Affinage

ATP7B

Copper-transporting ATPase 2 · UniProt P35670

Length
1465 aa
Mass
157.3 kDa
Annotated
2026-06-09
100 papers in source corpus 32 papers cited in narrative 32 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 6/6 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

ATP7B is a P1B-type copper-transporting ATPase that couples ATP hydrolysis to the translocation of copper across membranes and is the central effector of cellular and systemic copper homeostasis (PMID:35245129, PMID:22240481). Catalytic copper transport requires the conserved transmembrane CPC motif and a network of sulfur-containing transmembrane ligands that define a stepwise translocation pathway, while six N-terminal metal-binding domains (MBDs) regulate the enzyme: MBD1–3 form a regulatory unit relieved by Atox1-mediated copper delivery, and MBD6 docks at the cytoplasmic copper entry site to deliver copper to the transmembrane domain (PMID:37074913, PMID:9837819, PMID:31321400). Under basal copper, ATP7B resides in the trans-Golgi network where it supplies copper for holoceruloplasmin biosynthesis (PMID:9430732); upon copper elevation it undergoes a distinct, copper-dependent trafficking response — mechanistically separable from catalytic transport — to peripheral vesicles, lysosomes, and the apical/canalicular pole, enabling sequestration and excretion of excess copper into bile, with directionality conferred by AP-1 sorting complexes and lysosomal translocation aided by the dynactin subunit p62 (PMID:24909901, PMID:16472602, PMID:10942420, PMID:38032054). This trafficking is licensed by copper-dependent serine phosphorylation by protein kinase D, which also stabilizes ATP7B against proteasomal degradation (PMID:21189263), and ATP7B abundance is further controlled by COMMD1 (proteasomal) and clusterin (lysosomal) degradation routes that act on misfolded or oxidatively stressed protein (PMID:17919502, PMID:22130675). Beyond the liver, ATP7B buffers cytosolic copper in intestinal enterocytes to support chylomicron assembly and apolipoprotein B localization, and maintains choroid plexus copper homeostasis required for normal brain copper delivery during development (PMID:28958857, PMID:36626371). ATP7B is the gene mutated in Wilson disease, and characterized mutations impair the protein through diverse mechanisms including loss of catalytic/transport activity, defective copper-induced trafficking, and misfolding with ER retention and accelerated degradation — the frequent H1069Q variant being trapped in the ER and captured by HSP70 for ER-associated degradation (PMID:12557139, PMID:22240481, PMID:33288711).

Mechanistic history

Synthesis pass · year-by-year structured walk · 20 steps
  1. 1997 Medium

    Establishing that Wilson disease mutations directly impair ATP7B enzymatic function answered whether disease arises from loss of the protein's catalytic activity.

    Evidence Copper-stimulated ATPase activity assays in patient-derived lymphoblast lines carrying H1069Q and four other mutations

    PMID:9311736

    Open questions at the time
    • Did not resolve which step of the catalytic cycle is impaired
    • Patient cells may carry confounding genetic background
    • No distinction between catalytic vs. trafficking defects
  2. 1998 High

    In vivo rescue and yeast complementation established that ATP7B functions in copper transport coupled to ceruloplasmin biosynthesis at the Golgi and that the transmembrane CPC motif is essential for transport.

    Evidence Adenoviral WND cDNA delivery into LEC rats restoring Golgi ATP7B and holoceruloplasmin; yeast ccc2 complementation with CPC→SPS mutagenesis

    PMID:9430732 PMID:9837819

    Open questions at the time
    • Did not define the transmembrane copper coordination geometry
    • Mechanism of copper handoff to ceruloplasmin not resolved
  3. 2000 High

    Separating trafficking-competent from transport-competent mutants established that copper-induced redistribution is a distinct functional requirement from catalytic copper transport.

    Evidence Yeast complementation combined with copper-stimulated redistribution imaging of Wilson disease variants in CHO cells

    PMID:10942420

    Open questions at the time
    • Trafficking signals/machinery not identified
    • Did not address tissue-specific trafficking differences
  4. 2001 High

    The toxic milk mutant model showed copper-induced relocalization is required for copper resistance and that ATP7B targets a distinct late-endosomal/multivesicular destination separate from ATP7A.

    Evidence Transfection of CHO cells with mutant Wnd, copper resistance assays, and ultrastructural colocalization

    PMID:11157799

    Open questions at the time
    • Molecular basis of distinct destination unresolved
    • Late endosome identity not definitively marked
  5. 2003 High

    Localizing H1069Q to the ER and documenting secondary catecholamine enzyme deficits clarified that the most common mutation causes ER retention and that systemic copper dysregulation affects copper enzymes in non-expressing tissues.

    Evidence Immunogold EM of patient liver plus GFP-mutant imaging; Western blot/catecholamine measurement in Atp7b-/- adrenal glands

    PMID:12557139 PMID:12718440

    Open questions at the time
    • ER quality-control machinery acting on H1069Q not yet identified
    • Adrenal effect is secondary/indirect, not a direct ATP7B function
  6. 2006 High

    Demonstrating vesicular copper sequestration and exocytosis refined the excretion model away from direct canalicular membrane translocation.

    Evidence Immunofluorescence and copper accumulation assays in HepG2 and CHO cells with an endocytic-signal mutant

    PMID:16472602

    Open questions at the time
    • Identity of the exocytic vesicle compartment not fully defined
    • Endocytic retrieval machinery not identified
  7. 2007 High

    Identifying COMMD1 binding to the N-terminus established a copper-independent control of ATP7B stability distinct from its trafficking.

