id: P35670
gene_symbol: ATP7B
product_type: PROTEIN
status: COMPLETE
taxon:
  id: NCBITaxon:9606
  label: Homo sapiens
description: >-
  ATP7B (copper-transporting ATPase 2) is a P1B-type ATPase (EC 7.2.2.8)
  predominantly expressed in hepatocytes. It has two main physiological roles:
  (1) biosynthetic copper delivery to cuproenzymes (particularly ceruloplasmin)
  at the trans-Golgi network, and (2) biliary copper excretion via
  copper-responsive vesicular trafficking. Under basal copper conditions, ATP7B
  resides in the TGN where it loads copper into the secretory pathway. When
  intracellular copper rises, ATP7B traffics to pericanalicular vesicles that
  sequester excess copper and subsequently undergo exocytosis to excrete copper
  into bile. This vesicular sequestration mechanism (not direct plasma membrane
  transport) is the primary route for biliary copper elimination. ATP7B contains
  six N-terminal heavy metal-associated (HMA) domains, each with a GMXCXXC
  copper-binding motif, eight transmembrane domains with a conserved CPC motif
  essential for transport, and cytoplasmic nucleotide-binding and
  phosphorylation domains. The copper chaperone ATOX1 delivers copper to
  ATP7B and stimulates its catalytic activity. Loss-of-function mutations cause
  Wilson disease (MIM:277900), an autosomal recessive disorder of hepatic
  copper accumulation leading to liver cirrhosis and neurological damage.
alternative_products:
- name: 1 (A)
  id: P35670-1
- name: 2 (B)
  id: P35670-2
  sequence_note: VSP_000426, VSP_000427
- name: '3'
  id: P35670-3
  sequence_note: VSP_016559
- name: '4'
  id: P35670-4
  sequence_note: VSP_016560
- name: '5'
  id: P35670-5
  sequence_note: VSP_059175
existing_annotations:
# ============================================================
# MOLECULAR FUNCTION ANNOTATIONS
# ============================================================

# --- P-type monovalent copper transporter activity (6 annotations) ---
- term:
    id: GO:0140581
    label: P-type monovalent copper transporter activity
  evidence_type: IMP
  original_reference_id: PMID:9837819
  review:
    summary: >-
      IMP evidence from Forbes & Cox (1998) demonstrating that mutation of
      the CPC motif abolishes copper transport, directly establishing ATP7B
      as a P-type copper transporter. This is the strongest experimental
      evidence for this term.
    action: ACCEPT
    reason: >-
      Core molecular function of ATP7B. The CPC motif mutagenesis study
      directly demonstrates copper transport activity. This is the best
      evidence code for this annotation.
    supported_by:
      - reference_id: PMID:9837819
        supporting_text: >-
          Mutation of the CPC motif resulted in a nonfunctional protein,
          which demonstrates that this motif is essential for copper
          transport by ATP7B.
      - reference_id: PMID:22240481
        supporting_text: >-
          Properties of ATP7B variants with pathogenic amino-acid
          substitution varied greatly even if substitutions were in the
          same functional domain. Some variants had complete loss of
          catalytic and transport activity, whereas others lost transport
          activity but retained phosphor-intermediate formation or had
          partial losses of activity.
      - reference_id: file:human/ATP7B/ATP7B-deep-research-falcon.md
        supporting_text: >-
          ATP7B encodes the Wilson disease copper transporter, a **P1B-type
          (P-type) Cu(I)-transporting ATPase** whose well-supported
          GO-relevant biology centers on: (i) **ATP-driven Cu(I) export from
          the cytosol into the trans-Golgi network (TGN) lumen** for
          metallation of secretory cuproproteins, and (ii) **copper-induced
          trafficking** to post-Golgi vesicles/pericanalicular compartments to
          enable **cellular copper detoxification and biliary copper
          excretion** in hepatocytes.

