Affinage

ATP7B

Copper-transporting ATPase 2 · UniProt P35670

Length
1465 aa
Mass
157.3 kDa
Annotated
2026-04-28
100 papers in source corpus 33 papers cited in narrative 33 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

ATP7B is a P1B-type copper-transporting ATPase that resides in the trans-Golgi network under basal conditions, where it loads copper into cuproenzymes such as ceruloplasmin, and undergoes copper-dependent redistribution to vesicular/canalicular compartments to mediate biliary copper excretion (PMID:9430732, PMID:24909901, PMID:27034138). Cryo-EM structures reveal that the six N-terminal metal-binding domains (MBDs) interact with the actuator and phosphorylation domains in the copper-free state, while MBD6 docks at the cytosolic entry site of the transmembrane domain to deliver copper through a sulfur-coordinated pathway driven by the ATP-dependent catalytic cycle requiring the CPC motif and DKTGTIT phosphorylation site (PMID:35245129, PMID:37074913, PMID:9837819, PMID:16939419). Copper relay proceeds via Atox1 delivery to a regulatory MBD1–3 unit that releases autoinhibition, enabling copper loading of MBD5/MBD6 for transmembrane transport, while kinase-mediated phosphorylation of the MBD3–MBD4 linker and interactions with COMMD1 (proteasomal degradation), clusterin (lysosomal degradation), and HSP70 (ER-associated degradation of misfolded mutants) regulate ATP7B stability and trafficking (PMID:31321400, PMID:19405516, PMID:17919502, PMID:22130675, PMID:33288711). Loss-of-function mutations in ATP7B cause Wilson disease, as demonstrated by ER retention of common variants such as H1069Q and by functional rescue in the Long-Evans Cinnamon rat model (PMID:12557139, PMID:9430732, PMID:22240481).

Mechanistic history

Synthesis pass · year-by-year structured walk · 15 steps
  1. 1998 High

    Establishing that ATP7B is a functional copper transporter requiring the CPC motif and that it localizes to the Golgi where it loads copper onto ceruloplasmin answered the fundamental question of what ATP7B does in the cell.

    Evidence Yeast ccc2Δ complementation with CPC mutants; adenoviral ATP7B delivery restoring holoceruloplasmin in Wilson disease rat model

    PMID:9430732 PMID:9837819

    Open questions at the time
    • Structural basis for copper translocation through the membrane not yet resolved
    • Mechanism of copper entry from cytosol to transmembrane pathway unknown
  2. 2001 High

    Demonstrating that copper elevation triggers ATP7B redistribution from the TGN to multivesicular structures, and that disease mutations abolish this trafficking, established that regulated subcellular localization is integral to ATP7B function.

    Evidence Immunofluorescence and copper resistance assays in CHO cells expressing wild-type and tx-mutant ATP7B

    PMID:10942420 PMID:11157799

    Open questions at the time
    • Destination compartment identity (late endosome vs. lysosome vs. apical membrane) debated
    • Molecular determinants within ATP7B that control trafficking signals undefined
  3. 2003 High

    Localizing the common H1069Q mutation to the ER in patient liver tissue revealed that protein misfolding and mistrafficking, not solely loss of catalytic activity, is a major disease mechanism in Wilson disease.

    Evidence Immunogold EM on human liver biopsies; confocal microscopy of GFP-tagged mutants in hepatoma cells

    PMID:12557139

    Open questions at the time
    • Whether ER-retained mutants retain partial transport activity in situ was unknown
    • Degradation pathway for ER-retained ATP7B not yet identified
  4. 2007 High

    Showing that the DKTGTIT catalytic phosphorylation and TGE phosphatase motifs govern copper-dependent exit from the TGN established that the catalytic cycle itself drives trafficking, uncoupling it from direct copper binding to MBDs.

    Evidence Site-directed mutagenesis of catalytic domains with confocal imaging of copper-induced redistribution

    PMID:16939419

    Open questions at the time
    • How catalytic turnover is transduced into vesicle budding signals remained unclear
    • Coat proteins or adaptors mediating TGN exit not identified
  5. 2007 High

    Identifying COMMD1 as a stability regulator of ATP7B, with disease mutations enhancing COMMD1 binding and accelerating degradation, provided the first mechanism linking Wilson disease variants to altered proteostasis.