    Evidence GST pull-down, Co-IP, pulse-chase, and mutagenesis of N-terminal Wilson disease variants

    PMID:17919502

    Open questions at the time
    • Degradation pathway used by COMMD1 not specified in this study
    • How N-terminal mutations enhance COMMD1 binding structurally unclear
  8. 2008 Medium

    Epistasis testing placed copper-induced ATP7B translocation upstream of and independent from COMMD1- and Rab7-regulated endolysosomal trafficking.

    Evidence siRNA and dominant-negative Rab7 with confocal colocalization in multiple non-hepatic cell lines

    PMID:18974300

    Open questions at the time
    • Negative result; non-hepatic cells may differ from hepatocytes
    • Exact step where COMMD1 acts not pinpointed here
  9. 2009 High

    Catalytic-cycle and pharmacological-chaperone studies dissected the spectrum of mutant defects and showed cisplatin engages ATP7B catalytically but is not transported through the copper pathway.

    Evidence Phosphorylation/transport competition assays with deletion mutants in Huh7 cells; copper export, temperature-rescue and 4-PBA/curcumin treatment of misfolding mutants; cell-type comparison of renal vs. hepatic trafficking

    PMID:19141620 PMID:19416479 PMID:19937698

    Open questions at the time
    • Why cisplatin uncouples phosphorylation from trafficking unresolved
    • Tissue-specific processing basis for renal non-trafficking not identified
  10. 2010 High

    Identifying PKD phosphorylation explained how copper licenses both ATP7B stability and Golgi-to-vesicle trafficking.

    Evidence Microsomal phosphorylation assays with PKD inhibitor, serine-to-alanine mutagenesis, and trafficking imaging in COS-1/HepG2 cells

    PMID:21189263

    Open questions at the time
    • How copper binding activates PKD toward ATP7B unclear
    • Phosphatase counteracting this modification not identified
  11. 2011 High

    Resolving two parallel degradation routes (clusterin/lysosomal, COMMD1/proteasomal) defined non-redundant quality-control pathways governing ATP7B abundance.

    Evidence Reciprocal Co-IP, knockdown/overexpression, and lysosomal/proteasomal inhibitor experiments on endogenous ATP7B

    PMID:22130675

    Open questions at the time
    • Signals selecting one route vs. the other not defined
    • E3 ligase mediating COMMD1-linked proteasomal degradation unidentified
  12. 2012 High

    Systematic reconstitution of 28 disease variants categorized mutations into catalytic, transport, phosphointermediate, and stability/localization defect classes.

    Evidence Baculovirus/Sf9 ATPase and 64Cu vesicular transport assays with GFP-localization in mammalian cells

    PMID:22240481

    Open questions at the time
    • In-cell trafficking behavior of all variants not exhaustively mapped
    • Genotype-phenotype correlation to clinical severity not established here
  13. 2014 High

    Linking ATP7B to lysosomal copper import and dynactin-p62-driven lysosomal exocytosis provided a mechanism for biliary copper excretion.

    Evidence Live-cell imaging, ATP7B–p62/dynactin Co-IP, siRNA, and copper excretion assays in HepG2 and primary hepatocytes

    PMID:24909901

    Open questions at the time
    • Reconciling lysosomal exocytosis with transcytotic models unresolved
    • How copper is released across the canalicular membrane not defined
  14. 2016 Medium

    Demonstrating an intestinal copper-buffering role connected ATP7B to chylomicron assembly, and a polarized-hepatocyte study challenged the lysosomal exocytosis model in favor of microtubule-mediated transcytosis.

    Evidence X-ray fluorescence, EM, and enteroid imaging in Atp7b-/- mice; live-cell confocal organelle-marker tracking in polarized WIF-B cells

    PMID:27034138 PMID:28958857

    Open questions at the time
    • Conflicting excretion routes (lysosomal vs. transcytotic) not reconciled
    • Mechanistic link between copper buffering and apoB localization incomplete
  15. 2017 Medium

    Showing ATP7B forms stable dimers retained during trafficking provided the first architectural view of a human Cu-ATPase.

    Evidence Co-IP of differentially tagged variants and negative-stain EM of purified dimeric construct

    PMID:28842499

    Open questions at the time
    • Functional role of dimerization in transport/trafficking unknown
    • Low-resolution model; high-resolution dimer interface not defined
  16. 2019 Medium

    Defining the MBD copper-relay hierarchy and COMMD1–PtdIns(4,5)P2 coupling clarified intramolecular regulation and membrane-recruitment control of trafficking, and identified MTF1 as a metal-responsive transcriptional regulator.

    Evidence Yeast transport assays with cysteine-to-serine MBD mutants; quantitative colocalization with COMMD1 PtdIns(4,5)P2-binding mutant in HepG2 cells; EMSA and reporter assays for MTF1

    PMID:31321400 PMID:31515276 PMID:31596515

    Open questions at the time
    • Structural basis of MBD1–3 inhibition not directly visualized here
    • How COMMD1 lipid binding directs ATP7B at specific membranes incomplete
  17. 2020 High

    Identifying HSP70 capture of H1069Q and its pharmacological reversal defined a druggable basis for the most common Wilson disease defect.

    Evidence Proteomic interaction profiling, HSP70 inhibitor (domperidone) treatment, and trafficking/copper accumulation assays in hepatic cells

    PMID:33288711

    Open questions at the time
    • Whether HSP70 targeting generalizes to other misfolding mutants unclear
    • In vivo efficacy of HSP70 inhibition not established here
  18. 2021 Medium

    Identifying an LC3-interaction region linked ATP7B directly to autophagy regulation under copper stress.

