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Information on EC 7.2.2.9 - P-type Cu2+ transporter and Organism(s) Homo sapiens and UniProt Accession Q04656

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IUBMB Comments
A P-type ATPase that undergoes covalent phosphorylation during the transport cycle. The enzyme from the termophilic archaeon Archaeoglobus fulgidus is involved in copper extrusion from the cell [1,2].
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Homo sapiens
UNIPROT: Q04656
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The taxonomic range for the selected organisms is: Homo sapiens
The expected taxonomic range for this enzyme is: Bacteria, Eukaryota, Archaea
Synonyms
atp7b, atp7a, copper transporter, copper-transporting atpase, copper-transporting p-type atpase, menkes protein, cu-atpase, copper transporting p-type atpase, copper atpase, copper-transporting p-type, more
SYNONYM
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
copper(I)-transporting PIB-type ATPase
-
copper-transporting ATPase
-
Menkes copper ATPase
-
Menkes copper-transporting ATPase
-
Menkes disease protein
Menkes protein
-
MNK protein
-
adenosine 5'-triphosphatase
-
-
-
-
ATP hydrolase
-
-
-
-
ATP phosphohydrolase
-
-
-
-
ATP7B
ATPase
-
-
-
-
complex V
-
-
-
-
copper ATPase
-
-
copper translocating P-type ATPase
-
-
copper transporter
copper transporting ATPase
-
-
copper-ATPase
-
-
copper-translocating Menkes P-type ATPase
-
-
copper-translocating Wilson P-type ATPase
-
-
copper-transporting ATPase
copper-transporting P-type
-
-
copper-transporting P-type ATPase
Cu+-ATPase
-
-
Cu-ATPase
Cu-translocating P-type ATPase
-
-
Cu-transporting P-type ATPase
-
-
Cu2+-ATPase
CUA-1 ATPase
-
-
-
-
Menkes copper P-type ATPase
-
-
Menkes copper transporting P-type ATPase
-
-
Menkes copper-translocating P-type ATPase
-
-
Menkes disease-associated protein
-
-
-
-
Menkes disease-associated protein homolog
-
-
-
-
Menkes P-type ATPase
-
-
-
-
Menkes protein
-
-
MNK Cu-ATPase
-
-
Pinal night-specific ATPase
-
-
-
-
WCBD
-
-
-
-
Wilson copper ATPase
-
Wilson copper-transporting ATPase
-
Wilson copper-transporting P-type ATPase
-
-
-
-
Wilson disease copper-transporting ATPase
Wilson disease protein
Wilson disease-associated protein
-
-
-
-
Wilson disease-associated protein homolog
-
-
-
-
Wilson protein
Wilson's desease protein
-
-
Wilson's disease copper-transporting ATPase
-
-
Wilson's disease protein
-
-
WND Cu-ATPase
-
-
WND protein
-
additional information
REACTION
REACTION DIAGRAM
COMMENTARY hide
ORGANISM
UNIPROT
LITERATURE
ATP + H2O + Cu2+[side 1] = ADP + phosphate + Cu2+[side 2]
show the reaction diagram
the N-domain can not hydrolyse ATP
-
REACTION TYPE
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
hydrolysis of phosphoric ester
transmembrane transport
SYSTEMATIC NAME
IUBMB Comments
ATP phosphohydrolase (P-type, Cu2+-exporting)
A P-type ATPase that undergoes covalent phosphorylation during the transport cycle. The enzyme from the termophilic archaeon Archaeoglobus fulgidus is involved in copper extrusion from the cell [1,2].
CAS REGISTRY NUMBER
COMMENTARY hide
9000-83-3
-
SUBSTRATE
PRODUCT                       
REACTION DIAGRAM
ORGANISM
UNIPROT
COMMENTARY
(Substrate) hide
LITERATURE
(Substrate)
COMMENTARY
(Product) hide
LITERATURE
(Product)
Reversibility
r=reversible
ir=irreversible
?=not specified
ATP + H2O + Cu2+/in
ADP + phosphate + Cu2+/out
show the reaction diagram
ATP + H2O + Cu+/in
ADP + phosphate + Cu+/out
show the reaction diagram
Wilson protein domains 5 and 6 and their interplay with domain 4 and the copper chaperone HAH1 in copper uptake. Wilson protein domain 4 and domain 2 are two acceptors of Cu(I) from the cytosolic metallochaperone HAH1, which then somehow route copper to Wilson protein domain 5 and 6, before the ATP-driven transport of copper across the vesicular membrane
-
-
?
ATP + H2O + Cu2+/in
ADP + phosphate + Cu2+/out
show the reaction diagram
additional information
?
-
NATURAL SUBSTRATE
NATURAL PRODUCT
REACTION DIAGRAM
ORGANISM
UNIPROT
COMMENTARY
(Substrate) hide
LITERATURE
(Substrate)
COMMENTARY
(Product) hide
LITERATURE
(Product)
REVERSIBILITY
r=reversible
ir=irreversible
?=not specified
ATP + H2O + Cu2+/in
ADP + phosphate + Cu2+/out
show the reaction diagram
ATP + H2O + Cu2+/in
ADP + phosphate + Cu2+/out
show the reaction diagram
additional information
?