    Evidence Reciprocal Co-IP, GST pull-down, biosynthetic labeling of degradation rates in cells expressing WD mutants

    PMID:17919502

    Open questions at the time
    • Whether COMMD1-dependent degradation occurs via ubiquitin–proteasome pathway specifically was not shown
    • In vivo relevance in hepatocytes not yet tested
  6. 2009 High

    Mapping kinase-mediated phosphorylation to the MBD3–MBD4 linker and showing copper-induced conformational changes in the N-terminal domain revealed how copper binding is transduced into a regulatory signal for trafficking and catalysis.

    Evidence In vitro kinase assay, limited proteolysis, mass spectrometry identification of phosphosites

    PMID:19405516

    Open questions at the time
    • Identity of the responsible kinase unknown
    • Functional consequence of phosphorylation on trafficking not directly tested
  7. 2011 High

    Distinguishing COMMD1-mediated proteasomal degradation from clusterin-mediated lysosomal degradation of ATP7B revealed parallel quality-control pathways regulated by distinct stimuli including oxidative stress.

    Evidence Co-IP with pathway inhibitors (proteasome vs. lysosome), overexpression/knockdown in cell lines

    PMID:22130675

    Open questions at the time
    • Whether both pathways operate simultaneously in hepatocytes in vivo unknown
    • Ubiquitin ligase mediating proteasomal targeting not identified
  8. 2012 High

    Systematic functional profiling of 28 Wilson disease variants using direct 64Cu transport assays demonstrated that disease mutations produce a spectrum from complete catalytic loss to normal transport with impaired localization, refining genotype–phenotype understanding.

    Evidence Baculovirus-expressed ATP7B in Sf9 cells, 64Cu vesicular transport, GFP-fusion confocal in mammalian cells

    PMID:22240481

    Open questions at the time
    • In vivo functional rescue by individual variants not tested
    • Impact of compound heterozygosity on phenotype not addressed
  9. 2014 High

    Identifying lysosomal exocytosis as a copper excretion pathway — with ATP7B loading copper into lysosomes and p62/dynactin mediating their canalicular translocation — provided a mechanistic framework for hepatic copper disposal.

    Evidence Live imaging, Co-IP of ATP7B/p62-dynactin, siRNA knockdown, copper transport assays in hepatocytes

    PMID:24909901

    Open questions at the time
    • Conflicting data from polarized hepatocyte models suggesting transcytosis rather than lysosomal exocytosis [PMID:27034138]
    • Whether both pathways coexist in vivo unresolved
  10. 2017 Medium

    Demonstrating that ATP7B forms stable dimers and that intestinal ATP7B controls copper-dependent lipid metabolism expanded its functional scope beyond ceruloplasmin loading to systemic metabolic regulation.

    Evidence Co-purification of tagged constructs and negative-stain EM for dimerization; Atp7b−/− mice and 3D enteroids for lipid phenotype

    PMID:28842499 PMID:28958857

    Open questions at the time
    • Functional significance of dimerization for transport activity unknown
    • Molecular link between copper transport and apolipoprotein B mislocalization not defined
  11. 2019 Medium

    Systematic mutagenesis of individual MBD copper sites established a relay model in which Atox1-to-MBD1–3 copper delivery releases autoinhibition and MBD5/6 copper loading drives transmembrane transport, clarifying the division of labor among six MBDs.

    Evidence Yeast complementation with strategic Cys-to-Ser mutations blocking individual MBD copper binding

    PMID:31321400

    Open questions at the time
    • Direct structural visualization of the copper-loaded relay intermediates lacking
    • Whether all six MBDs are simultaneously occupied in vivo unknown
  12. 2020 High

    Identifying HSP70 as a triage factor that accelerates ER degradation of H1069Q-ATP7B, and showing that pharmacological HSP70 inhibition rescues mutant trafficking and function, opened a therapeutic avenue for the most common Wilson disease mutation.

    Evidence MS-based interactomics, Co-IP, HSP70 inhibitor domperidone rescue of trafficking and copper export

    PMID:33288711

    Open questions at the time
    • Whether domperidone rescues other ER-retained ATP7B mutants unknown
    • Long-term efficacy and liver-specific effects not tested in vivo
  13. 2022 High

    Cryo-EM structures of copper-free frog ATP7B revealed how N-terminal MBDs interact with the actuator/phosphorylation domains and identified a gated cytoplasmic copper entrance lined by charged residues, providing the first atomic framework for the transport cycle.