    Evidence In vitro LIR3 peptide binding with mutagenesis and colocalization/KO-rescue autophagy readouts in HepG2 cells

    PMID:34831341

    Open questions at the time
    • Single-lab finding; in vitro binding not confirmed for full-length protein in vivo
    • Physiological consequence of ATP7B–LC3B interaction incompletely defined
  19. 2022 High

    Cryo-EM of the E2-Pi state and a rigorous negative result on frameshifting clarified, respectively, the transmembrane copper pathway/regulation and that ATP7B is decoded without ribosomal frameshifting.

    Evidence Cryo-EM of frog ATP7B; dual-luciferase reporter comparison plus ribosome profiling analysis for frameshifting

    PMID:35245129 PMID:36115342

    Open questions at the time
    • Copper-bound and trafficking-competent conformations not captured in E2-Pi state
    • Functional asymmetry of dimer not addressed by monomeric structure
  20. 2023 High

    Human E1-state cryo-EM, AP-1-dependent polarized sorting, and the choroid plexus phenotype together resolved MBD6 docking at the copper entry site, the apical transcytotic route directed by AP-1, and a developmental brain copper-delivery role.

    Evidence Cryo-EM of human ATP7B in three states; polarized-cell imaging with AP-1A/AP-1B CRISPR KO and MS partner ID; Atp7b-/- choroid plexus IHC, lipidomics, and immunofluorescence

    PMID:36626371 PMID:37074913 PMID:38032054

    Open questions at the time
    • Full copper-translocation cycle intermediates still incompletely resolved
    • How AP-1B isoform selectivity is achieved mechanistically unclear
    • Reconciliation of apical transcytotic vs. lysosomal excretion routes still open

Open questions

Synthesis pass · forward-looking unresolved questions
  • How the conflicting models of biliary copper excretion (lysosomal exocytosis vs. microtubule-mediated transcytosis) are reconciled, and how copper is ultimately released across the canalicular membrane, remains unresolved.
  • No unified model integrating lysosomal and transcytotic excretion routes
  • Mechanism of final copper release into bile undefined
  • Tissue-specific trafficking regulation across liver, intestine, kidney, and brain not mechanistically unified

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0005215 transporter activity 5 GO:0140657 ATP-dependent activity 4 GO:0016787 hydrolase activity 3
Localization
GO:0005783 endoplasmic reticulum 3 GO:0005794 Golgi apparatus 3 GO:0031410 cytoplasmic vesicle 3 GO:0005764 lysosome 2 GO:0005768 endosome 2 GO:0005886 plasma membrane 1
Pathway
R-HSA-382551 Transport of small molecules 4 R-HSA-1430728 Metabolism 3 R-HSA-1643685 Disease 3 R-HSA-392499 Metabolism of proteins 3 R-HSA-5653656 Vesicle-mediated transport 3
Partners
ATOX1CLUCOMMD1DCTN4HSPA1AMAP1LC3BPRKD1TFEB