- term:
    id: GO:0140581
    label: P-type monovalent copper transporter activity
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  review:
    summary: >-
      Phylogenetic inference consistent with direct experimental evidence.
      Redundant with the IMP annotation from PMID:9837819.
    action: ACCEPT
    reason: >-
      Redundant with the IMP evidence. IBA is consistent but adds no new
      information beyond the direct experimental demonstration.

- term:
    id: GO:0140581
    label: P-type monovalent copper transporter activity
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  review:
    summary: >-
      Electronic annotation redundant with IMP evidence.
    action: ACCEPT
    reason: Redundant with IMP from PMID:9837819.

- term:
    id: GO:0140581
    label: P-type monovalent copper transporter activity
  evidence_type: NAS
  original_reference_id: PMID:12763797
  review:
    summary: >-
      NAS from Tsivkovskii et al. (2002) on functional properties of ATP7B.
      Redundant with IMP evidence.
    action: ACCEPT
    reason: Redundant with IMP from PMID:9837819.

- term:
    id: GO:0140581
    label: P-type monovalent copper transporter activity
  evidence_type: TAS
  original_reference_id: PMID:16472602
  review:
    summary: >-
      TAS from Cater et al. (2006) vesicular sequestration study.
      Redundant with IMP evidence.
    action: ACCEPT
    reason: Redundant with IMP from PMID:9837819.

- term:
    id: GO:0140581
    label: P-type monovalent copper transporter activity
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-936895
  review:
    summary: >-
      Reactome pathway annotation for ATP7B transporting Cu1+ to Golgi lumen.
      Redundant with IMP evidence.
    action: ACCEPT
    reason: Redundant with IMP from PMID:9837819.

# --- Copper ion transmembrane transporter activity ---
- term:
    id: GO:0005375
    label: copper ion transmembrane transporter activity
  evidence_type: IEA
  original_reference_id: GO_REF:0000117
  review:
    summary: >-
      Electronic annotation. This is a parent term of GO:0140581 (P-type
      monovalent copper transporter activity). The more specific term is
      preferred.
    action: MODIFY
    reason: >-
      Redundant with the more specific GO:0140581. The parent term adds no
      information beyond what the child term already captures.
    proposed_replacement_terms:
      - id: GO:0140581
        label: P-type monovalent copper transporter activity

- term:
    id: GO:0005375
    label: copper ion transmembrane transporter activity
  evidence_type: IDA
  original_reference_id: PMID:26004889
  review:
    summary: >-
      IDA from functional characterization of ATP7B mutations using yeast
      complementation assay. Correct but less specific than GO:0140581.
    action: MODIFY
    reason: >-
      The IDA evidence is strong but should use the more specific child term
      GO:0140581 (P-type monovalent copper transporter activity) since ATP7B
      is a P-type ATPase.
    proposed_replacement_terms:
      - id: GO:0140581
        label: P-type monovalent copper transporter activity

# --- ATPase-coupled cation transporter activity ---
- term:
    id: GO:0019829
    label: ATPase-coupled monoatomic cation transmembrane transporter activity
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  review:
    summary: >-
      Electronic annotation. Parent term of GO:0140581.
    action: MARK_AS_OVER_ANNOTATED
    reason: >-
      Overly general. Redundant with the more specific GO:0140581.

# --- Copper ion binding ---
- term:
    id: GO:0005507
    label: copper ion binding
  evidence_type: IDA
  original_reference_id: PMID:12029094
  review:
    summary: >-
      IDA from Walker et al. (2002) demonstrating that ATOX1 transfers copper
      to ATP7B N-terminal domain in a saturable manner, and that copper
      binding stimulates catalytic activity.
    action: ACCEPT
    reason: >-
      Directly demonstrated copper binding to the N-terminal HMA domains.
      Core to ATP7B function as each of the six HMA domains binds Cu(I).
    supported_by:
      - reference_id: PMID:12029094
        supporting_text: >-
          We demonstrate that Atox1 transfers copper to the purified
          amino-terminal domain of WNDP (N-WNDP) in a dose-dependent and
          saturable manner.