    Evidence Cryo-EM at near-atomic resolution with domain interaction mapping

    PMID:35245129

    Open questions at the time
    • Only copper-free state resolved; copper-bound conformational changes inferred
    • Frog ortholog — human-specific features may differ
  14. 2023 High

    Human ATP7B cryo-EM structures in E1 apo, copper-bound, and cisplatin-bound states confirmed MBD6 docking at the transmembrane copper entry site and delineated the sulfur-coordinated translocation pathway, completing the structural picture across catalytic states.

    Evidence Cryo-EM of human ATP7B in multiple states with comparative analysis to frog E2-Pi structure

    PMID:37074913

    Open questions at the time
    • E2 state of human ATP7B not yet resolved
    • Structural basis for copper release into the luminal side not defined
  15. 2023 High

    Identifying AP-1A and AP-1B as mediators of ATP7B directionality in polarized epithelia resolved a long-standing question of how TGN retention and copper-dependent apical sorting are coordinated.

    Evidence MS interactomics, AP-1 isoform-specific knockouts, confocal trafficking in polarized epithelial cells

    PMID:38032054

    Open questions at the time
    • Whether AP-1 regulation applies identically in primary hepatocytes vs. epithelial models untested
    • Phosphorylation-dependent recognition by AP-1 adaptors not demonstrated

Open questions

Synthesis pass · forward-looking unresolved questions
  • Key unresolved questions include the identity of the kinase phosphorylating the MBD3–MBD4 linker, the structural basis for copper release into the TGN/vesicle lumen, reconciliation of lysosomal exocytosis versus transcytosis models of hepatic copper excretion, and whether ATP7B dimerization is required for transport activity.
  • Kinase identity unknown
  • Luminal copper release mechanism not structurally resolved
  • Lysosomal exocytosis vs. transcytosis debate unresolved
  • Functional role of dimerization untested

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0140657 ATP-dependent activity 5 GO:0005215 transporter activity 4 GO:0140096 catalytic activity, acting on a protein 1
Localization
GO:0005794 Golgi apparatus 5 GO:0031410 cytoplasmic vesicle 4 GO:0005783 endoplasmic reticulum 3 GO:0005886 plasma membrane 2 GO:0005764 lysosome 1
Pathway
R-HSA-382551 Transport of small molecules 4 R-HSA-5653656 Vesicle-mediated transport 4 R-HSA-1430728 Metabolism 3 R-HSA-392499 Metabolism of proteins 3 R-HSA-9609507 Protein localization 3 R-HSA-9612973 Autophagy 1
Partners
AP1M1ATOX1CLUCOMMD1DCTN4GLRXHSPA1AMAP1LC3B