-
COFACTOR
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
IMAGE
METALS and IONS
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
copper
the enzyme contains two Cu(I)-binding sites. Copper binding within the His-Met-loop stabilizes Cu(I) and protects it from oxidation, which may further aid the transfer of copper from ATP7A to acceptor proteins
Cu+
structural characterization of the apo- and copper(I)-form of the third domain of ATP7A. Investigation of the interaction of MNK3 (the third metal-binding domain, a copper(I)-transporrting ATPase) with the partner human protein HAH1. MNK3 is the most differentiated metal-binding domain in ATP7A. Metallation of MNK3 could be an event quite suited to signal high intracellular copper(I) concentration and could trigger the appropriate response
Mg2+
required
additional information
INHIBITOR
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
IMAGE
Bathocuproine disulfonate
-
a copper chelator, reduced ATP7B activity
cisplatin
DDP, shown to inhibit the transport of copper, pH 4.6
Cu2+
shown to inhibit the transport of cisplatin
vanadate
-
50% inactivation at 0.05 mM
additional information
-
in hepatocytes, ATP7B-mediated efflux does not play a major role in determining cell sensitivity to cis-diamminedichloroplatinum
-
ACTIVATING COMPOUND
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
IMAGE
glutaredoxin
is essential for ATPase function and catalysis either the reduction of intramolecular disulphide bonds or the deglutathionylation of the cysteine residues within the CxxC motifs to facilitate copper-binding for subsequent transport
cis-diamminedichloroplatinum
-
DDP, stimulates catalytic phosphorylation of ATP7B
-
glutaredoxin
is essential for ATPase function and catalysis either the reduction of intramolecular disulphide bonds or the deglutathionylation of the cysteine residues within the CxxC motifs to facilitate copper-binding for subsequent transport
glutaredoxin-1
-
is essential in interaction with ATP7A and ATP7B via their N-termini for stabilizing their activities
-
Insulin
increase of mRNA and protein levels of ATP7A
-
KM VALUE [mM]
SUBSTRATE
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
IMAGE
0.0009 - 2.02
ATP
additional information
additional information
-
Km-value for copper varies insignificantly between different mutants and wild-type enzyme
-
SPECIFIC ACTIVITY [µmol/min/mg]
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
0.081
-
partially purifed recombinant ATP7B in microsomes, copper-dependent, steady-state ATPase, 37°C, pH 6.0, in presence of copper and copper chelator
0.112
-
partially purifed recombinant ATP7B in microsomes, copper-dependent, steady-state ATPase, 37°C, pH 6.0 in presence of copper
additional information
pH OPTIMUM
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
5
-
assay at
6
-
assay at
6.9
transport assay at
7.5
assay at
pH RANGE
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
4.6 - 6.9
ability of wild-type ATP7B to transport copper when exposed to 2 microM copper shown to be greater at pH 4.6 than at pH 6.9, ATP-dependent accumulation of cisplatin shown at 4.6
TEMPERATURE OPTIMUM
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
25
assay at
ORGANISM
COMMENTARY hide
LITERATURE
UNIPROT
SEQUENCE DB
SOURCE
SOURCE TISSUE
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
SOURCE
model for the ATP7A trafficking in enterocytes
Manually annotated by BRENDA team
ATP7A shown to be expressed in 23.5% of clinical colon cancer specimens but not in the adjacent normal epithelium
Manually annotated by BRENDA team
Menkes disease protein, i.e. ATP7A
Manually annotated by BRENDA team
ATP7A is present on apical domains of duodenal enterocytes in control rats and on brush-border and basolateral membrane domains in iron-deprived rats
Manually annotated by BRENDA team
isolated from Menkes disease patients, transfection with ATP7A
Manually annotated by BRENDA team
overexpressing ATP7A or ATP7B
Manually annotated by BRENDA team
fetal. Menkes disease protein, i.e. ATP7A
Manually annotated by BRENDA team
cellular distribution of ATP7B, stable ATP7B pool localized to the tight junctions that seal the bile canaliculi shown
Manually annotated by BRENDA team
ATP7B is expressed in bile duct epithelial cells, where it may mediate copper secretion into bile fluid
Manually annotated by BRENDA team
-
expression is greater in lactating tissue than in nonlactating tissue, detected in luminal epithelial cells of the alveoli and ducts but not in myoepithelial cells
Manually annotated by BRENDA team
-
ATP7A and ATP7B
Manually annotated by BRENDA team
the overexpression of ATP7B in hepatocellular carcinoma might be associated with unfavorable clinical outcome in patients treated with cisplantin-based chemotherapy
Manually annotated by BRENDA team
-
-
Manually annotated by BRENDA team
-
hippocampal, neuronal MNK trafficking may occur independently of its catalytic cycle
Manually annotated by BRENDA team
heterologous expression into Xenopus laevis
Manually annotated by BRENDA team
Wilson disease protein is present only in the syncytiotrophoblast
Manually annotated by BRENDA team
additional information
LOCALIZATION
ORGANISM
UNIPROT
COMMENTARY hide
GeneOntology No.
LITERATURE
SOURCE
within ARPE-19 cell the Wilson disease protein shows a perinuclear and cytoplasmic distribution
Manually annotated by BRENDA team
-
97 kDa variant
Manually annotated by BRENDA team
-
mainly localized in the late endosomes in both the steady and copper-loaded states. ATP7B translocates copper from the cytosol to the late endosomal lumen, thus participating in biliary copper excretion via lysosomes
Manually annotated by BRENDA team
ATP7B interaction with p62 is a key component of the copper-induced trafficking pathway that delivers ATP7B to subapical vesicles of hepatocytes for the removal of excess copper into bile
Manually annotated by BRENDA team
-
64 kDa variant
Manually annotated by BRENDA team
in HepG2 cells, elevated copper levels stimulates trafficking of ATP7B to pericanalicular vesicles. Mutations of an endocytic retrieval signal in ATP7B cause the protein to constitutively localize to vesicles and not to plasma membrane. The vesicular compartment is the final trafficking destination for ATP7B
Manually annotated by BRENDA team
within ARPE-19 cell the Wilson disease protein shows a perinuclear and cytoplasmic distribution
-
Manually annotated by BRENDA team
the enzyme redistributes from Golgi apparatus into vesicles in high copper conditions
Manually annotated by BRENDA team
additional information
GENERAL INFORMATION
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
malfunction
inactivation of ATP7A results in the neurodegenerative disorder Menkes disease
physiological function
ATP7A and ATP7B are two human P1B-type ATPases that have a crucial role in maintaining copper(I) homeostasis
malfunction
metabolism
physiological function
additional information
UNIPROT
ENTRY NAME
ORGANISM
NO. OF AA
NO. OF TRANSM. HELICES
MOLECULAR WEIGHT[Da]
SOURCE
SEQUENCE
LOCALIZATION PREDICTION?