Evidence

Reading pass · 32 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 (E2-Pi) state revealed: a ring of negatively charged residues lines the cytoplasmic copper entrance gated by a conserved basic residue; a network of copper-coordinating ligands in the transmembrane domain delineates a stepwise copper transport pathway; the N-terminal metal-binding domains interact with both the A and P cytoplasmic domains, poised to exert copper-dependent regulation of ATP hydrolysis coupled to transmembrane copper transport. Cryo-electron microscopy structure determination Science advances High 35245129
2023 Cryo-EM structures of human ATP7B in the E1 state (apo, putative copper-bound, and putative cisplatin-bound forms) showed that the sixth N-terminal metal-binding domain (MBD6) binds at the cytoplasmic copper entry site of the transmembrane domain (TMD), 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 structure supports an ATP-driven copper transport model. Cryo-electron microscopy structure determination (multiple states) Cell reports High 37074913
2014 In response to elevated copper, ATP7B moves from the Golgi to lysosomes, imports copper into their lumen, and then enables lysosomal exocytosis through interaction with the p62 subunit of dynactin, allowing lysosome translocation toward the canalicular pole of hepatocytes for copper excretion into bile. Live-cell fluorescence microscopy, Co-IP (ATP7B–p62/dynactin), siRNA knockdown, copper accumulation/excretion assays in HepG2 cells and primary hepatocytes Developmental cell High 24909901
2006 ATP7B mediates vesicular sequestration of excess intracellular copper rather than direct translocation across the canalicular membrane; elevated copper stimulates ATP7B trafficking to pericanalicular vesicles in HepG2 cells; mutation of an endocytic retrieval signal causes constitutive vesicular localization; wild-type and mutant ATP7B cause CHO cells to accumulate copper in vesicles that subsequently undergo exocytosis. Immunofluorescence microscopy, copper accumulation assays in CHO cells expressing wild-type and endocytic-signal mutant ATP7B, site-directed mutagenesis Gastroenterology High 16472602
1998 Introduction of WND (ATP7B) cDNA via recombinant adenovirus into LEC rats (Wilson disease model) restored ATP7B protein to the Golgi apparatus and rescued synthesis of holoceruloplasmin (oxidase-active, copper-bound ceruloplasmin) in plasma, directly demonstrating that ATP7B functions in copper transport coupled with ceruloplasmin biosynthesis and that the Golgi is the functional site. Adenovirus-mediated gene delivery, immunofluorescence and subcellular fractionation, Western blot and plasma ceruloplasmin oxidase activity measurement in LEC rats The Journal of biological chemistry High 9430732
1998 The conserved CPC (Cys-Pro-Cys) motif in the membrane-spanning segment of ATP7B is essential for copper transport; mutation of CPC to SPS abolished ATP7B function in yeast complementation of ccc2 mutants. Five Wilson disease missense mutations in predicted membrane-spanning segments retained partial copper transport activity in yeast. Yeast complementation assay (ccc2 mutant rescue), site-directed mutagenesis of ATP7B cDNA American journal of human genetics High 9837819
2000 Wilson disease ATP7B variant proteins that retain copper transport activity in yeast (Asp765Asn, Leu776Val) showed mislocalization in CHO cells and impaired copper-dependent redistribution; the CPC→SPS mutant and Gly943Ser localized normally to the Golgi but could not redistribute in response to copper, indicating that copper-induced trafficking is a distinct functional requirement from catalytic copper transport. Yeast complementation assay, transient transfection of CHO cells, triple-label immunofluorescence microscopy Human molecular genetics High 10942420
2007 COMMD1 specifically interacts with the amino-terminal region of ATP7B independently of intracellular copper levels and ATOX1 expression. Four Wilson disease patient-derived N-terminal mutations significantly increased ATP7B binding to COMMD1, leading to mislocalization and increased degradation of ATP7B. COMMD1 markedly decreases the stability of newly synthesized ATP7B but does not affect copper-induced trafficking. GST pull-down, co-immunoprecipitation, immunofluorescence microscopy, site-directed mutagenesis, biosynthetic pulse-chase labeling Gastroenterology High 17919502
2011 Clusterin and COMMD1 independently interact with ATP7B and facilitate its degradation via distinct pathways: clusterin via the lysosomal pathway and COMMD1 via the proteasomal pathway. The clusterin–ATP7B interaction is enhanced by oxidative stress or ATP7B mutation; COMMD1–ATP7B interaction increases only with misfolding mutations. Endogenous ATP7B exists in a complex with both clusterin and COMMD1 simultaneously, but these interactions are neither competitive nor cooperative. Co-immunoprecipitation, overexpression and siRNA knockdown, Western blot for endogenous protein levels, lysosomal and proteasomal inhibitor experiments The Journal of biological chemistry High 22130675
2010 Protein kinase D (PKD) phosphorylates serine residues of ATP7B at the trans-Golgi network; this phosphorylation protects ATP7B from proteasome-mediated degradation and is required for its trafficking from the Golgi to cytosolic vesicles. Both PKD-mediated phosphorylation and subsequent trafficking are copper-dependent: mutations of critical copper-binding sites completely prevented both. Mutation of Ser-478/481/1121/1453 to Ala markedly reduced ATP7B trafficking. Microsomal phosphorylation assays with PKD inhibitor CID755673, Western blot, site-directed mutagenesis, confocal microscopy in COS-1 and HepG2 cells, proteasome inhibitor (MG132) experiments The Journal of biological chemistry High 21189263
2019 Copper relay through the N-terminal metal-binding domains (MBDs) of ATP7B follows a defined mechanistic model: MBD1-3 form a regulatory unit; copper delivery via Atox1 to this unit and loading of MBD3 promotes release of inhibitory interactions; MBD4 can be mutated without large effect; intact copper sites in MBD5 or MBD6 are required for copper transport; only MBD6 can deliver copper to truncated ATP7B lacking all six MBDs, suggesting a specific docking role for MBD6. Yeast copper transport assay with strategic cysteine-to-serine mutations blocking individual MBD copper-binding sites in full-length and truncated ATP7B constructs Metallomics : integrated biometal science High 31321400