Evidence

Reading pass · 33 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2022 Cryo-EM structure of frog ATP7B in a copper-free state revealed that the six N-terminal metal-binding domains interact with both the A and P domains, a ring of negatively charged residues lines the cytoplasmic copper entrance gated by a conserved basic residue, and a network of copper-coordinating ligands in the membrane delineates a stepwise copper transport pathway. Cryo-electron microscopy structural determination Science advances High 35245129
2023 Cryo-EM structures of human ATP7B in E1 state (apo, copper-bound, and cisplatin-bound forms) showed that the sixth metal-binding domain (MBD6) binds at the cytosolic copper entry site of the transmembrane domain, facilitating copper delivery from MBD6 to the TMD; sulfur-containing residues in the TMD mark the copper transport pathway; comparison with E2-Pi frog ATP7B supported an ATP-driven copper transport model. Cryo-electron microscopy structural determination with comparative analysis Cell reports High 37074913
2014 In response to elevated copper, ATP7B moves from the Golgi to lysosomes, imports copper into lysosomal lumen, and enables lysosomal exocytosis through interaction with p62 subunit of dynactin, allowing lysosome translocation toward the canalicular pole of hepatocytes for copper excretion. Live imaging, Co-IP, siRNA knockdown, copper transport assays in hepatocytes Developmental cell High 24909901
1998 Mutation of the conserved CPC (Cys-Pro-Cys) motif in the transmembrane domain of ATP7B results in a non-functional protein, demonstrating this motif is essential for copper transport; Wilson disease missense mutations in membrane-spanning segments retain partial copper transport activity as assessed by yeast complementation. Yeast complementation assay (ccc2 mutant rescue), site-directed mutagenesis American journal of human genetics High 9837819
1998 ATP7B protein introduced by adenovirus-mediated gene delivery localizes to the Golgi apparatus in hepatocytes and restores holoceruloplasmin synthesis (copper loading of ceruloplasmin) in the Long-Evans Cinnamon rat Wilson disease model. Recombinant adenovirus gene delivery, immunofluorescence, subcellular fractionation, Western blot, plasma ceruloplasmin assay The Journal of biological chemistry High 9430732
2007 COMMD1 specifically interacts with the amino-terminal region of ATP7B independent of copper levels or ATOX1 expression; four Wilson disease mutations in this region enhance binding to COMMD1 and increase ATP7B degradation rate, indicating COMMD1 regulates ATP7B stability. GST pull-down, co-immunoprecipitation, immunofluorescence, site-directed mutagenesis, biosynthetic labeling Gastroenterology High 17919502
2011 Clusterin and COMMD1 independently interact with ATP7B and down-regulate it via distinct degradation pathways: clusterin facilitates lysosomal degradation of ATP7B, while COMMD1 targets it to the proteasomal pathway; oxidative stress enhances clusterin/ATP7B interaction but not COMMD1/ATP7B interaction. Co-immunoprecipitation, overexpression/knockdown, pathway inhibitor studies, Western blot The Journal of biological chemistry High 22130675
2000 Certain Wilson disease ATP7B variants (Asp765Asn, Leu776Val) retain copper transport activity in yeast but show defective copper-induced subcellular redistribution in mammalian cells; the CPC motif mutant localizes normally but cannot redistribute in response to copper; Arg778Leu is mislocalized to the endoplasmic reticulum. Yeast complementation assay, transient transfection of CHO cells, triple-label immunofluorescence microscopy Human molecular genetics High 10942420
2007 ATP7B trafficking from the TGN is regulated by its copper-translocation cycle: mutation of the phosphorylation domain (DKTGTIT) blocks copper-induced redistribution from the TGN, while mutation of the phosphatase domain (TGE) traps ATP7B at cytosolic vesicular compartments; copper binding to the six N-terminal MBDs or the CPC motif is not essential for trafficking, but copper itself is required. Site-directed mutagenesis, copper chelation studies, confocal microscopy in mammalian cells The Biochemical journal High 16939419
2009 The N-terminal domain of ATP7B is phosphorylated by an ATP-dependent kinase; copper binding to the N-terminal domain alters its conformation (protecting MBD1-2 and MBD4-5 linkers from proteolysis while exposing MBD2-3 and MBD3-4 regions) and facilitates phosphorylation by 25-30%; mass spectrometry identified the loop connecting MBD3 and MBD4 as the phosphorylation region. In vitro kinase assay, limited proteolysis, 2D gel electrophoresis, mass spectrometry Biochemistry High 19405516
2001 The toxic milk (tx) mouse mutation in Wnd/ATP7B disrupts copper-induced relocalization from the TGN and abrogates copper resistance in CHO cells; wild-type ATP7B and ATP7A (MNK) both reside in the TGN under basal copper but sort to different destinations upon copper elevation; elevated copper causes ATP7B accumulation in large multi-vesicular structures resembling late endosomes. cDNA transfection in CHO cells, co-localization immunofluorescence, ultrastructural studies, copper resistance assay Human molecular genetics High 11157799
2003 H1069Q-ATP7B is trapped in the endoplasmic reticulum rather than the TGN in human liver hepatocytes and hepatoma cells; truncated ATP7B mutants show diffuse/clustered cytoplasmic patterns distinct from TGN or ER. Immunogold electron microscopy of human liver tissue, confocal microscopy of GFP-tagged ATP7B mutants in HuH-7 and HepG2 cells Gastroenterology High 12557139