- term:
    id: GO:0005507
    label: copper ion binding
  evidence_type: IDA
  original_reference_id: PMID:14709553
  review:
    summary: >-
      IDA from Lutsenko group quantifying copper binding stoichiometry to
      ATP7B and its chaperone ATOX1.
    action: ACCEPT
    reason: >-
      Provides additional quantitative evidence for copper binding.
      Confirms Cu(I) binding via six N-terminal HMA domains with CXXC motifs.
    supported_by:
      - reference_id: PMID:14709553
        supporting_text: >-
          The WND and Menkes proteins are distinguished from other P-type
          ATPases by the presence of six soluble N-terminal metal-binding
          domains containing a conserved CXXC metal-binding motif.

- term:
    id: GO:0005507
    label: copper ion binding
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  review:
    summary: Phylogenetic inference consistent with IDA evidence.
    action: ACCEPT
    reason: Redundant with IDA evidence.

- term:
    id: GO:0005507
    label: copper ion binding
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  review:
    summary: Electronic annotation redundant with IDA evidence.
    action: ACCEPT
    reason: Redundant with IDA from PMID:12029094.

# --- ATP binding ---
- term:
    id: GO:0005524
    label: ATP binding
  evidence_type: IDA
  original_reference_id: PMID:16567646
  review:
    summary: >-
      IDA from Dmitriev & Bhattacharjee (2006) NMR solution structure of the
      N-domain, showing distinct nucleotide-binding environment.
    action: ACCEPT
    reason: >-
      ATP binding is essential for the catalytic cycle of this P-type ATPase.
      The N-domain structure reveals the nucleotide-binding site.
    supported_by:
      - reference_id: PMID:16567646
        supporting_text: >-
          the nucleotide coordination environment of ATP7B within this fold
          is different. The residues H1069, G1099, G1101, I1102, G1149,
          and N1150 conserved in the P(1B)-ATPase subfamily contribute to
          ATP binding.

- term:
    id: GO:0005524
    label: ATP binding
  evidence_type: IDA
  original_reference_id: PMID:15205462
  review:
    summary: >-
      IDA from Tsivkovskii et al. (2004) analyzing nucleotide-binding domain
      properties and Wilson disease mutations affecting ATP binding.
    action: KEEP_AS_NON_CORE
    reason: >-
      Additional IDA evidence for ATP binding, confirms functional importance.
      Redundant with PMID:16567646.

- term:
    id: GO:0005524
    label: ATP binding
  evidence_type: IEA
  original_reference_id: GO_REF:0000002
  review:
    summary: Electronic annotation redundant with IDA evidence.
    action: KEEP_AS_NON_CORE
    reason: Redundant with IDA from PMID:16567646.

# --- Nucleotide binding ---
- term:
    id: GO:0000166
    label: nucleotide binding
  evidence_type: IEA
  original_reference_id: GO_REF:0000002
  review:
    summary: >-
      Overly general parent term of GO:0005524 (ATP binding).
    action: MARK_AS_OVER_ANNOTATED
    reason: >-
      Redundant with the more specific GO:0005524 (ATP binding) which has
      IDA support.

# --- ATP hydrolysis activity ---
- term:
    id: GO:0016887
    label: ATP hydrolysis activity
  evidence_type: IEA
  original_reference_id: GO_REF:0000002
  review:
    summary: >-
      ATP hydrolysis is integral to the P-type ATPase catalytic cycle.
      However, this is implicit in the GO:0140581 (P-type monovalent copper
      transporter activity) annotation.
    action: KEEP_AS_NON_CORE
    reason: >-
      While correct, the ATPase activity is part of the copper transport
      mechanism already captured by GO:0140581. Acceptable as supplementary.