ATP7A_HUMAN
1500
7
163373
Swiss-Prot
-
MOLECULAR WEIGHT
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
165000
180000
-
x * 180000, ATP7A, SDS-PAGE, x * 165000, ATP7B, SDS-PAGE
195000
x * 195000, GST-tagged enzyme, SDS-PAGE
64000
-
x * 97000, splicing variant in cytosol and plasma membrane, SDS-PAGE, x * 64000, splicing variant in nucleus, SDS-PAGE
97000
-
x * 97000, splicing variant in cytosol and plasma membrane, SDS-PAGE, x * 64000, splicing variant in nucleus, SDS-PAGE
SUBUNIT
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
additional information
POSTTRANSLATIONAL MODIFICATION
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
phosphoprotein
-
phosphoprotein
additional information
-
ATP7B in Hep-G2 and HEK-293 cells differ in size, but not in post-translational modifications
CRYSTALLIZATION (Commentary)
ORGANISM
UNIPROT
LITERATURE
solution structures of ATP-free and ATP-bound N-MNK
PROTEIN VARIANTS
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
G853R
the mutation occurring in the A-domain of ATP7A affects the network of communication with the other domains of the enzyme
G860V
the mutation occurring in the A-domain of ATP7A destabilizes the fold of the domain
L873R
the mutation occurring in the A-domain of ATP7A affects the network of communication within the domain
M672G/M674A/H676A/H677G/H682A/H683G
the mutant shows decreased affinity for copper. The mutations within the His/Met-rich segment Met672-Pro707 (HM-loop) do not prevent the ability of the enzyme to form a phosphorylated intermediate during ATP hydrolysis but inhibit subsequent dephosphorylation, a step associated with copper release
M687A/M692A
the mutant shows decreased affinity for copper. The mutations within the His/Met-rich segment Met672-Pro707 (HM-loop) do not prevent the ability of the enzyme to form a phosphorylated intermediate during ATP hydrolysis but inhibit subsequent dephosphorylation, a step associated with copper release
C1375S
the mutant exhibits trafficking behavior similar to that observed for the wild type enzyme
C983A/C985A
-
site-directed mutagenesis of CXC copper binding motif in the transmembrane copper site TM6, absence of alkali labile phosphoenzyme formation
D1027A
inactivating mutation of catalytic Asp1027, surface targeting
D1027N
-
site-directed mutagenesis of the P domain, absence of alkali labile phosphoenzyme formation
D1230A
-
retains 21% of the activity compared to wild type
D1267V
naturally occuring mutation in the ATP-binding loop of ATP7B, deleterious mutation, unable to grow under iron limitation
D40A
-
site-directed mutagenesis, inactive mutant
DD1219/1220AA
-
retains 80% of the activity compared to wild type
E1064A
the mutation abolishes ATP binding to the N-domain. In the cell, neither the stability nor targeting of mutant E1064A to the trans-Golgi network differs significantly from the wild type enzyme
E1064K
located in the ATP-binding domain, marked impairment in copper transport function, identified as disease-causing mutation
E1173G
naturally occuring mutation in the ATP-binding loop of ATP7B, temperature-sensitive mutant, unable to complement the enzyme-deficient yeast mutant at 37°C, but complement the enzyme-deficient yeast mutant at 30°C
E45A
-
site-directed mutagenesis, inactive mutant
F37A
-
site-directed mutagenesis, the mutant is partially copper-responsive
F39A
-
site-directed mutagenesis, inactive mutant
F39W
-
site-directed mutagenesis, inactive mutant
G1000R
naturally occuring mutation in the ATP-binding loop of ATP7B, deleterious mutation, unable to grow under iron limitation
G1101R
naturally occuring mutation in the ATP-binding loop of ATP7B, deleterious mutation, unable to grow under iron limitation
G1176E
naturally occuring mutation in the ATP-binding loop of ATP7B, intermediate mutant, unable to grow at 37°C without addition of copper or iron
G1287S
naturally occuring mutation in the ATP-binding loop of ATP7B, intermediate mutant, unable to grow under iron limitation
G43A
-
site-directed mutagenesis, inactive mutant
H1069Q
thermolabile mutant with impaired ATP binding. The mutation greatly destabilizes protein both in vitro and in cells
H1086Q
-
retains 20% of the activity compared to wild type
I1102T
naturally occuring mutation in the ATP-binding loop of ATP7B, deleterious mutation, unable to grow under iron limitation
I1148T
naturally occuring mutation in the ATP-binding loop of ATP7B, mild mutation, unable to grow under iron limitation
K1097A
-
retains 91% of the activity compared to wild type
K1233M
-
retains 17% of the activity compared to wild type
L1043P
naturally occuring mutation in the ATP-binding loop of ATP7B, deleterious mutation, unable to grow under iron limitation
L1083F
partial complementation at 30°C, severe deficit at 37°C observed, marked impairment in copper transport function found, identified as disease-causing mutation
L1373P
the mutant exhibits abnormal trafficking behavior, the half-life of the mutant protein is significantly shorter than that of the wild type enzyme
L1373R
the mutant exhibits abnormal trafficking behavior, the half-life of the mutant protein is significantly shorter than that of the wild type enzyme
M1169V
partial complementation at 30°C and 37°C observed, partial reduction in ATP7B function´´, identified as disease-causing mutation
N1366A
-
inactive
N41A
-
site-directed mutagenesis, the mutant is partially copper-responsive
N41S
-
site-directed mutagenesis, the mutant is partially copper-responsive
P1379
the mutant exhibits trafficking behavior similar to that observed for the wild type enzyme
P1386S
-
naturally occuring mutation, a transition mutation of c.4156C>T in exon 22
R1208G
-
retains the activity of the wild type
R1228T
naturally occuring mutation in the ATP-binding loop of ATP7B, the mutant behaves similar to the wild-type enzyme, complements the enzyme-deficient yeast mutant
S1432A
-
site-directed mutagenesis of a constitutively phosphorylated site, mutation leads to mislocation of the enzyme in presence of Cu2+
S1469A
-
site-directed mutagenesis of a copper-responsive phosphorylation site, mutation leads to mislocation of the enzyme in presence of Cu2+
T1434M
the mutant exhibits trafficking behavior similar to that observed for the wild type enzyme
T991M
naturally occuring mutation in the ATP-binding loop of ATP7B, mild mutation