2017 Human ATP7B forms stable dimers in eukaryotic cells; the dimer interface is formed by conserved domains (not the N-terminal MBDs 1–4, which are unique to human ATP7B). Dimeric structure is retained during trafficking between intracellular compartments. A low-resolution 3D model by negative-stain EM of purified dimeric 1-4ΔMBD-7B provided the first structural insight into the overall architecture of a human Cu-ATPase. Co-immunoprecipitation of differentially tagged variants, purification of ATP7B after membrane solubilization, negative-stain electron microscopy, single-particle analysis The Journal of biological chemistry Medium 28842499
2009 Cisplatin binds to ATP7B and stimulates catalytic phosphorylation (EC50 similar to copper), but unlike copper it does not induce trafficking of ATP7B in hepatoma cells and does not compete with copper in a transport assay. Deletion of the first four copper-binding sites of ATP7B abolishes cisplatin-induced phosphorylation; mutation of the first five sites does not. These data indicate that cisplatin interacts functionally with ATP7B but is not actively transported through the copper translocation pathway. ATPase phosphorylation assay, copper transport competition assay, confocal microscopy (trafficking), site-directed deletion mutagenesis in Huh7 hepatoma cells The Journal of biological chemistry High 19141620
2004 Both ATP7A and ATP7B sequester platinum drugs (cisplatin, carboplatin, oxaliplatin) into vesicular compartments, reducing cytoplasmic platinum available to reach DNA. Fibroblasts engineered to express ATP7B showed increased platinum in isolated vesicles for all three drugs. Copper triggered ATP7A relocalization but platinum drugs did not, indicating the sequestration mechanism is distinct from the copper-stimulated trafficking response. Engineered cell lines (Menkes fibroblasts ± ATP7B or ATP7A expression), whole-cell and vesicle platinum accumulation assays, cytotoxicity assays, immunofluorescence Molecular pharmacology Medium 15213293
2003 H1069Q-ATP7B is trapped in the endoplasmic reticulum rather than localizing to the trans-Golgi network in both human Wilson disease patient liver tissue (immunogold EM) and in HuH-7/HepG2 hepatoma cells. Truncated ATP7B mutants show diffuse cytoplasmic distribution distinct from TGN or ER, while most missense mutants distribute similarly to wild-type. Immunogold electron microscopy of patient liver biopsies, confocal microscopy of GFP-tagged ATP7B mutants in hepatoma cells Gastroenterology High 12557139
2001 The toxic milk (tx) mutation in murine Wilson protein (Wnd) disrupts copper-induced relocalization of Wnd in CHO cells and abolishes Wnd-mediated copper resistance. With elevated copper, wild-type Wnd accumulates in large multivesicular structures resembling late endosomes, distinct from the post-Golgi destination of ATP7A/MNK, even when both proteins are in the same cell. Transient transfection of CHO cells, copper resistance assays, colocalization immunofluorescence, ultrastructural analysis (electron microscopy) Human molecular genetics High 11157799
2009 In kidney, ATP7B does not traffic in response to elevated copper (unlike hepatic ATP7B and ATP7A), and therefore is unlikely to mediate copper export. Renal ATP7B is 2–3 kDa smaller than hepatic ATP7B, suggesting cell-specific processing; lack of trafficking is not due to absence of kinase-mediated phosphorylation or co-expression of ATP7A. Recombinant ATP7B expressed in renal cells traffics differently from in hepatic cells. Immunofluorescence microscopy, subcellular fractionation, Western blot, RT-PCR of ATP7B mRNA variants across cell types, comparison of endogenous renal vs. hepatic ATP7B Traffic (Copenhagen, Denmark) Medium 19416479
2019 COMMD1 binds both ATP7B and phosphatidylinositol(4,5)-bisphosphate [PtdIns(4,5)P2]; COMMD1 modulates copper-responsive ATP7B trafficking through recruitment to PtdIns(4,5)P2 membranes. Decreased COMMD1 causes loss of ATP7B from lysosomes and TGN under high copper and leads to early endosome accumulation of ATP7B; excess COMMD1 also disrupts ATP7B trafficking. A COMMD1 mutant unable to bind PtdIns(4,5)P2 had little impact on ATP7B trafficking. Quantitative colocalization analysis by confocal microscopy, siRNA knockdown and overexpression of COMMD1, PtdIns(4,5)P2-binding mutant of COMMD1 in HepG2 cells Journal of cell science Medium 31515276
2023 ATP7B and ATP7A reside on distinct TGN domains under limiting copper. In high copper, ATP7B traffics to the apical membrane via common recycling endosomes, apical sorting endosomes, and apical recycling endosomes (transcytotic route), while ATP7A traffics basolaterally. The AP-1A complex provides directionality and TGN retention for both Cu-ATPases; the AP-1B complex governs copper-independent trafficking of ATP7B to the apical domain specifically. Knockout of pan-AP-1 disrupts sorting of both ATPases. Polarized epithelial cell imaging (confocal microscopy), mass spectrometry identification of regulatory partners, AP-1A and AP-1B isoform-specific CRISPR knockouts, analysis of Wilson disease-causing ATP7B trafficking mutants Journal of cell science High 38032054
2009 Wilson disease mutations that cause protein misfolding result in reduced ATP7B expression (protein but not mRNA) and ER retention. Culturing cells at 30°C increases expression and normalizes localization of mutant ATP7B. Four distinct mutations retained residual copper export capacity. Pharmacological chaperones 4-phenylbutyrate (4-PBA) and curcumin partially restored protein expression of most ATP7B mutants. Western blot, immunofluorescence microscopy, copper export assays, temperature-rescue experiments, homology modeling, pharmacological chaperone treatment in transfected cell lines Hepatology (Baltimore, Md.) High 19937698
2012 ATP7B variants causing Wilson disease disrupt the protein's function through diverse mechanisms: some cause complete loss of catalytic and transport activity; others lose transport activity but retain phosphointermediate formation; yet others have partial activity losses. Transport-competent variants differ in stability and subcellular localization in mammalian cells. Baculovirus/Sf9 expression system, ATPase catalytic activity assay, 64Cu transport into vesicles, GFP-tagged protein localization by confocal microscopy in mammalian cells Gastroenterology High 22240481