# --- Metal ion binding ---
- term:
    id: GO:0046872
    label: metal ion binding
  evidence_type: IEA
  original_reference_id: GO_REF:0000002
  review:
    summary: >-
      Overly general parent of GO:0005507 (copper ion binding).
    action: MARK_AS_OVER_ANNOTATED
    reason: >-
      Too general. The specific copper ion binding term (GO:0005507) with
      IDA evidence is preferred.

# --- Protein binding (uninformative) ---
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:12968035
  review:
    summary: >-
      IPI for interaction with COMMD1/MURR1. The term "protein binding" is
      uninformative per curation guidelines.
    action: MARK_AS_OVER_ANNOTATED
    reason: >-
      Per GO curation guidelines, "protein binding" (GO:0005515) is too vague
      and does not convey the specific biological role of the interaction.
      COMMD1 interaction is relevant to copper homeostasis and ATP7B
      stability/degradation, but a more specific MF term should be used if
      available.
    supported_by:
      - reference_id: PMID:12968035
        supporting_text: >-
          the Wilson disease protein directly interacts with the human
          homologue of Murr1 in vitro and in vivo and that this interaction
          is mediated via the copper binding, amino terminus of this ATPase.

- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:17919502
  review:
    summary: >-
      IPI for interactions with COMMD1 and ATOX1. Uninformative term.
    action: MARK_AS_OVER_ANNOTATED
    reason: >-
      "Protein binding" is uninformative. The ATOX1 interaction represents
      copper chaperone-mediated metal transfer, and COMMD1 interaction
      affects ATP7B stability.
    supported_by:
      - reference_id: PMID:17919502
        supporting_text: >-
          Four WD patient-derived mutations in this region of ATP7B
          significantly increased its binding to COMMD1. Two of these
          mutations also resulted in mislocalization and increased
          degradation rate of ATP7B.

- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:16554302
  review:
    summary: >-
      IPI for copper-dependent interaction with DCTN4 (dynactin p62).
      Uninformative term.
    action: MARK_AS_OVER_ANNOTATED
    reason: >-
      "Protein binding" is uninformative. The DCTN4 interaction is
      copper-dependent and likely facilitates retrograde trafficking.

- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:16884690
  review:
    summary: >-
      IPI for copper-dependent interaction with glutaredoxin (GRX1).
      Uninformative term.
    action: MARK_AS_OVER_ANNOTATED
    reason: >-
      "Protein binding" is uninformative. GRX1 interaction may facilitate
      copper binding by reducing disulfide bridges in HMA domains.

- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:16676348
  review:
    summary: >-
      IPI for interaction with ZBTB16/PLZF hepatocytic isoform.
      Uninformative term.
    action: MARK_AS_OVER_ANNOTATED
    reason: >-
      "Protein binding" is uninformative. The PLZF interaction connects
      ATP7B to ERK signaling but the functional significance is less clear.

# ============================================================
# BIOLOGICAL PROCESS ANNOTATIONS
# ============================================================

# --- Copper ion transport ---
- term:
    id: GO:0006825
    label: copper ion transport
  evidence_type: IDA
  original_reference_id: PMID:26004889
  review:
    summary: >-
      IDA from yeast complementation assay showing ATP7B variants affect
      copper transport.
    action: ACCEPT
    reason: >-
      Core biological process of ATP7B. Directly demonstrated by functional
      assays.
    supported_by:
      - reference_id: PMID:26004889
        supporting_text: >-
          Expression of human wild type ATP7B gene in ccc2Δ mutant yeast
          restored the growth deficiency and copper transport activity;
          however, expression of the mutant forms did not restore the copper
          transport functions and only partially supported the cell growth.

- term:
    id: GO:0006825
    label: copper ion transport
  evidence_type: IGI
  original_reference_id: PMID:26004889
  review:
    summary: >-
      IGI evidence from same study, likely from genetic interaction data
      in yeast.
    action: KEEP_AS_NON_CORE
    reason: Redundant with IDA from same publication.