T994I
-
naturally occuring mutation, a transition mutation of c.2981C>T in exon 15
V1106D
located in the ATP-binding domain, marked impairment in copper transport function, identified as disease-causing mutation
V1239G
naturally occuring mutation in the ATP-binding loop of ATP7B, deleterious mutation, unable to grow under iron limitation
V42A
-
site-directed mutagenesis, inactive mutant
X1466R
the mutant exhibits trafficking behavior similar to that observed for the wild type enzyme
Y44A
-
site-directed mutagenesis, inactive mutant
Y44W
-
site-directed mutagenesis, the mutant is partially copper-responsive
additional information
GENERAL STABILITY
ORGANISM
UNIPROT
LITERATURE
the C-terminus of ATP7B is necessary for protein stability
PURIFICATION (Commentary)
ORGANISM
UNIPROT
LITERATURE
chitin resin column chromatography
recombinant His-tagged ATP7A or MNK from Escherichia coli strain BL21(DE3)
enzyme is truncated by 5 of the six metal binding domains and endowed with an N-terminal histidine-tag for affinity purification, recombinantly expressed in Escherichia coli and reconstituted into proteoliposomes
fusion protein of glutathione-S-transferase and Wilson-disease protein expressed in Escherichia coli
-
isolation of membrane vesicles from yeast expressing recombinant enzyme
-
purification of fusion protein by chitin affinity chromatography
-
recombinant ATP7B from Spodoptera frugiperda Sf9 cell membranes
-
recombinant myc-tagged ATP7B is isolated from the microsomal fraction of COS-1 cell homogenates
-
recombinantly expressed domain 1, 3, 4, 5 and 6
CLONED (Commentary)
ORGANISM
UNIPROT
LITERATURE
expressed in Sf9 insect cells
expression in CHO-K1 cells
expression of a chimeric metal bidnding sequence with the Menkes disease protein carrying the binding motif of bacterial Hg(II) binding protein MerP. This chimeric protein shows differences in structure and the dynamics of the binding site that may account for metal specificity
expression of the DNA sequence encoding MNK3, corresponding to amino acids 275-352 of ATP7A in Escherichia coli strain BL21 (DE3)pLysS. Introduction of a C-terminal expression tag including His6 to ease purification
gene ATP7A, overexpression of His-tagged ATP7A or MNK in Escherichia coli strain BL21(DE3), overexpression of the soluble nucleotide-binding domain of MNK protein, comprising amino acids 1051-1231
ATP7A and ATP7B genotyping
-
ATP7A is located on Xq13.2-13.3, spans about 150 kb and has 23 exons, ATP7B is located on chromosome 13, spans about 80 kb and contains 21 exons, ATP7A and ATP7B expression pattern analysis, overview
-
ATP7B expression in Sf9 insect cells, epitope-tagged ATP7B-HA56 variant generated and expressed in oocytes of Xenopus laevis, N-terminal and C-terminal deletions included to analyze delivery of ATP7B-HA56 from the membrane, wild-type ATP7B used as a control
CHO-K1 cells are transfected with wild-type human MNK cDNA
-
cloning of the 5'-end of the Wilson disease gene ATP7B
-
construction and expression of the fusion protein of glutathione-S-transferase and Wilson-disease protein and expression in Escherichia coli
-
DNA sequence and genetic structure analysis of ATP7B from renal and hepatic tissue and comparison, recombinant ATP7B expressed in renal cells is similar to hepatic protein in size and trafficking, ATP7B lacking the exon 1 sequence shows cell-specific trafficking in polarized renal and hepatic cells, overview
-
enzyme is expressed using pGEX-4T-2, subcloned into pGEX-6P-2 and expressed in Escherichia coli strain BL21
-
expressed in SV40-transformed Menkes-null fibroblasts
expression in Escherichia coli as a GST fusion protein
-
expression in Escherichia coli of the N-domain fused with a chitin-binding domain, several N-domain mutants cloned using the same procedure
-
expression in Saccharomyces cerevisiae
-
expression in Spodoptera frugiperda Sf-9 cells
expression of ATP7B in Spodoptera frugiperda Sf9 cell membranes via baculovirus transfection, overexpression of ATP7B in ovary cells causes increased cellular resistance to cisplatin, a chemotherapeutic agent
-
expression of domain 1, 3, 4, 5 and 6 in Escherichia coli
expression of Menkes disease protein with an N-terminal Glu-Glu tag in Sf9 cells
-
expression of mutant enzymes in MDCK cells and in CHO cells
-
expression of the wild type and mutant proteins in Saccharomyces cerevisiae
-
expression of the wild type and truncated mutants in COS-7 cells
-
expression of wild type and several mutants in Saccharomyces cerevisiae and CHO cells
-
expression of wild-type and mutant ATP7B ATP binding loops in ccc2-deficient Saccharomyces cerevisiae strain
expression of wild-type and mutant myc-tagged ATP7Bs in COS1 cells using an adenoviral vector
-
gene ATP7A, genetic mapping and expression analysis of splicing variants, overview
-
gene ATP7A, located on chromosome Xq13.1-q21, genotyping
-
gene ATP7B, expression in HEK-293 cells and in mesenchymal stem cells derived from bone marrow, viability of these cells is significantly enhanced after ATP7B transduction, expression analysis, overview
-
infection of Sf9 cells with baculoviral constructs encoding wild-type ATP7B and a mutant variant unable to transport copper
mutant variants of ATP7B expressed in protease-deficient Saccharomyces cerevisiae strain BJ2168 and in ccc2 and fet3 mutant strains lacking functional CCC2 and FET3 genes
overexpression of ATP7A and ATP7B in Me32a cells mediating resistance to bioavailable platinum analogue agents DDP and JM118, expression of ATP7A and ATP7B in the two-hydrid expression system for interaction analysis
-
rescue and correction of the Cu accumulation defect by expression of wild type MNK in non-polarized BHK cells
-
the enzyme is truncated by 5 of the six metal binding domains and endowed with an N-terminal histidine-tag for affinity purification. This construct is able to functionally complement a yeast strain defective in its native copper ATPase CCC2. Expression in Escherichia coli
EXPRESSION
ORGANISM
UNIPROT
LITERATURE
iron deprivation induces all three splicing variants 5-7fold
-
APPLICATION
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
drug development
medicine
studies on copper deficiency during pregnancy, Menkes and Wilson disease
drug development
review on transport mechanisms of platinum-based antitumor agents
medicine
REF.