2009 Cisplatin binds to the N-terminal copper-binding domain of ATP7B and stimulates catalytic phosphorylation with EC50 similar to copper; deletion of the first four copper-binding sites abolishes cisplatin-induced phosphorylation; unlike copper, cisplatin does not induce trafficking of ATP7B, nor does it compete with copper in a transport assay, arguing against active cisplatin transport through the copper translocation pathway as the mechanism of resistance. In vitro phosphorylation assay, competitive copper transport assay, cell trafficking microscopy, N-terminal domain deletion mutants The Journal of biological chemistry High 19141620
2013 ATP7A and ATP7B mediate ATP-dependent translocation of platinum drugs (cisplatin, carboplatin, oxaliplatin) in a fashion similar to copper, as measured by electrical recordings on microsomal fractions; NMR and ESI-MS showed that platinum drugs bind to the first N-terminal metal-binding domain of ATP7A. Electrical measurements on solid-supported membranes with recombinant Cu-ATPases, NMR spectroscopy, ESI-MS Angewandte Chemie (International ed. in English) High 24375922
2012 Wilson disease ATP7B variants show diverse functional defects: some have complete loss of catalytic and transport activity, others retain phospho-intermediate formation but lose transport activity, and others have partial activity losses; transport-competent variants differ in stability and subcellular localization in mammalian cells. Baculovirus expression in Sf9 cells, catalytic activity measurement, 64Cu transport into vesicles, GFP-fusion confocal microscopy in mammalian cells Gastroenterology High 22240481
2006 Glutaredoxin (GRX1) interacts with the N-terminus of both ATP7A and ATP7B in a copper-dependent manner requiring intact MxCxxC metal-binding motifs; the interaction is related to the number of metal-binding domains available, suggesting GRX1 facilitates copper-binding by reducing disulfide bonds or deglutathionylating cysteine residues in the CxxC motifs. Yeast two-hybrid, co-immunoprecipitation from mammalian cells, site-directed mutagenesis Biochemical and biophysical research communications Medium 16884690
2009 Renal ATP7B does not traffic from the TGN in response to copper elevation (unlike hepatic ATP7B), appears 2-3 kDa smaller than hepatic ATP7B, suggesting cell-type-specific regulation; this likely explains why renal ATP7B cannot compensate for ATP7A loss in Menkes disease and instead may function in intracellular copper storage. Subcellular fractionation, immunofluorescence microscopy, mRNA analysis, recombinant expression in renal vs. hepatic cells Traffic (Copenhagen, Denmark) Medium 19416479
2017 Human ATP7B forms stable dimers in eukaryotic cells; deletion of the four N-terminal metal-binding domains does not disrupt dimerization, indicating the dimer interface involves domains conserved across Cu-ATPases; dimeric structure is retained during trafficking between intracellular compartments; negative-stain electron microscopy provided a low-resolution 3D model showing domain positions and dimer interface. Co-purification of differentially tagged constructs, negative-stain electron microscopy, single-particle analysis The Journal of biological chemistry Medium 28842499
2019 Copper relay through the N-terminus of ATP7B follows a model in which MBD1-3 forms a regulatory unit; copper delivery via Atox1 to this unit promotes release of inhibitory interactions; an intact copper site in either MBD5 or MBD6 is required for copper transport; MBD6 alone can deliver copper to truncated ATP7B lacking all six MBDs, suggesting a docking role for MBD6. Yeast functional complementation assay with strategic cysteine-to-serine mutations blocking individual MBD copper binding Metallomics : integrated biometal science Medium 31321400
2009 Wilson disease mutations reduce ATP7B protein expression without affecting mRNA, with retention of mutant ATP7B in the endoplasmic reticulum; reduced expression is rescued by culturing at 30°C or by pharmacological chaperones 4-phenylbutyrate and curcumin, which partially restore protein expression and localization of multiple ATP7B missense mutants. Cell-based expression assays, immunofluorescence, copper export functional assay, pharmacological chaperone treatment, homology modeling Hepatology (Baltimore, Md.) Medium 19937698
2020 The H1069Q mutation promotes ATP7B interaction with HSP70, accelerating ER degradation of the mutant protein; the HSP70 inhibitor-based drug domperidone rescues trafficking and function of ATP7B-H1069Q by impairing its exposure to the HSP70 proteostatic network. Proteomics (mass spectrometry-based interactome), co-immunoprecipitation, cell-based trafficking assays, copper export functional assay, pharmacological rescue Proceedings of the National Academy of Sciences of the United States of America High 33288711
2004 ATP7A and ATP7B sequester cisplatin and carboplatin into vesicular compartments, increasing cellular resistance; vesicles from ATP7B-expressing cells contained more platinum after cisplatin and carboplatin exposure; unlike copper, platinum drugs did not trigger relocalization of ATP7A from perinuclear region. Engineered cell lines expressing ATP7A or ATP7B, platinum drug cytotoxicity assays, vesicle isolation with platinum measurement, immunofluorescence Molecular pharmacology High 15213293
