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Reviewed, UniProtKB/Swiss-Prot Q04656 (ATP7A_HUMAN)

Last modified November 4, 2008. Version 110. Feed History...

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Names and origin · Protein attributes · General annotation (Comments) · Ontologies · Alternative products · Sequence annotation (Features) · Sequences · References · Web resources · Cross-references · Entry information · Relevant documents

Names and origin

Protein namesRecommended name:
    Copper-transporting ATPase 1
    EC=3.6.3.4
Alternative name(s):
    Copper pump 1
    Menkes disease-associated protein
Gene names
Name: ATP7A
Synonyms: MC1, MNK
OrganismHomo sapiens (Human)
Taxonomic identifier9606 [NCBI]
Taxonomic lineageEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresPrimatesHaplorrhiniCatarrhiniHominidaeHomo

Protein attributes

Sequence length1500 AA.
Sequence statusComplete.
Sequence processingThe displayed sequence is not processed.
Protein existenceEvidence at protein level.

General annotation (Comments)

Function

May supply copper to copper-requiring proteins within the secretory pathway, when localized in the trans-Golgi network. Under conditions of elevated extracellular copper, it relocalized to the plasma membrane where it functions in the efflux of copper from cells.

Catalytic activity

ATP + H(2)O + Cu(2+)(In) = ADP + phosphate + Cu(2+)(Out).

Subunit structure

Monomer.

Subcellular location

Golgi apparatustrans-Golgi network membrane; Multi-pass membrane protein. Cell membrane; Multi-pass membrane protein. Note= Cycles constitutively between the trans-Golgi network (TGN) and the plasma membrane. Predominantly found in the TGN and relocalized to the plasma membrane in response to elevated copper levels.

Isoform 3: CytoplasmcytosolProbable.

Isoform 5: Endoplasmic reticulum.

Tissue specificity

Found in most tissues except liver. Isoform 3 is widely expressed including in liver cell lines. Isoform 1 is expressed in fibroblasts, choriocarcinoma, colon carcinoma and neuroblastoma cell lines. Isoform 2 is expressed in fibroblasts, colon carcinoma and neuroblastoma cell lines.

Domain

The C-terminal di-leucine, 1487-Leu-Leu-1488, is an endocytic targeting signal which functions in retrieving recycling from the plasma membrane to the TGN. Mutation of the di-leucine signal results in the accumulation of the protein in the plasma membrane.

Involvement in disease

Defects in ATP7A are the cause of Menkes disease (MNKD) [MIM:309400]; also known as kinky hair disease. MNKD is an X-linked recessive disorder of copper metabolism characterized by generalized copper deficiency. MNKD results in progressive neurodegeneration and connective-tissue disturbances: focal cerebral and cerebellar degeneration, early growth retardation, peculiar hair, hypopigmentation, cutis laxa, vascular complications and death in early childhood. The clinical features result from the dysfunction of several copper-dependent enzymes.

Defects in ATP7A are the cause of occipital horn syndrome (OHS) [MIM:304150]; also known as X-linked cutis laxa. OHS is an X-linked recessive disorder of copper metabolism. Common features are unusual facial appearance, skeletal abnormalities, chronic diarrhea and genitourinary defects. The skeletal abnormalities included occipital horns, short, broad clavicles, deformed radii, ulnae and humeri, narrowing of the rib cage, undercalcified long bones with thin cortical walls and coxa valga.

Sequence similarities

Belongs to the cation transport ATPase (P-type) family. Type IB subfamily.

Contains 6 HMA domains.

Ontologies

Keywords

   Biological processCopper transport
Ion transport
Transport
   Cellular componentCell membrane
Cytoplasm
Endoplasmic reticulum
Golgi apparatus
Membrane
   Coding sequence diversityAlternative splicing
Polymorphism
   DiseaseDisease mutation
   DomainRepeat
Transmembrane
   LigandATP-binding
Copper
Magnesium
Metal-binding
Nucleotide-binding
   Molecular functionHydrolase
   PTMGlycoprotein
Phosphoprotein
   Technical term3D-structure

Gene Ontology (GO)