2016 ATP7B in intestinal enterocytes maintains a copper gradient along the duodenal crypt-villus axis; it buffers copper levels in the cytosol via rapid copper-dependent enlargement of ATP7B-containing vesicles and increased ATP7B levels. Loss of intestinal ATP7B (Atp7b-/- mice) causes reduced copper storage pools, accumulation of triglyceride-filled vesicles, mislocalization of apolipoprotein B, and loss of chylomicrons, linking ATP7B-mediated copper buffering to chylomicron assembly. Immunohistochemistry, X-ray fluorescence for copper distribution, electron microscopy, immunoblotting in Atp7b-/- mice; fluorescent confocal microscopy of primary 3D enteroids with copper treatment and chelation Gastroenterology High 28958857
2008 Copper-induced translocation of ATP7B from Golgi to dispersed vesicles is independent of Rab7-regulated endolysosomal trafficking and independent of COMMD1/Murr1: RNAi depletion of COMMD1 or Rab7 (or dominant-negative Rab7) did not impair ATP7B translocation; no colocalization of translocating ATP7B with COMMD1 or Rab7 markers was observed. COMMD1 acts at a later step in the copper excretion pathway. Confocal microscopy, siRNA knockdown of COMMD1 and Rab7, dominant-negative Rab7 expression in multiple non-hepatic cell lines The American journal of pathology Medium 18974300
2016 Transcription factor EB (TFEB) directly binds to CLEAR (coordinated lysosomal expression and regulation) sites in the proximal promoter and first intron of ATP7B upon platinum exposure, driving ATP7B transcription in platinum-resistant ovarian cancer cells. Suppression of TFEB inhibits ATP7B expression and increases cisplatin toxicity in resistant cells. ChIP assay (TFEB binding to ATP7B CLEAR elements), luciferase reporter assays with ATP7B promoter fragments, TFEB siRNA knockdown, cisplatin sensitivity assays in IGROV-CP20 cells Cells Medium 35053335
2019 MTF1 (metal regulatory transcription factor 1) specifically binds to the metal-responsive element MREe in the ATP7B promoter, and this interaction significantly increases ATP7B promoter-driven reporter gene expression, identifying MTF1 as a transcriptional regulator of ATP7B. Electrophoretic mobility shift assay (EMSA), MatInspector computational analysis followed by experimental EMSA validation, luciferase reporter assay Annals of human genetics Medium 31596515
2020 The frequent H1069Q substitution promotes ATP7B interaction with HSP70, accelerating ER-associated degradation of the mutant protein and causing copper accumulation in hepatic cells. The HSP70 inhibitor domperidone (an FDA-approved drug) impairs HSP70–ATP7B-H1069Q interaction, recovering trafficking and function of the mutant protein. Proteomics (protein interaction landscape of H1069Q vs. wild-type ATP7B), HSP70 inhibitor experiments, copper accumulation assays, confocal microscopy of mutant ATP7B trafficking in hepatic cells Proceedings of the National Academy of Sciences of the United States of America High 33288711
2021 ATP7B directly interacts with LC3B via a conserved LC3-interaction region (LIR3) at the C-terminal end of ATP7B; replacing the conserved hydrophobic residues W1452 and L1455 significantly reduced interaction. Autophagy induction enhances colocalization of ATP7B and LC3B on autophagosome membranes in HepG2 cells. ATP7B-deficient HepG2 cells show autophagy deficiency under elevated copper, complemented by re-expression of ATP7B. In silico LIR prediction, in vitro pulldown/binding assay (LIR3 peptide with LC3B), site-directed mutagenesis of LIR3, confocal colocalization in HepG2 cells, CRISPR ATP7B-knockout HepG2 cells with autophagy readouts Cells Medium 34831341
2016 ATP7B traffics from TGN to the bile canaliculus via basolateral sorting, endocytosis, and microtubule-mediated transcytosis through the subapical compartment; trafficking ATP7B is not incorporated into lysosomes. Copper addition does not cause relocalization of lysosomes or appearance of lysosome markers at the bile canaliculus, arguing against the lysosomal exocytosis model for biliary copper excretion. Live-cell and fixed confocal microscopy in polarized hepatocyte (WIF-B) cells, colocalization with organelle markers, copper treatment, lysosome marker tracking Journal of cell science Medium 27034138
2003 Loss of ATP7B in adrenal glands of Atp7b-/- mice causes reduced levels of dopamine beta-hydroxylase (DBH) protein and its products norepinephrine and epinephrine, even though Atp7b mRNA is not normally expressed in adrenal tissue. This indicates that copper-requiring enzymes in tissues remote from those expressing ATP7B are affected secondarily through systemic copper dysregulation. Western blot and catecholamine measurement in Atp7b-/- vs. wild-type mouse adrenal glands; RT-PCR to confirm absence of Atp7b mRNA in adrenal; copper level measurement Neurochemical research Medium 12718440
2023 During postnatal development, Atp7b is necessary for normal morphology and function of choroid plexus (ChPl); loss of Atp7b causes reorganization of ChPl cytoskeleton and cell-cell contacts, loss of Slc31a1 from the apical membrane, and decreased microvilli and cilia length and number. In ChPl lacking Atp7b, Atp7a is upregulated but remains intracellular, limiting copper transport into the brain and causing transient copper deficit with catecholamine imbalance and brain lipidome changes. Immunohistochemistry, Western blot, mass spectrometry (brain lipidome), RT-PCR, immunofluorescence microscopy in Atp7b-/- mouse choroid plexus PLoS genetics Medium 36626371
1997 Lymphoblast cell lines from Wilson disease patients homozygous for H1069Q and four other ATP7B mutations all demonstrated significantly decreased copper-stimulated ATPase activity, establishing that these mutations directly impair the enzymatic function of ATP7B. ATPase activity assay in patient-derived lymphoblast cell lines American journal of human genetics Medium 9311736
2022 Lack of evidence for ribosomal frameshifting in ATP7B mRNA decoding: apparent frameshifting detected with dual-luciferase polyprotein reporters was an artifact; when tested in a reporter system releasing reporters without polyprotein context, no frameshifting was detected above background. This refutes the proposed frameshifting mechanism for ATP7B expression. Dual luciferase reporter assays (two different reporter architectures), ribosome profiling data analysis, phylogenetic analysis of proposed frameshifting site Molecular cell High 36115342