2019 COMMD1 modulates copper-responsive ATP7B trafficking through PtdIns(4,5)P2 binding; decreased COMMD1 results in loss of ATP7B from lysosomes and TGN under high copper; COMMD1 overexpression or mutation of its PtdIns(4,5)P2-binding site disrupts ATP7B trafficking itinerary and reduces copper export. Quantitative colocalization analysis, COMMD1 overexpression/knockdown, COMMD1 PtdIns(4,5)P2-binding mutants, confocal microscopy in HepG2 cells Journal of cell science Medium 31515276
2016 ATP7B is transported from the TGN to the bile canaliculus by basolateral sorting, endocytosis, and microtubule-mediated transcytosis through the subapical compartment; ATP7B trafficking vesicles are not incorporated into lysosomes; copper addition does not cause lysosome relocalization or appearance of lysosome markers at the bile canaliculus. Confocal microscopy, transcytosis assays, lysosome marker co-localization, microtubule disruption, polarized hepatocyte cell models Journal of cell science Medium 27034138
2023 In polarized epithelia, ATP7B traverses common recycling endosomes, apical sorting endosomes, and apical recycling endosomes en route to the apical membrane; the AP-1A complex provides directionality and TGN retention for ATP7B, while AP-1B governs copper-independent trafficking of ATP7B; pan-AP-1 knockout disrupts sorting of ATP7B. Mass spectrometry interactomics, AP-1 isoform-specific knockouts, confocal microscopy in polarized epithelial cells, trafficking assays with Wilson disease mutants Journal of cell science High 38032054
2021 ATP7B contains LC3-interaction regions (LIRs) and directly interacts with LC3B in vitro through a conserved C-terminal LIR3 (W1452, L1455); ATP7B and LC3B colocalize on autophagosome membranes under induced autophagy; ATP7B-deficient HepG2 cells show autophagy deficiency under elevated copper, rescued by heterologous ATP7B expression. In silico LIR prediction, in vitro binding assay, site-directed mutagenesis of LIR residues, confocal colocalization, CRISPR/Cas9 knockout complementation Cells Medium 34831341
2003 Loss of ATP7B in Atp7b-/- mice reduces dopamine beta-hydroxylase (DBH) protein levels and activity and decreases norepinephrine and epinephrine in adrenal glands, demonstrating that ATP7B deficiency affects copper delivery to cuproenzymes even in tissues (adrenal) that do not normally express ATP7B. Comparison of Atp7b-/- and wild-type mice, Western blot, catecholamine measurement Neurochemical research Medium 12718440
2006 A hepatocytic isoform of PLZF (lacking the BTB domain) interacts with the C-terminal region of ATP7B; both proteins co-localize in trans-Golgi complexes in HepG2 cells; disruption of PLZF reduces ERK activity, and ATP7B expression enhances ERK kinase activity through its C-terminal region. Yeast two-hybrid, co-immunoprecipitation, immunostaining, ERK activity assay, Drosophila in vivo transgenic validation Journal of cellular biochemistry Medium 16676348
2008 Copper-induced translocation of ATP7B from the Golgi to dispersed vesicles occurs independently of COMMD1/Murr1 or Rab7-regulated endosomal trafficking; siRNA depletion of COMMD1 or Rab7 or dominant-negative Rab7 does not impair ATP7B translocation. Confocal microscopy, RNA interference, dominant-negative Rab7 expression The American journal of pathology Medium 18974300
2022 TFEB directly binds to CLEAR sites in the proximal promoter and first intron of ATP7B upon platinum drug exposure, accelerating ATP7B transcription; TFEB suppression inhibits ATP7B expression and increases cisplatin sensitivity in resistant ovarian cancer cells. ChIP, luciferase reporter assays with ATP7B CLEAR regions, TFEB siRNA knockdown, cisplatin cytotoxicity assay Cells Medium 35053335
2020 Co-expression of ATP7B mutants A595T and G1061E (mimicking compound-heterozygous state) reveals inter-mutant interactions that alter intracellular localization and trafficking under both low and high copper conditions, distinct from either mutant expressed alone; regulatory domain mutations (A595T, S1362A, S1426I) reduce Cu-transport without affecting TGN targeting, while ATP-binding domain mutations (G1061E, G1101R) cause ER retention. Transient transfection, confocal microscopy, 64Cu transport assay, co-expression studies Scientific reports Medium 32778786
2023 Atp7b inactivation in mice disrupts normal morphology and function of choroid plexus during postnatal development, causes reorganization of cytoskeleton and cell-cell contacts, loss of Slc31a1 from the apical membrane, and reduction in microvilli/cilia length and number; this results in transient copper deficit in the brain with catecholamine imbalance and lipidome changes. Atp7b-/- mouse model, immunofluorescence, proteomics, lipidomics, copper measurement PLoS genetics Medium 36626371
2017 ATP7B in mouse intestine maintains a copper gradient along the duodenal crypt-villus axis by copper-dependent enlargement of ATP7B-containing vesicles; loss of intestinal ATP7B causes triglyceride-filled vesicle accumulation in enterocytes, mislocalization of apolipoprotein B, and loss of chylomicrons, linking copper regulation by ATP7B to lipid metabolism. Atp7b-/- mouse model, 3D enteroids, immunohistochemistry, X-ray fluorescence, electron microscopy, fluorescent confocal microscopy Gastroenterology High 28958857