   Biological processT-helper cell differentiation

Inferred from sequence or structural similarity. Source: UniProtKB

alveolus development

Inferred from sequence or structural similarity. Source: UniProtKB

blood vessel remodeling

Inferred from sequence or structural similarity. Source: UniProtKB

cartilage development

Inferred from sequence or structural similarity. Source: UniProtKB

cellular copper ion homeostasis

Inferred from mutant phenotype. Source: UniProtKB

cerebellar Purkinje cell differentiation

Inferred from sequence or structural similarity. Source: UniProtKB

collagen fibril organization

Inferred from sequence or structural similarity. Source: UniProtKB

copper ion export

Inferred from sequence or structural similarity. Source: UniProtKB

copper ion import

Inferred from sequence or structural similarity. Source: UniProtKB

detoxification of copper ion

Inferred from sequence or structural similarity. Source: UniProtKB

dopamine metabolic process

Inferred from sequence or structural similarity. Source: UniProtKB

elastic fiber assembly

Inferred from sequence or structural similarity. Source: UniProtKB

elastin biosynthetic process

Inferred from sequence or structural similarity. Source: UniProtKB

epinephrine metabolic process

Inferred from sequence or structural similarity. Source: UniProtKB

hair follicle morphogenesis

Inferred from sequence or structural similarity. Source: UniProtKB

locomotory behavior

Inferred from sequence or structural similarity. Source: UniProtKB

mitochondrion organization

Inferred from sequence or structural similarity. Source: UniProtKB

negative regulation of metalloenzyme activity

Inferred from sequence or structural similarity. Source: UniProtKB

neurite morphogenesis

Inferred from sequence or structural similarity. Source: UniProtKB

neuroprotection

Inferred from sequence or structural similarity. Source: UniProtKB

norepinephrine metabolic process

Inferred from sequence or structural similarity. Source: UniProtKB

peptidyl-lysine modification

Inferred from sequence or structural similarity. Source: UniProtKB

pigmentation

Inferred from sequence or structural similarity. Source: UniProtKB

positive regulation of metalloenzyme activity

Inferred from sequence or structural similarity. Source: UniProtKB

positive regulation of oxidoreductase activity

Inferred from direct assay. Source: UniProtKB

pyramidal neuron development

Inferred from sequence or structural similarity. Source: UniProtKB

regulation of oxidative phosphorylation

Inferred from sequence or structural similarity. Source: UniProtKB

removal of superoxide radicals

Inferred from sequence or structural similarity. Source: UniProtKB

serotonin metabolic process

Inferred from sequence or structural similarity. Source: UniProtKB

skin development

Inferred from sequence or structural similarity. Source: UniProtKB

tryptophan metabolic process

Inferred from sequence or structural similarity. Source: UniProtKB

   Cellular componentbasolateral plasma membrane

Inferred from direct assay. Source: UniProtKB

cell soma

Inferred from sequence or structural similarity. Source: UniProtKB

late endosome

Inferred from direct assay. Source: UniProtKB

neuron projection

Inferred from sequence or structural similarity. Source: UniProtKB

perinuclear region of cytoplasm

Inferred from direct assay. Source: UniProtKB

trans-Golgi network

Inferred from direct assay. Source: UniProtKB

trans-Golgi network transport vesicle

Inferred from mutant phenotype. Source: HGNC

   Molecular functionATP binding

Traceable author statement. Source: HGNC

copper-dependent protein binding

Inferred from physical interaction. Source: UniProtKB

copper-exporting ATPase activity

Inferred from sequence or structural similarity. Source: UniProtKB

superoxide dismutase copper chaperone activity

Inferred from sequence or structural similarity. Source: UniProtKB

Complete GO annotation...

Alternative products

This entry describes 6 isoforms produced by alternative splicing. [Align] [Select]
Isoform 4 (identifier: Q04656-1)

This isoform has been chosen as the 'canonical' sequence. All positional information in this entry refers to it. This is also the sequence that appears in the downloadable versions of the entry.
Isoform 1 (identifier: Q04656-2)

The sequence of this isoform differs from the canonical sequence as follows:
     1-1: M → MRKLSIRKRDNNLLK
Isoform 2 (identifier: Q04656-3)

The sequence of this isoform differs from the canonical sequence as follows:
     1-1: M → MRKLSIRKRD...EELAVHNECY
Isoform 3 (identifier: Q04656-4)

Also known as: 2-16;

The sequence of this isoform differs from the canonical sequence as follows:
     42-1038: Missing.
Notes: Lacks 6 transmembrane regions and 5 heavy-metal-associated (HMA) domains.
Isoform 5 (identifier: Q04656-5)

The sequence of this isoform differs from the canonical sequence as follows:
     725-802: Missing.
Notes: Lacks the transmembrane domains 3 and 4. Expressed at a low level in several tissues of normal individuals and is the only isoform found in patients with OHS.
Isoform 6 (identifier: Q04656-6)

Also known as: NML45;

The sequence of this isoform differs from the canonical sequence as follows:
     1-1: M → MRKLSIRKRDNNLLKECNEEIK
     53-81: DPKLQTPKTLQEAIDDMGFDAVIHNPDPL → AHWFGFAALDGICSNGCFICFCSTFFSSL
     82-1499: Missing.
Notes: Lacks all transmembrane regions and 5 heavy-metal-associated (HMA) domains, but has a putative nuclear localization signal attached at the N-terminus.