AUTHORS
TITLE
JOURNAL
VOL.
PAGES
YEAR
ORGANISM (UNIPROT)
PUBMED ID
SOURCE
Vulpe, C.; Levinson, B.; Whitney, S.; Packman, S.; Gitschier, J.
Isolation of a candidate gene for Menkes disease and evidence that it encodes a copper-transporting ATPase
Nature
3
7-13
1993
Homo sapiens
Manually annotated by BRENDA team
Petrukhin, K.; Lutsenko, S.; Chernov, I.; Ross, B.M.; Kaplan, J.H.; Giliam, T.C.
Characterization of the Wilson disease gene encoding a P-type copper transporting ATPase: genomic organization, alternative splicing, and structural function predictions
Hum. Mol. Genet.
3
1647-1656
1994
Homo sapiens
Manually annotated by BRENDA team
DiDonato,M.; Narindrasorasak, S.; Sarkar, B.
Expression, purification, and metal binding characteristics of the putative copper binding domain from the Wilson disease copper transporting ATPase (ATP7B)
Adv. Exp. Med. Biol.
448
165-173
1999
Homo sapiens
Manually annotated by BRENDA team
DiDonato, M.; Hsu, H.F.; Narindrasorasak, S.; Que, L.; Sarkar, B.
Copper-induced conformational changes in the N-terminal domain of the Wilson disease copper-transporting ATPase
Biochemistry
39
1890-1896
2000
Homo sapiens
Manually annotated by BRENDA team
Harada, M.; Sakisaka, S.; Kawaguchi, T.; Kimura, R.; Taniguchi, E.; Koga, H.; Hanada, S.; Baba, S.; Furuta, K.; Kumashiro, R.; Sugiyama, T.; Sata, M.
Copper does not alter the intracellular distribution of ATP7B, a copper-transporting ATPase
Biochem. Biophys. Res. Commun.
275
871-876
2000
Homo sapiens
Manually annotated by BRENDA team
Ackland, M.L.; Anikijenko, P.; Michalczyk, A.; Mercer, J.F.B.
Expression of Menkes copper-transporting ATPase, MNK, in lactating human breast: possible role in copper transport into milk
J. Histochem. Cytochem.
47
1553-1561
1999
Homo sapiens
Manually annotated by BRENDA team
Quian, Y.; Tiffany-Castiglioni, E.; Welsh, J.; Harris, E.D.
Copper efflux from murine microvascular cells requires expression of the Menkes disease Cu-ATPase
J. Nutr.
128
1276-1282
1998
Homo sapiens, Mus musculus
Manually annotated by BRENDA team
Voskoboinik, I.; Strausak, D.; Greenough, M.; Brooks, H.; Petris, M.; Smith, S.; Mercer, J.F.; Camakaris, J.
Functional analysis of the N-terminal CXXC metal-binding motifs in the human Menkes copper-transporting P-type ATPase expressed in cultured mammalian cells
J. Biol. Chem.
274
22008-22012
1999
Homo sapiens
Manually annotated by BRENDA team
Voskoboinik, I.; Mar, J.; Camakaris, J.
Mutational analysis of the Menkes copper P-type ATPase (ATP7A)
Biochem. Biophys. Res. Commun.
301
488-494
2003
Homo sapiens
Manually annotated by BRENDA team
Fatemi, N.; Sarkar, B.
Structural and functional insights of Wilson disease copper-transporting ATPase
J. Bioenerg. Biomembr.
34
339-349
2002
Homo sapiens
Manually annotated by BRENDA team
Lutsenko, S.; Efremov, R.G.; Tsivkovskii, R.; Walker, J.M.
Human copper-transporting ATPase ATP7B (the Wilson's disease protein): biochemical properties and regulation
J. Bioenerg. Biomembr.
34
351-362
2002
Homo sapiens
Manually annotated by BRENDA team
Voskoboinik, I.; Camakaris, J.
Menkes copper-translocating P-type ATPase (ATP7A): Biochemical and cell biology properties, and role in Menkes disease
J. Bioenerg. Biomembr.
34
363-371
2002
Homo sapiens
Manually annotated by BRENDA team
Voskoboinik, I.; Mar, J.; Strausak, D.; Camakaris, J.
The regulation of catalytic activity of the Menkes copper-translocating P-type ATPase. Role of high affinity copper-binding sites
J. Biol. Chem.
276
28620-28627
2001
Homo sapiens
Manually annotated by BRENDA team
Vanderwerf, S.M.; Cooper, M.J.; Stetsenko, I.V.; Lutsenko, S.
Copper specifically regulates intracellular phosphorylation of the Wilson's disease protein, a human copper-transporting ATPase
J. Biol. Chem.
276
36289-36294
2001
Homo sapiens
Manually annotated by BRENDA team
DiDonato, M.; Zhang, J.; Que, L.Jr.; Sarkar, B.
Zinc binding to the NH2-terminal domain of the Wilson disease copper-transporting ATPase: implications for in vivo metal ion-mediated regulation of ATPase activity
J. Biol. Chem.
277
13409-13414
2002
Homo sapiens
Manually annotated by BRENDA team
Morgan, C.T.; Tsivkovskii, R.; Kosinsky, Y.A.; Efremov, R.G.; Lutsenko, S.