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 357 17531189
1997 Identification and analysis of mutations in the Wilson disease gene (ATP7B): population frequencies, genotype-phenotype correlation, and functional analyses. American journal of human genetics 258 9311736
2014 Wilson disease protein ATP7B utilizes lysosomal exocytosis to maintain copper homeostasis. Developmental cell 235 24909901
2006 Regional distribution of mutations of the ATP7B gene in patients with Wilson disease: impact on genetic testing. Human genetics 188 16791614
1998 Restoration of holoceruloplasmin synthesis in LEC rat after infusion of recombinant adenovirus bearing WND cDNA. The Journal of biological chemistry 135 9430732
2007 Distinct Wilson's disease mutations in ATP7B are associated with enhanced binding to COMMD1 and reduced stability of ATP7B. Gastroenterology 127 17919502
1998 Functional characterization of missense mutations in ATP7B: Wilson disease mutation or normal variant? American journal of human genetics 126 9837819
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 123 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
2002 Copper-transporting P-type adenosine triphosphatase (ATP7B) as a cisplatin based chemoresistance marker in ovarian carcinoma: comparative analysis with expression of MDR1, MRP1, MRP2, LRP and BCRP. International journal of cancer 117 12216079
2005 Mutation analysis of the ATP7B gene and genotype/phenotype correlation in 227 patients with Wilson disease. Molecular genetics and metabolism 112 15967699
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
2006 ATP7B mediates vesicular sequestration of copper: insight into biliary copper excretion. Gastroenterology 109 16472602
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 92 18000748
2017 The Function of ATPase Copper Transporter ATP7B in Intestine. Gastroenterology 91 28958857
2004 Wilson disease: novel mutations in the ATP7B gene and clinical correlation in Brazilian patients. Human mutation 86 15024742
2016 Activation of liver X receptor/retinoid X receptor pathway ameliorates liver disease in Atp7B(-/-) (Wilson disease) mice. Hepatology (Baltimore, Md.) 84 26679751
2016 Spectrum and Classification of ATP7B Variants in a Large Cohort of Chinese Patients with Wilson's Disease Guides Genetic Diagnosis. Theranostics 83 27022412
1998 ATP7B (WND) protein. The international journal of biochemistry & cell biology 79 9785470
2011 Clusterin and COMMD1 independently regulate degradation of the mammalian copper ATPases ATP7A and ATP7B. The Journal of biological chemistry 74 22130675
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 73 35245129
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 69 17268820
2008 Atp7b-/- mice as a model for studies of Wilson's disease. Biochemical Society transactions 68 19021531
2021 Copper Imbalance in Alzheimer's Disease: Meta-Analysis of Serum, Plasma, and Brain Specimens, and Replication Study Evaluating ATP7B Gene Variants. Biomolecules 66 34209820
2003 Mutation spectrum and polymorphisms in ATP7B identified on direct sequencing of all exons in Chinese Han and Hui ethnic patients with Wilson's disease. Clinical genetics 66 14986826
2021 Direct Measurement of ATP7B Peptides Is Highly Effective in the Diagnosis of Wilson Disease. Gastroenterology 63 33640437
2015 Geographic distribution of ATP7B mutations in Wilson disease. Annals of human biology 61 26207595
2006 p.H1069Q mutation in ATP7B and biochemical parameters of copper metabolism and clinical manifestation of Wilson's disease. Movement disorders : official journal of the Movement Disorder Society 58 16211609
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
2009 Cell-specific trafficking suggests a new role for renal ATP7B in the intracellular copper storage. Traffic (Copenhagen, Denmark) 51 19416479
2002 Human copper-transporting ATPase ATP7B (the Wilson's disease protein): biochemical properties and regulation. Journal of bioenergetics and biomembranes 51 12539962
2022 Cuproptosis-Related Gene - SLC31A1, FDX1 and ATP7B - Polymorphisms are Associated with Risk of Lung Cancer. Pharmacogenomics and personalized medicine 50 35923305
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
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 48 38186308
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
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 44 27499330
2017 Dynamics of the metal binding domains and regulation of the human copper transporters ATP7B and ATP7A. IUBMB life 42 28271598
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
2022 ATP7B gene therapy of autologous reprogrammed hepatocytes alleviates copper accumulation in a mouse model of Wilson's disease. Hepatology (Baltimore, Md.) 36 35340061
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
2010 Involvement of protein kinase D in expression and trafficking of ATP7B (copper ATPase). The Journal of biological chemistry 35 21189263
2024 Epidemiology of Wilson's Disease and Pathogenic Variants of the ATP7B Gene Leading to Diversified Protein Disfunctions. International journal of molecular sciences 34 38397079
2008 Copper-induced translocation of the Wilson disease protein ATP7B independent of Murr1/COMMD1 and Rab7. The American journal of pathology 33 18974300
2005 The Wilson disease protein ATP7B resides in the late endosomes with Rab7 and the Niemann-Pick C1 protein. The American journal of pathology 33 15681833
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
2010 Differential expression of ATP7A, ATP7B and CTR1 in adult rat dorsal root ganglion tissue. Molecular pain 31 20836889
2008 New mutations in the Wilson disease gene, ATP7B: implications for molecular testing. Genetic testing 30 18373411
2017 Restraint of presynaptic protein levels by Wnd/DLK signaling mediates synaptic defects associated with the kinesin-3 motor Unc-104. eLife 29 28925357
