ATP7A
Domain
The nucleotide-binding domain consists of a twisted six-stranded antiparallel beta-sheet flanked by two pairs of alpha-helices, forming a hydrophobic pocket that interacts with the adenine ring of ATP. The ATP binding site comprises residues located in alpha-1 and alpha-2 helices and beta-2 and beta-3 strands, which are involved in van der Waal's interactions, and Glu-1081 which forms a hydrogen bond with the adenine ring.
The heavy-metal-associated domain (HMA) coordinates a Cu(+) ion via the cysteine residues within the CXXC motif. The transfer of Cu(+) ion from ATOX1 to ATP7A involves the formation of a three-coordinate Cu(+)-bridged heterodimer where the metal is shared between the two metal binding sites of ATOX1 and ATP7A. The Cu(+) ion appears to switch between two coordination modes, forming two links with one protein and one with the other. Cisplatin, a chemotherapeutic drug, can bind the CXXC motif and hinder the release of Cu(+) ion.
Contains three di-leucine motifs in the C-terminus which are required for recycling from the plasma membrane to the TGN. The di-leucine 1487-Leu-Leu-1488 motif mediates endocytosis at the plasma membrane, whereas the di-leucine 1467-Leu-Leu-1468 motif is a sorting signal for retrograde trafficking to TGN via early endosomes.
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:28389643, PubMed:31283225). 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:11092760, PubMed:28389643). 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 (By similarity) (PubMed:28389643). In the melanosomes of pigmented cells, provides copper cofactor to TYR to form an active TYR holoenzyme for melanin biosynthesis (By similarity).
Involvement in disease
Menkes disease
MNK
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. A mild form of the disease has been described, in which cerebellar ataxia and moderate developmental delay predominate.
None
The disease is caused by variants affecting the gene represented in this entry.
Occipital horn syndrome
OHS
An X-linked recessive disorder of copper metabolism. Common features are unusual facial appearance, skeletal abnormalities, chronic diarrhea and genitourinary defects. The skeletal abnormalities include 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.
None
The disease is caused by variants affecting the gene represented in this entry.
Neuronopathy, distal hereditary motor, X-linked
HMNX
A form of distal hereditary motor neuronopathy, a heterogeneous group of neuromuscular disorders caused by selective degeneration of motor neurons in the anterior horn of the spinal cord, without sensory deficit in the posterior horn. The overall clinical picture consists of a classical distal muscular atrophy syndrome in the legs without clinical sensory loss. The disease starts with weakness and wasting of distal muscles of the anterior tibial and peroneal compartments of the legs. Later on, weakness and atrophy may expand to the proximal muscles of the lower limbs and/or to the distal upper limbs.
None
The disease is caused by variants affecting the gene represented in this entry.
Sequence Similarities
Belongs to the cation transport ATPase (P-type) (TC 3.A.3) family. Type IB subfamily.
Tissue Specificity
Widely expressed including in heart, brain, lung, muscle, kidney, pancreas, and to a lesser extent placenta (PubMed:8490646, PubMed:8490659). Expressed in fibroblasts, aortic smooth muscle cells, aortic endothelial cells and umbilical vein endothelial cells (at protein level) (PubMed:16371425).
Isoform 3
Expressed in cerebellum and brain cortex.
Cellular localization
- Golgi apparatus
- trans-Golgi network membrane
- Multi-pass membrane protein
- Cell membrane
- Multi-pass membrane protein
- Melanosome membrane
- Multi-pass membrane protein
- Early endosome membrane
- Multi-pass membrane protein
- Cell projection
- Axon
- Cell projection
- Dendrite
- Postsynaptic density
- 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).
- Isoform 3
- Cytoplasm
- Cytosol
- Isoform 5
- Endoplasmic reticulum
Alternative names
MC1, MNK, ATP7A, Copper-transporting ATPase 1, Copper pump 1, Menkes disease-associated protein