of alternatively spliced exon 10 in the ATP7A gene abolishes Golgi localization of the menkes protein and produces the occipital horn syndrome.”  Qi M.et.al.   9467005
[11] “Evidence for a Menkes-like protein with a nuclear targeting sequence.”  Reddy M.C.et.al.   10970802
[12] “Immunocytochemical localization of the Menkes copper transport protein (ATP7A) to the trans-Golgi network.”  Dierick H.A.et.al.   9147644
[13] “The Menkes protein (ATP7A; MNK) cycles via the plasma membrane both in basal and elevated extracellular copper using a C-terminal di-leucine endocytic signal.”  Petris M.J.et.al.   10484781
[14] “Solution structure of the fourth metal-binding domain from the Menkes copper-transporting ATPase.”  Gitschier J.et.al.   9437429
[15] “Mutation spectrum of ATP7A, the gene defective in Menkes disease.”  Tuemer Z.et.al.   10079817
[16] “Diverse mutations in patients with Menkes disease often lead to exon skipping.”  Das S.et.al.   7977350
[17] “Identification of point mutations in 41 unrelated patients affected with Menkes disease.”  Tuemer Z.et.al.   8981948
[18] “A C2055T transition in exon 8 of the ATP7A gene is associated with exon skipping in an occipital horn syndrome family.”  Ronce N.et.al.   9246006
[19] “Defective copper-induced trafficking and localization of the Menkes protein in patients with mild and copper-treated classical Menkes disease.”  Ambrosini L.et.al.   10401004
[20] “Identification of three novel mutations in the MNK gene in three unrelated Japanese patients with classical Menkes disease.”  Ogawa A.et.al.   10319589
[21] “A novel frameshift mutation in exon 23 of ATP7A (MNK) results in occipital horn syndrome and not in Menkes disease.”  Dagenais S.L.et.al.   11431706
[22] “ATP7A gene mutations in 16 patients with Menkes disease and a patient with occipital horn syndrome.”  Gu Y.-H.et.al.   11241493
[23] “Identification of four novel mutations in classical Menkes disease and successful prenatal DNA diagnosis.”  Hahn S.et.al.   11350187
[24] “Identification and analysis of 21 novel disease-causing amino acid substitutions in the conserved part of ATP7A.”  Moeller L.B.et.al.   15981243
Structure:
1AW0   1KVI   1KVJ   1Q8L   1S6O   1S6U   1Y3J   1Y3K   1YJR   1YJT   [...more]

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Predict TMSs (Predict number of transmembrane segments)
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FASTA formatted sequence 
1:	MDPSMGVNSV TISVEGMTCN SCVWTIEQQI GKVNGVHHIK VSLEEKNATI IYDPKLQTPK 
61:	TLQEAIDDMG FDAVIHNPDP LPVLTDTLFL TVTASLTLPW DHIQSTLLKT KGVTDIKIYP 
121:	QKRTVAVTII PSIVNANQIK ELVPELSLDT GTLEKKSGAC EDHSMAQAGE VVLKMKVEGM 
181:	TCHSCTSTIE GKIGKLQGVQ RIKVSLDNQE ATIVYQPHLI SVEEMKKQIE AMGFPAFVKK 
241:	QPKYLKLGAI DVERLKNTPV KSSEGSQQRS PSYTNDSTAT FIIDGMHCKS CVSNIESTLS 
301:	ALQYVSSIVV SLENRSAIVK YNASSVTPES LRKAIEAVSP GLYRVSITSE VESTSNSPSS 
361:	SSLQKIPLNV VSQPLTQETV INIDGMTCNS CVQSIEGVIS KKPGVKSIRV SLANSNGTVE 
421:	YDPLLTSPET LRGAIEDMGF DATLSDTNEP LVVIAQPSSE MPLLTSTNEF YTKGMTPVQD 
481:	KEEGKNSSKC YIQVTGMTCA SCVANIERNL RREEGIYSIL VALMAGKAEV RYNPAVIQPP 
541:	MIAEFIRELG FGATVIENAD EGDGVLELVV RGMTCASCVH KIESSLTKHR GILYCSVALA 
601:	TNKAHIKYDP EIIGPRDIIH TIESLGFEAS LVKKDRSASH LDHKREIRQW RRSFLVSLFF 
661:	CIPVMGLMIY MMVMDHHFAT LHHNQNMSKE EMINLHSSMF LERQILPGLS VMNLLSFLLC 
721:	VPVQFFGGWY FYIQAYKALK HKTANMDVLI VLATTIAFAY SLIILLVAMY ERAKVNPITF 
781:	FDTPPMLFVF IALGRWLEHI AKGKTSEALA KLISLQATEA TIVTLDSDNI LLSEEQVDVE 
841:	LVQRGDIIKV VPGGKFPVDG RVIEGHSMVD ESLITGEAMP VAKKPGSTVI AGSINQNGSL 
901:	LICATHVGAD TTLSQIVKLV EEAQTSKAPI QQFADKLSGY FVPFIVFVSI ATLLVWIVIG 
961:	FLNFEIVETY FPGYNRSISR TETIIRFAFQ ASITVLCIAC PCSLGLATPT AVMVGTGVGA 
1021:	QNGILIKGGE PLEMAHKVKV VVFDKTGTIT HGTPVVNQVK VLTESNRISH HKILAIVGTA 
1081:	ESNSEHPLGT AITKYCKQEL DTETLGTCID FQVVPGCGIS CKVTNIEGLL HKNNWNIEDN 
1141:	NIKNASLVQI DASNEQSSTS SSMIIDAQIS NALNAQQYKV LIGNREWMIR NGLVINNDVN 
1201:	DFMTEHERKG RTAVLVAVDD ELCGLIAIAD TVKPEAELAI HILKSMGLEV VLMTGDNSKT 
1261:	ARSIASQVGI TKVFAEVLPS HKVAKVKQLQ EEGKRVAMVG DGINDSPALA MANVGIAIGT 
1321:	GTDVAIEAAD VVLIRNDLLD VVASIDLSRE TVKRIRINFV FALIYNLVGI PIAAGVFMPI 
1381:	GLVLQPWMGS AAMAASSVSV VLSSLFLKLY RKPTYESYEL PARSQIGQKS PSEISVHVGI 
1441:	DDTSRNSPKL GLLDRIVNYS RASINSLLSD KRSLNSVVTS EPDKHSLLVG DFREDDDTAL