The distinct functional properties of the nucleotide-binding domain of ATP7B, the human copper-transporting ATPase: analysis of the Wilson disease mutations E1064A, H1069Q, R1151H, and C1104F
J. Biol. Chem.
279
36363-36371
2004
Homo sapiens
Manually annotated by BRENDA team
Sugeno, H.; Takebayashi, Y.; Higashimoto, M.; Ogura, Y.; Shibukawa, G.; Kanzaki, A.; Terada, K.; Sugiyama, T.; Watanabe, K.; Katoh, R.; Nitta, Y.; Fukushima, T.; Koyama, Y.; Inoue, N.; Sekikawa, K.; Ogawa, K.; Sato, Y.; Takenoshita, S.
Expression of copper-transporting P-type adenosine triphosphatase (ATP7B) in human hepatocellular carcinoma
Anticancer Res.
24
1045-1048
2004
Homo sapiens (P35670), Homo sapiens
Manually annotated by BRENDA team
Lim, C.M.; Cater, M.A.; Mercer, J.F.; La Fontaine, S.
Copper-dependent interaction of glutaredoxin with the N termini of the copper-ATPases (ATP7A and ATP7B) defective in Menkes and Wilson diseases
Biochem. Biophys. Res. Commun.
348
428-436
2006
Homo sapiens (P35670), Homo sapiens (Q04656)
Manually annotated by BRENDA team
Hung, Y.H.; Layton, M.J.; Voskoboinik, I.; Mercer, J.F.; Camakaris, J.
Purification and membrane reconstitution of catalytically active Menkes copper transporting P-type ATPase (MNK; ATP7A)
Biochem. J.
401
569-579
2007
Homo sapiens
Manually annotated by BRENDA team
Bunce, J.; Achila, D.; Hetrick, E.; Lesley, L.; Huffman, D.L.
Copper transfer studies between the N-terminal copper binding domains one and four of human Wilson protein
Biochim. Biophys. Acta
1760
907-912
2006
Homo sapiens (Q64446), Homo sapiens
Manually annotated by BRENDA team
Fanni, D.; Pilloni, L.; Orru, S.; Coni, P.; Liguori, C.; Serra, S.; Lai, M.L.; Uccheddu, A.; Contu, L.; Van Eyken, P.; Faa, G.
Expression of ATP7B in normal human liver
Eur. J. Histochem.
49
371-378
2005
Homo sapiens (P35670), Homo sapiens
Manually annotated by BRENDA team
Portmann, R.; Solioz, M.
Purification and functional reconstitution of the human Wilson copper ATPase, ATP7B
FEBS Lett.
579
3589-3595
2005
Homo sapiens (P35670), Homo sapiens
Manually annotated by BRENDA team
Cater, M.A.; La Fontaine, S.; Shield, K.; Deal, Y.; Mercer, J.F.
ATP7B mediates vesicular sequestration of copper: insight into biliary copper excretion
Gastroenterology
130
493-506
2006
Homo sapiens (P35670)
Manually annotated by BRENDA team
Hsi, G.; Cullen, L.M.; Moira Glerum, D.; Cox, D.W.
Functional assessment of the carboxy-terminus of the Wilson disease copper-transporting ATPase, ATP7B
Genomics
83
473-481
2004
Homo sapiens (P35670)
Manually annotated by BRENDA team
Krajacic, P.; Qian, Y.; Hahn, P.; Dentchev, T.; Lukinova, N.; Dunaief, J.L.
Retinal localization and copper-dependent relocalization of the Wilson and Menkes disease proteins
Invest. Ophthalmol. Vis. Sci.
47
3129-3134
2006
Homo sapiens (P35670), Homo sapiens, Mus musculus (Q64430), Mus musculus
Manually annotated by BRENDA team
Ravia, J.J.; Stephen, R.M.; Ghishan, F.K.; Collins, J.F.
Menkes copper ATPase (Atp7a) is a novel metal-responsive gene in rat duodenum, and immunoreactive protein is present on brush-border and basolateral membrane domains
J. Biol. Chem.
280
36221-36227
2005
Homo sapiens (Q04656)
Manually annotated by BRENDA team
Lim, C.M.; Cater, M.A.; Mercer, J.F.; La Fontaine, S.
Copper-dependent interaction of dynactin subunit p62 with the N terminus of ATP7B but not ATP7A
J. Biol. Chem.
281
14006-14014
2006
Homo sapiens (P35670), Homo sapiens
Manually annotated by BRENDA team
Banci, L.; Bertini, I.; Cantini, F.; DellaMalva, N.; Herrmann, T.; Rosato, A.; Wthrich, K.
Solution structure and intermolecular interactions of the third metal-binding domain of ATP7A, the Menkes disease protein
J. Biol. Chem.
281
29141-29147
2006
Homo sapiens (Q04656), Homo sapiens
Manually annotated by BRENDA team
Hardman, B.; Manuelpillai, U.; Wallace, E.M.; van de Waasenburg, S.; Cater, M.; Mercer, J.F.; Ackland, M.L.
Expression and localization of menkes and Wilson copper transporting ATPases in human placenta
Placenta
25
512-517
2004
Homo sapiens (P35670), Homo sapiens (Q04656)
Manually annotated by BRENDA team
Achila, D.; Banci, L.; Bertini, I.; Bunce, J.; Ciofi-Baffoni, S.; Huffman, D.L.
Structure of human Wilson protein domains 5 and 6 and their interplay with domain 4 and the copper chaperone HAH1 in copper uptake
Proc. Natl. Acad. Sci. USA
103
5729-5734
2006
Homo sapiens (P35670), Homo sapiens
Manually annotated by BRENDA team
DeSilva, T.M.; Veglia, G.; Opella, S.J.
Solution structures of the reduced and Cu(I) bound forms of the first metal binding sequence of ATP7A associated with Menkes disease
Proteins
61
1038-1049
2005
Homo sapiens (Q04656), Homo sapiens
Manually annotated by BRENDA team
Lutsenko, S.; LeShane, E.S.; Shinde, U.