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2007 Trafficking of the copper-ATPases, ATP7A and ATP7B: role in copper homeostasis. Archives of biochemistry and biophysics 352 17531189
2014 Wilson disease protein ATP7B utilizes lysosomal exocytosis to maintain copper homeostasis. Developmental cell 232 24909901
2006 Regional distribution of mutations of the ATP7B gene in patients with Wilson disease: impact on genetic testing. Human genetics 187 16791614
1998 Restoration of holoceruloplasmin synthesis in LEC rat after infusion of recombinant adenovirus bearing WND cDNA. The Journal of biological chemistry 135 9430732
1998 Functional characterization of missense mutations in ATP7B: Wilson disease mutation or normal variant? American journal of human genetics 126 9837819
2007 Distinct Wilson's disease mutations in ATP7B are associated with enhanced binding to COMMD1 and reduced stability of ATP7B. Gastroenterology 125 17919502
2000 Copper-dependent trafficking of Wilson disease mutant ATP7B proteins. Human molecular genetics 124 10942420
2012 Diverse functional properties of Wilson disease ATP7B variants. Gastroenterology 122 22240481
2004 Modulation of the cellular pharmacology of cisplatin and its analogs by the copper exporters ATP7A and ATP7B. Molecular pharmacology 119 15213293
2009 Therapeutic Targeting of ATP7B in Ovarian Carcinoma. Clinical cancer research : an official journal of the American Association for Cancer Research 117 19470734
2004 The H1069Q mutation in ATP7B is associated with late and neurologic presentation in Wilson disease: results of a meta-analysis. Journal of hepatology 112 15519648
2009 Reduced expression of ATP7B affected by Wilson disease-causing mutations is rescued by pharmacological folding chaperones 4-phenylbutyrate and curcumin. Hepatology (Baltimore, Md.) 107 19937698
2003 Defective cellular localization of mutant ATP7B in Wilson's disease patients and hepatoma cell lines. Gastroenterology 100 12557139
2007 Copper-transporting ATPases ATP7A and ATP7B: cousins, not twins. Journal of bioenergetics and biomembranes 91 18000748
2017 The Function of ATPase Copper Transporter ATP7B in Intestine. Gastroenterology 89 28958857
2004 Wilson disease: novel mutations in the ATP7B gene and clinical correlation in Brazilian patients. Human mutation 86 15024742
2016 Spectrum and Classification of ATP7B Variants in a Large Cohort of Chinese Patients with Wilson's Disease Guides Genetic Diagnosis. Theranostics 80 27022412
1998 ATP7B (WND) protein. The international journal of biochemistry & cell biology 79 9785470
2013 Translocation of platinum anticancer drugs by human copper ATPases ATP7A and ATP7B. Angewandte Chemie (International ed. in English) 78 24375922
2001 Effect of the toxic milk mutation (tx) on the function and intracellular localization of Wnd, the murine homologue of the Wilson copper ATPase. Human molecular genetics 74 11157799
2022 Structure of the Wilson disease copper transporter ATP7B. Science advances 72 35245129
2011 Clusterin and COMMD1 independently regulate degradation of the mammalian copper ATPases ATP7A and ATP7B. The Journal of biological chemistry 72 22130675
2007 Hepatic copper-transporting ATPase ATP7B: function and inactivation at the molecular and cellular level. Biometals : an international journal on the role of metal ions in biology, biochemistry, and medicine 68 17268820
2003 Expression of copper-transporting P-type adenosine triphosphatase (ATP7B) as a chemoresistance marker in human oral squamous cell carcinoma treated with cisplatin. Oral oncology 63 12509969
2021 Direct Measurement of ATP7B Peptides Is Highly Effective in the Diagnosis of Wilson Disease. Gastroenterology 61 33640437
2015 Geographic distribution of ATP7B mutations in Wilson disease. Annals of human biology 61 26207595
2004 Correlation of ATP7B genotype with phenotype in Chinese patients with Wilson disease. World journal of gastroenterology 57 14966923