Sequence annotation (Features)

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifier

Molecule processing

Chain1 – 15001500Copper-transporting ATPase 1
PRO_0000046311

Regions

Topological domain1 – 653653Cytoplasmic Potential
Transmembrane654 – 67522 Potential
Topological domain676 – 71439Extracellular Potential
Transmembrane715 – 73420 Potential
Topological domain735 – 7417Cytoplasmic Potential
Transmembrane742 – 76221 Potential
Topological domain763 – 78119Extracellular Potential
Transmembrane782 – 80221 Potential
Topological domain803 – 936134Cytoplasmic Potential
Transmembrane937 – 95923 Potential
Topological domain960 – 98930Extracellular Potential
Transmembrane990 – 101122 Potential
Topological domain1012 – 1356345Cytoplasmic Potential
Transmembrane1357 – 137418 Potential
Topological domain1375 – 138511Extracellular Potential
Transmembrane1386 – 140520 Potential
Topological domain1406 – 150095Cytoplasmic Potential
Domain9 – 7567HMA 1
Domain172 – 23867HMA 2
Domain278 – 34467HMA 3
Domain378 – 44467HMA 4
Domain489 – 55567HMA 5
Domain565 – 63167HMA 6
Motif1487 – 14882Endocytosis signal
Compositional bias355 – 3628Poly-Ser

Sites

Active site104414-aspartylphosphate intermediate By similarity
Metal binding13011Magnesium By similarity
Metal binding13051Magnesium By similarity

Amino acid modifications

Modified residue3531Phosphoserine By similarity
Modified residue3571Phosphoserine By similarity
Glycosylation6861N-linked (GlcNAc...) Potential
Glycosylation9751N-linked (GlcNAc...) Potential

Natural variations

Alternative sequence11M → MRKLSIRKRDNNLLK in isoform 1.
VSP_000419
Alternative sequence11M → MRKLSIRKRDNNLLKPSSAS SLGIAVSLGRPVLSRSSSGT VNLLEEVGLHIRDTAFSSTK LLEAISTVSAQVEELAVHNE CY in isoform 2.
VSP_000420
Alternative sequence11M → MRKLSIRKRDNNLLKECNEE IK in isoform 6.
VSP_000421
Alternative sequence42 – 1038997Missing in isoform 3.
VSP_000424
Alternative sequence53 – 8129DPKLQ…NPDPL → AHWFGFAALDGICSNGCFIC FCSTFFSSL in isoform 6.
VSP_000422
Alternative sequence82 – 14991418Missing in isoform 6.
VSP_000423
Alternative sequence725 – 80278Missing in isoform 5.
VSP_000425
Natural variant6291A → P in MNKD.
VAR_000699
Natural variant6371S → L in OHS.
VAR_009999
Natural variant6691T → I: dbSNP rs2234935.
VAR_016119
Natural variant7031R → H: dbSNP rs2234936.
VAR_016120
Natural variant7061L → R in MNKD.
VAR_023261
Natural variant7271G → R in MNKD.
VAR_000700
Natural variant7671V → L: dbSNP rs2227291.
VAR_010000
Natural variant8441R → H in MNKD.
VAR_023262
Natural variant8531G → R in MNKD.
VAR_023263
Natural variant8601G → V in MNKD.
VAR_023264
Natural variant8731L → R in MNKD.
VAR_010001
Natural variant8761G → E in MNKD.
VAR_010002
Natural variant8761G → R in MNKD.
VAR_023265
Natural variant9241Q → R in MNKD.
VAR_023266
Natural variant10001C → R in MNKD.
VAR_010003
Natural variant10061L → P in MNKD.
VAR_000701
Natural variant10071A → V in MNKD.
VAR_023267
Natural variant10151G → D in MNKD.
VAR_023268
Natural variant10191G → D in MNKD.
VAR_000702
Natural variant10441D → G in MNKD.
VAR_023269
Natural variant11001L → P in MNKD.
VAR_023270
Natural variant11181G → D in MNKD.
VAR_023271
Natural variant12551G → R in MNKD.
VAR_023272
Natural variant12821K → E in MNKD.
VAR_023273
Natural variant13001G → E in MNKD.
VAR_010004
Natural variant13021G → R in MNKD.
VAR_010005
Natural variant13021G → V in MNKD.
VAR_010006
Natural variant13041N → K in MNKD.
VAR_023274
Natural variant13051D → A in MNKD.
VAR_010007
Natural variant13151G → R in MNKD.
VAR_023275
Natural variant13251A → V in MNKD.
VAR_023276
Natural variant13441S → R in MNKD.
VAR_023277
Natural variant13451I → F in MNKD.