Biochemical basis of regulation of human copper-transporting ATPases
Arch. Biochem. Biophys.
463
134-148
2007
Homo sapiens (P35670), Homo sapiens (Q04656), Homo sapiens
Manually annotated by BRENDA team
Lutsenko, S.; Gupta, A.; Burkhead, J.L.; Zuzel, V.
Cellular multitasking: The dual role of human Cu-ATPases in cofactor delivery and intracellular copper balance
Arch. Biochem. Biophys.
476
22-32
2008
Homo sapiens (P35670), Homo sapiens (Q04656), Homo sapiens
Manually annotated by BRENDA team
Hardman, B.; Michalczyk, A.; Greenough, M.; Camakaris, J.; Mercer, J.F.; Ackland, M.L.
Hormonal regulation of the Menkes and Wilson copper-transporting ATPases in human placental Jeg-3 cells
Biochem. J.
402
241-250
2007
Homo sapiens (P35670), Homo sapiens (Q04656)
Manually annotated by BRENDA team
Loerinczi, E.; Tsivkovskii, R.; Haase, W.; Bamberg, E.; Lutsenko, S.; Friedrich, T.
Delivery of the Cu-transporting ATPase ATP7B to the plasma membrane in Xenopus oocytes
Biochim. Biophys. Acta
1778
896-906
2008
Homo sapiens (P35670)
Manually annotated by BRENDA team
Bartee, M.Y.; Lutsenko, S.
Hepatic copper-transporting ATPase ATP7B: function and inactivation at the molecular and cellular level
Biometals
20
627-637
2007
Homo sapiens (P35670)
Manually annotated by BRENDA team
Kuo, M.T.; Chen, H.H.; Song, I.S.; Savaraj, N.; Ishikawa, T.
The roles of copper transporters in cisplatin resistance
Cancer Metastasis Rev.
26
71-83
2007
Homo sapiens (P35670), Homo sapiens (Q04656), Homo sapiens
Manually annotated by BRENDA team
Owatari, S.; Akune, S.; Komatsu, M.; Ikeda, R.; Firth, S.D.; Che, X.F.; Yamamoto, M.; Tsujikawa, K.; Kitazono, M.; Ishizawa, T.; Takeuchi, T.; Aikou, T.; Mercer, J.F.; Akiyama, S.; Furukawa, T.
Copper-transporting P-type ATPase, ATP7A, confers multidrug resistance and its expression is related to resistance to SN-38 in clinical colon cancer
Cancer Res.
67
4860-4868
2007
Homo sapiens (Q04656), Homo sapiens
Manually annotated by BRENDA team
Hernandez, S.; Tsuchiya, Y.; Garcia-Ruiz, J.P.; Lalioti, V.; Nielsen, S.; Cassio, D.; Sandoval, I.V.
ATP7B copper-regulated traffic and association with the tight junctions: copper excretion into the bile
Gastroenterology
134
1215-1223
2008
Homo sapiens (P35670)
Manually annotated by BRENDA team
Hsi, G.; Cullen, L.M.; Macintyre, G.; Chen, M.M.; Glerum, D.M.; Cox, D.W.
Sequence variation in the ATP-binding domain of the Wilson disease transporter, ATP7B, affects copper transport in a yeast model system
Hum. Mutat.
29
491-501
2008
Homo sapiens (P35670), Homo sapiens
Manually annotated by BRENDA team
de Bie, P.; Muller, P.; Wijmenga, C.; Klomp, L.W.
Molecular pathogenesis of Wilson and Menkes disease: correlation of mutations with molecular defects and disease phenotypes
J. Med. Genet.
44
673-688
2007
Homo sapiens (P35670)
Manually annotated by BRENDA team
Safaei, R.; Otani, S.; Larson, B.J.; Rasmussen, M.L.; Howell, S.B.
Transport of cisplatin by the copper efflux transporter ATP7B
Mol. Pharmacol.
73
461-468
2008
Homo sapiens (P35670)
Manually annotated by BRENDA team
Braiterman, L.; Nyasae, L.; Guo, Y.; Bustos, R.; Lutsenko, S.; Hubbard, A.
Apical targeting and Golgi retention signals reside within a 9-amino acid sequence in the copper-ATPase, ATP7B
Am. J. Physiol. Gastrointest. Liver Physiol.
296
G433-G444
2009
Homo sapiens
Manually annotated by BRENDA team
Veldhuis, N.A.; Gaeth, A.P.; Pearson, R.B.; Gabriel, K.; Camakaris, J.
The multi-layered regulation of copper translocating P-type ATPases
Biometals
22
177-190
2009
Saccharomyces cerevisiae, Homo sapiens
Manually annotated by BRENDA team
Ahmed, Z.; Deyama, Y.; Yoshimura, Y.; Suzuki, K.
Cisplatin sensitivity of oral squamous carcinoma cells is regulated by Na+,K+-ATPase activity rather than copper-transporting P-type ATPases, ATP7A and ATP7B
Cancer Chemother. Pharmacol.
63
643-650
2009
Homo sapiens
Manually annotated by BRENDA team
Leonhardt, K.; Gebhardt, R.; Moessner, J.; Lutsenko, S.; Huster, D.
Functional interactions of Cu-ATPase ATP7B with cisplatin and the role of ATP7B in the resistance of cells to the drug
J. Biol. Chem.
284
7793-7802
2009
Homo sapiens
Manually annotated by BRENDA team
Ke, B.X.; Llanos, R.M.; Mercer, J.F.
ATP7A transgenic and nontransgenic mice are resistant to high copper exposure
J. Nutr.
138
693-697
2008
Homo sapiens
Manually annotated by BRENDA team
Zhang, Y.; Li, M.; Yao, Q.; Chen, C.
Roles and mechanisms of copper transporting ATPases in cancer pathogenesis
Med. Sci. Monit.
15
RA1-RA5
2009
Homo sapiens
Manually annotated by BRENDA team
Yan, S.; Wu, G.