2014 Structural and metabolic changes in Atp7b-/- mouse liver and potential for new interventions in Wilson's disease. Annals of the New York Academy of Sciences 29 24697742
2011 Early gestational gene transfer with targeted ATP7B expression in the liver improves phenotype in a murine model of Wilson's disease. Gene therapy 28 22158007
2016 Mutational analysis of ATP7B in Chinese Wilson disease patients. American journal of translational research 27 27398169
2010 Mutation analysis and characterization of alternative splice variants of the Wilson disease gene ATP7B. Hepatology (Baltimore, Md.) 27 20931554
2022 Full-length ATP7B reconstituted through protein trans-splicing corrects Wilson disease in mice. Molecular therapy. Methods & clinical development 26 36092366
2018 Presumed missense and synonymous mutations in ATP7B gene cause exon skipping in Wilson disease. Liver international : official journal of the International Association for the Study of the Liver 26 29637721
2002 Expression in mouse kidney of membrane copper transporters Atp7a and Atp7b. Nephron 26 12372948
2022 TFEB Regulates ATP7B Expression to Promote Platinum Chemoresistance in Human Ovarian Cancer Cells. Cells 25 35053335
2015 Rho1-Wnd signaling regulates loss-of-cell polarity-induced cell invasion in Drosophila. Oncogene 25 25961917
2003 A mutation in the ATP7B copper transporter causes reduced dopamine beta-hydroxylase and norepinephrine in mouse adrenal. Neurochemical research 25 12718440
1998 Physiologic function of the Wilson disease gene product, ATP7B. The American journal of clinical nutrition 25 9587140
2020 Activation of HIF-1 signaling ameliorates liver steatosis in zebrafish atp7b deficiency (Wilson's disease) models. Biochimica et biophysica acta. Molecular basis of disease 24 32446740
2019 COMMD1 and PtdIns(4,5)P2 interaction maintain ATP7B copper transporter trafficking fidelity in HepG2 cells. Journal of cell science 24 31515276
2021 Mutation analysis of the ATP7B gene and genotype-phenotype correlation in Chinese patients with Wilson disease. BMC gastroenterology 23 34470610
2021 Direct Interaction of ATP7B and LC3B Proteins Suggests a Cooperative Role of Copper Transportation and Autophagy. Cells 23 34831341
2023 Regulation of the apico-basolateral trafficking polarity of the homologous copper-ATPases ATP7A and ATP7B. Journal of cell science 22 38032054
2005 Expression of ATP7B in normal human liver. European journal of histochemistry : EJH 22 16377579
2019 Copper relay path through the N-terminus of Wilson disease protein, ATP7B. Metallomics : integrated biometal science 20 31321400
2023 Atp7b-dependent choroid plexus dysfunction causes transient copper deficit and metabolic changes in the developing mouse brain. PLoS genetics 19 36626371
2016 Functional analysis and drug response to zinc and D-penicillamine in stable ATP7B mutant hepatic cell lines. World journal of gastroenterology 19 27122662
2024 CircSpna2 attenuates cuproptosis by mediating ubiquitin ligase Keap1 to regulate the Nrf2-Atp7b signalling axis in depression after traumatic brain injury in a mouse model. Clinical and translational medicine 18 39581695
2019 MTF1 binds to metal-responsive element e within the ATP7B promoter and is a strong candidate in regulating the ATP7B expression. Annals of human genetics 18 31596515
2004 Expression of copper-transporting P-type adenosine triphosphatase (ATP7B) in human hepatocellular carcinoma. Anticancer research 18 15154620
2003 Wilson disease protein ATP7B is localized in the late endosomes in a polarized human hepatocyte cell line. International journal of molecular medicine 18 12579329
2023 ATP7B R778L mutant hepatocytes resist copper toxicity by activating autophagy and inhibiting necroptosis. Cell death discovery 17 37717021
2022 Pathogenicity of Intronic and Synonymous Variants of ATP7B in Wilson Disease. The Journal of molecular diagnostics : JMD 17 36343861
2020 ATP7B knockout disturbs copper and lipid metabolism in Caco-2 cells. PloS one 17 32155648
2020 CRISPR/Cas9-mediated correction of mutated copper transporter ATP7B. PloS one 17 32997714
2019 Association of the canine ATP7A and ATP7B with hepatic copper accumulation in Dobermann dogs. Journal of veterinary internal medicine 17 31254371
2017 Atp7a and Atp7b regulate copper homeostasis in developing male germ cells in mice. Metallomics : integrated biometal science 17 28820536
2016 Basolateral sorting and transcytosis define the Cu+-regulated translocation of ATP7B to the bile canaliculus. Journal of cell science 17 27034138
2010 Overexpressed ATP7B protects mesenchymal stem cells from toxic copper. Biochemical and biophysical research communications 17 20362556
2010 Six novel ATP7B mutations in Thai patients with Wilson disease. European journal of medical genetics 17 21034864
2022 Lack of evidence for ribosomal frameshifting in ATP7B mRNA decoding. Molecular cell 16 36115342
2020 Pharmacoproteomics pinpoints HSP70 interaction for correction of the most frequent Wilson disease-causing mutant of ATP7B. Proceedings of the National Academy of Sciences of the United States of America 16 33288711
2018 Metallothionein is elevated in liver and duodenum of Atp7b(-/-) mice. Biometals : an international journal on the role of metal ions in biology, biochemistry, and medicine 16 29732486
2014 The effect of zinc and D-penicillamine in a stable human hepatoma ATP7B knockout cell line. PloS one 16 24892424
2013 Mutation analysis of ATP7B gene in Turkish Wilson disease patients: identification of five novel mutations. European journal of medical genetics 16 23333878
2011 Prevalence of ATP7B Gene Mutations in Iranian Patients With Wilson Disease. Hepatitis monthly 16 22308153
2010 ATP7B expression is associated with in vitro sensitivity to cisplatin in non-small cell lung cancer. Oncology letters 16 22966294
2019 Genetic analysis of ATP7B in 102 south Indian families with Wilson disease. PloS one 15 31059521

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