2006 Copper-dependent interaction of glutaredoxin with the N termini of the copper-ATPases (ATP7A and ATP7B) defective in Menkes and Wilson diseases. Biochemical and biophysical research communications 53 16884690
2020 ATP7B variant penetrance explains differences between genetic and clinical prevalence estimates for Wilson disease. Human genetics 52 32248359
2009 Functional interactions of Cu-ATPase ATP7B with cisplatin and the role of ATP7B in the resistance of cells to the drug. The Journal of biological chemistry 52 19141620
2002 Human copper-transporting ATPase ATP7B (the Wilson's disease protein): biochemical properties and regulation. Journal of bioenergetics and biomembranes 51 12539962
2020 Metabolic dysregulation in the Atp7b-/- Wilson's disease mouse model. Proceedings of the National Academy of Sciences of the United States of America 50 31924743
2009 Cell-specific trafficking suggests a new role for renal ATP7B in the intracellular copper storage. Traffic (Copenhagen, Denmark) 50 19416479
2007 Copper binding to the N-terminal metal-binding sites or the CPC motif is not essential for copper-induced trafficking of the human Wilson protein (ATP7B). The Biochemical journal 49 16939419
2022 Cuproptosis-Related Gene - SLC31A1, FDX1 and ATP7B - Polymorphisms are Associated with Risk of Lung Cancer. Pharmacogenomics and personalized medicine 48 35923305
2007 Identification of novel ATP7B gene mutations and their functional roles in Korean patients with Wilson disease. Human mutation 48 17587212
2013 Linkage disequilibrium and haplotype analysis of the ATP7B gene in Alzheimer's disease. Rejuvenation research 46 22950421
2002 Copper-transporting P-type adenosine triphosphatase (ATP7B) is expressed in human breast carcinoma. Japanese journal of cancer research : Gann 46 11802810
2008 Expression of copper-transporting P-type adenosine triphosphatase (ATP7B) correlates with cisplatin resistance in human non-small cell lung cancer xenografts. Oncology reports 45 18636185
2024 Combination of the cuproptosis inducer disulfiram and anti‑PD‑L1 abolishes NSCLC resistance by ATP7B to regulate the HIF‑1 signaling pathway. International journal of molecular medicine 44 38186308
2023 Structures of the human Wilson disease copper transporter ATP7B. Cell reports 44 37074913
2016 Non-ceruloplasmin bound copper and ATP7B gene variants in Alzheimer's disease. Metallomics : integrated biometal science 43 27499330
2018 Whole-exome sequencing identifies novel pathogenic variants across the ATP7B gene and some modifiers of Wilson's disease phenotype. Liver international : official journal of the International Association for the Study of the Liver 41 30230192
2017 Spectrum of ATP7B mutations and genotype-phenotype correlation in large-scale Chinese patients with Wilson Disease. Clinical genetics 41 27982432
2017 Dynamics of the metal binding domains and regulation of the human copper transporters ATP7B and ATP7A. IUBMB life 40 28271598
2013 Independent pathways downstream of the Wnd/DLK MAPKKK regulate synaptic structure, axonal transport, and injury signaling. The Journal of neuroscience : the official journal of the Society for Neuroscience 35 23904612
2009 The loop connecting metal-binding domains 3 and 4 of ATP7B is a target of a kinase-mediated phosphorylation. Biochemistry 35 19405516
2008 Copper-induced translocation of the Wilson disease protein ATP7B independent of Murr1/COMMD1 and Rab7. The American journal of pathology 33 18974300
2019 Copper-dependent ATP7B up-regulation drives the resistance of TMEM16A-overexpressing head-and-neck cancer models to platinum toxicity. The Biochemical journal 32 31790150
2017 Human copper transporter ATP7B (Wilson disease protein) forms stable dimers in vitro and in cells. The Journal of biological chemistry 32 28842499
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