Quantitative relationship between mutated amino-acid sequence of human copper-transporting ATPases and their related diseases
Mol. Divers.
12
119-129
2008
Homo sapiens
Manually annotated by BRENDA team
Barnes, N.; Bartee, M.Y.; Braiterman, L.; Gupta, A.; Ustiyan, V.; Zuzel, V.; Kaplan, J.H.; Hubbard, A.L.; Lutsenko, S.
Cell-specific trafficking suggests a new role for renal ATP7B in the intracellular copper storage
Traffic
10
767-779
2009
Homo sapiens
Manually annotated by BRENDA team
Kennerson, M.L.; Nicholson, G.A.; Kaler, S.G.; Kowalski, B.; Mercer, J.F.; Tang, J.; Llanos, R.M.; Chu, S.; Takata, R.I.; Speck-Martins, C.E.; Baets, J.; Almeida-Souza, L.; Fischer, D.; Timmerman, V.; Taylor, P.E.; Scherer, S.S.; Ferguson, T.A.; Bird, T.D.; De Jonghe, P.; Feely, S.M.; Shy, M.E.; Garbern, J.Y.
Missense mutations in the copper transporter gene ATP7A cause X-linked distal hereditary motor neuropathy
Am. J. Hum. Genet.
86
343-352
2010
Homo sapiens
Manually annotated by BRENDA team
Collins, J.F.; Hua, P.; Lu, Y.; Ranganathan, P.N.
Alternative splicing of the Menkes copper Atpase (Atp7a) transcript in the rat intestinal epithelium
Am. J. Physiol. Gastrointest. Liver Physiol.
297
G695-G707
2009
Homo sapiens, Rattus norvegicus
Manually annotated by BRENDA team
Sauer, V.; Siaj, R.; Todorov, T.; Zibert, A.; Schmidt, H.H.
Overexpressed ATP7B protects mesenchymal stem cells from toxic copper
Biochem. Biophys. Res. Commun.
395
307-311
2010
Homo sapiens
Manually annotated by BRENDA team
Banci, L.; Bertini, I.; Cantini, F.; Migliardi, M.; Natile, G.; Nushi, F.; Rosato, A.
Solution structures of the actuator domain of ATP7A and ATP7B, the Menkes and Wilson disease proteins
Biochemistry
48
7849-7855
2009
Homo sapiens (Q04656), Homo sapiens
Manually annotated by BRENDA team
Luoma, L.M.; Deeb, T.M.; Macintyre, G.; Cox, D.W.
Functional analysis of mutations in the ATP loop of the Wilson disease copper transporter, ATP7B
Hum. Mutat.
31
569-577
2010
Saccharomyces cerevisiae, Homo sapiens (P35670), Homo sapiens, Saccharomyces cerevisiae BJ2168
Manually annotated by BRENDA team
Veldhuis, N.A.; Valova, V.A.; Gaeth, A.P.; Palstra, N.; Hannan, K.M.; Michell, B.J.; Kelly, L.E.; Jennings, I.; Kemp, B.E.; Pearson, R.B.; Robinson, P.J.; Camakaris, J.
Phosphorylation regulates copper-responsive trafficking of the Menkes copper transporting P-type ATPase
Int. J. Biochem. Cell Biol.
41
2403-2412
2009
Cricetulus griseus, Homo sapiens
Manually annotated by BRENDA team
La Fontaine, S.; Ackland, M.L.; Mercer, J.F.
Mammalian copper-transporting P-type ATPases, ATP7A and ATP7B: emerging roles
Int. J. Biochem. Cell Biol.
42
206-209
2010
Homo sapiens, Mus musculus
Manually annotated by BRENDA team
Pilankatta, R.; Lewis, D.; Adams, C.M.; Inesi, G.
High yield heterologous expression of wild-type and mutant Cu+-ATPase (ATP7B, Wilson disease protein) for functional characterization of catalytic activity and serine residues undergoing copper-dependent phosphorylation
J. Biol. Chem.
284
21307-21316
2009
Homo sapiens
Manually annotated by BRENDA team
Banci, L.; Bertini, I.; Cantini, F.; Inagaki, S.; Migliardi, M.; Rosato, A.
The binding mode of ATP revealed by the solution structure of the N-domain of human ATP7A
J. Biol. Chem.
285
2537-2544
2010
Homo sapiens (Q04656), Homo sapiens
Manually annotated by BRENDA team
LeShane, E.S.; Shinde, U.; Walker, J.M.; Barry, A.N.; Blackburn, N.J.; Ralle, M.; Lutsenko, S.
Interactions between copper-binding sites determine the redox status and conformation of the regulatory N-terminal domain of ATP7B
J. Biol. Chem.
285
6327-6336
2010
Homo sapiens (P35670), Homo sapiens
Manually annotated by BRENDA team
Braiterman, L.; Nyasae, L.; Leves, F.; Hubbard, A.L.
Critical roles for the COOH terminus of the Cu-ATPase ATP7B in protein stability, trans-Golgi network retention, copper sensing, and retrograde trafficking
Am. J. Physiol. Gastrointest. Liver Physiol.
301
G69-G81
2011
Homo sapiens (P35670)
Manually annotated by BRENDA team
Dmitriev, O.Y.; Bhattacharjee, A.; Nokhrin, S.; Uhlemann, E.M.; Lutsenko, S.
Difference in stability of the N-domain underlies distinct intracellular properties of the E1064A and H1069Q mutants of copper-transporting ATPase ATP7B
J. Biol. Chem.
286
16355-16362
2011
Homo sapiens (P35670)
Manually annotated by BRENDA team
Barry, A.N.; Otoikhian, A.; Bhatt, S.; Shinde, U.; Tsivkovskii, R.; Blackburn, N.J.; Lutsenko, S.
The lumenal loop Met672-Pro707 of copper-transporting ATPase ATP7A binds metals and facilitates copper release from the intramembrane sites
J. Biol. Chem.
286
26585-26594
2011
Homo sapiens (Q04656), Homo sapiens
Manually annotated by BRENDA team