Reviewed, UniProtKB/Swiss-Prot Q04656 (ATP7A_HUMAN)

Names and origin

Protein names

Recommended 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

Organism

Homo sapiens (Human)

Taxonomic identifier

9606 [NCBI]

Taxonomic lineage

Eukaryota › Metazoa › Chordata › Craniata › Vertebrata › Euteleostomi › Mammalia › Eutheria › Euarchontoglires › Primates › Haplorrhini › Catarrhini › Hominidae › Homo

Protein attributes

Sequence length	1500 AA.
Sequence status	Complete.
Sequence processing	The displayed sequence is not processed.
Protein existence	Evidence 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 apparatus › trans-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: Cytoplasm › cytosolProbable. 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 process	Copper transport Ion transport Transport
Cellular component	Cell membrane Cytoplasm Endoplasmic reticulum Golgi apparatus Membrane
Coding sequence diversity	Alternative splicing Polymorphism
Disease	Disease mutation
Domain	Repeat Transmembrane
Ligand	ATP-binding Copper Magnesium Metal-binding Nucleotide-binding
Molecular function	Hydrolase
PTM	Glycoprotein Phosphoprotein
Technical term	3D-structure
Gene Ontology (GO)
Biological process	T-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 component	basolateral 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 function	ATP 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 key	Position(s)	Length	Description	Graphical view	Feature identifier
Molecule processing
	Chain	1 – 1500	1500	Copper-transporting ATPase 1		PRO_0000046311
Regions
	Topological domain	1 – 653	653	Cytoplasmic Potential
	Transmembrane	654 – 675	22	Potential
	Topological domain	676 – 714	39	Extracellular Potential
	Transmembrane	715 – 734	20	Potential
	Topological domain	735 – 741	7	Cytoplasmic Potential
	Transmembrane	742 – 762	21	Potential
	Topological domain	763 – 781	19	Extracellular Potential
	Transmembrane	782 – 802	21	Potential
	Topological domain	803 – 936	134	Cytoplasmic Potential
	Transmembrane	937 – 959	23	Potential
	Topological domain	960 – 989	30	Extracellular Potential
	Transmembrane	990 – 1011	22	Potential
	Topological domain	1012 – 1356	345	Cytoplasmic Potential
	Transmembrane	1357 – 1374	18	Potential
	Topological domain	1375 – 1385	11	Extracellular Potential
	Transmembrane	1386 – 1405	20	Potential
	Topological domain	1406 – 1500	95	Cytoplasmic Potential
	Domain	9 – 75	67	HMA 1
	Domain	172 – 238	67	HMA 2
	Domain	278 – 344	67	HMA 3
	Domain	378 – 444	67	HMA 4
	Domain	489 – 555	67	HMA 5
	Domain	565 – 631	67	HMA 6
	Motif	1487 – 1488	2	Endocytosis signal
	Compositional bias	355 – 362	8	Poly-Ser
Sites
	Active site	1044	1	4-aspartylphosphate intermediate By similarity
	Metal binding	1301	1	Magnesium By similarity
	Metal binding	1305	1	Magnesium By similarity
Amino acid modifications
	Modified residue	353	1	Phosphoserine By similarity
	Modified residue	357	1	Phosphoserine By similarity
	Glycosylation	686	1	N-linked (GlcNAc...) Potential
	Glycosylation	975	1	N-linked (GlcNAc...) Potential
Natural variations
	Alternative sequence	1	1	M → MRKLSIRKRDNNLLK in isoform 1.		VSP_000419
	Alternative sequence	1	1	M → MRKLSIRKRDNNLLKPSSAS SLGIAVSLGRPVLSRSSSGT VNLLEEVGLHIRDTAFSSTK LLEAISTVSAQVEELAVHNE CY in isoform 2.		VSP_000420
	Alternative sequence	1	1	M → MRKLSIRKRDNNLLKECNEE IK in isoform 6.		VSP_000421
	Alternative sequence	42 – 1038	997	Missing in isoform 3.		VSP_000424
	Alternative sequence	53 – 81	29	DPKLQ…NPDPL → AHWFGFAALDGICSNGCFIC FCSTFFSSL in isoform 6.		VSP_000422
	Alternative sequence	82 – 1499	1418	Missing in isoform 6.		VSP_000423
	Alternative sequence	725 – 802	78	Missing in isoform 5.		VSP_000425
	Natural variant	629	1	A → P in MNKD.		VAR_000699
	Natural variant	637	1	S → L in OHS.		VAR_009999
	Natural variant	669	1	T → I: dbSNP rs2234935.		VAR_016119
	Natural variant	703	1	R → H: dbSNP rs2234936.		VAR_016120
	Natural variant	706	1	L → R in MNKD.		VAR_023261
	Natural variant	727	1	G → R in MNKD.		VAR_000700
	Natural variant	767	1	V → L: dbSNP rs2227291.		VAR_010000
	Natural variant	844	1	R → H in MNKD.		VAR_023262
	Natural variant	853	1	G → R in MNKD.		VAR_023263
	Natural variant	860	1	G → V in MNKD.		VAR_023264
	Natural variant	873	1	L → R in MNKD.		VAR_010001
	Natural variant	876	1	G → E in MNKD.		VAR_010002
	Natural variant	876	1	G → R in MNKD.		VAR_023265
	Natural variant	924	1	Q → R in MNKD.		VAR_023266
	Natural variant	1000	1	C → R in MNKD.		VAR_010003
	Natural variant	1006	1	L → P in MNKD.		VAR_000701
	Natural variant	1007	1	A → V in MNKD.		VAR_023267
	Natural variant	1015	1	G → D in MNKD.		VAR_023268
	Natural variant	1019	1	G → D in MNKD.		VAR_000702
	Natural variant	1044	1	D → G in MNKD.		VAR_023269
	Natural variant	1100	1	L → P in MNKD.		VAR_023270
	Natural variant	1118	1	G → D in MNKD.		VAR_023271
	Natural variant	1255	1	G → R in MNKD.		VAR_023272
	Natural variant	1282	1	K → E in MNKD.		VAR_023273
	Natural variant	1300	1	G → E in MNKD.		VAR_010004
	Natural variant	1302	1	G → R in MNKD.		VAR_010005
	Natural variant	1302	1	G → V in MNKD.		VAR_010006
	Natural variant	1304	1	N → K in MNKD.		VAR_023274
	Natural variant	1305	1	D → A in MNKD.		VAR_010007
	Natural variant	1315	1	G → R in MNKD.		VAR_023275
	Natural variant	1325	1	A → V in MNKD.		VAR_023276
	Natural variant	1344	1	S → R in MNKD.		VAR_023277
	Natural variant	1345	1	I → F in MNKD.