- term:
    id: GO:0006825
    label: copper ion transport
  evidence_type: IMP
  original_reference_id: PMID:9837819
  review:
    summary: >-
      IMP from CPC motif mutagenesis study showing loss of copper transport.
    action: KEEP_AS_NON_CORE
    reason: >-
      Strong evidence but redundant with IDA from PMID:26004889 for the same
      term.

- term:
    id: GO:0006825
    label: copper ion transport
  evidence_type: IGI
  original_reference_id: PMID:12572677
  review:
    summary: >-
      IGI from Schaefer & Bhatt (2003) on copper-induced trafficking of
      Cu-ATPases.
    action: KEEP_AS_NON_CORE
    reason: Redundant with other evidence for this term.

# --- Copper ion export ---
- term:
    id: GO:0060003
    label: copper ion export
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  review:
    summary: >-
      Phylogenetic inference that ATP7B mediates copper ion export. This is
      the correct directional term - ATP7B exports copper out of the
      cytoplasm into the Golgi lumen and vesicles.
    action: ACCEPT
    reason: >-
      Correct and important annotation. ATP7B mediates copper export from
      the cytoplasm into the TGN lumen (for ceruloplasmin biosynthesis) and
      into vesicles (for biliary excretion). Well supported by literature.
    supported_by:
      - reference_id: PMID:16472602
        supporting_text: >-
          This report provides compelling evidence that the primary mechanism
          of biliary copper excretion involves ATP7B-mediated vesicular
          sequestration of copper rather than direct copper translocation
          across the canalicular membrane.
      - reference_id: PMID:12763797
        supporting_text: >-
          Wilson's disease protein (WNDP) is a copper-transporting P(1)-type
          ATPase which plays a key role in normal distribution of copper in
          a number of tissues, particularly in the liver and the brain.

# --- Copper ion IMPORT (INCORRECT) ---
- term:
    id: GO:0015677
    label: copper ion import
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  review:
    summary: >-
      INCORRECT annotation. ATP7B mediates copper EXPORT (into
      Golgi/vesicles/bile), NOT import into the cell. Copper import into
      cells is performed by CTR1/SLC31A1. The IBA phylogenetic inference
      has incorrectly assigned the direction of transport.
    action: REMOVE
    reason: >-
      ATP7B is a copper exporter, not importer. It transports copper from
      the cytoplasm into the Golgi lumen and vesicles. Copper import into
      cells is mediated by CTR1 (SLC31A1). This is a fundamental error in
      the phylogenetic inference.
    supported_by:
      - reference_id: PMID:16472602
        supporting_text: >-
          The Wilson protein (ATP7B) regulates levels of systemic copper by
          excreting excess copper into bile.
      - reference_id: PMID:12763797
        supporting_text: >-
          Wilson's disease protein (WNDP) is a copper-transporting P(1)-type
          ATPase which plays a key role in normal distribution of copper in
          a number of tissues, particularly in the liver and the brain.
      - reference_id: file:human/ATP7B/ATP7B-deep-research-falcon.md
        supporting_text: >-
          The supported directionality is **export from cytosol into
          TGN/vesicle lumen and ultimately bile**, not import into cytosol.
          Copper uptake into cells is mediated by other proteins (e.g., CTR1),
          not ATP7B.

# --- Intracellular copper ion homeostasis ---
- term:
    id: GO:0006878
    label: intracellular copper ion homeostasis
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  review:
    summary: >-
      ATP7B is central to intracellular copper homeostasis in hepatocytes,
      maintaining copper balance through biosynthetic copper loading and
      biliary excretion.
    action: ACCEPT
    reason: >-
      Core biological process. ATP7B directly maintains copper homeostasis
      by exporting excess copper. Loss of function causes copper
      accumulation (Wilson disease).
    supported_by:
      - reference_id: PMID:16472602
        supporting_text: >-
          The Wilson protein (ATP7B) regulates levels of systemic copper by
          excreting excess copper into bile.

- term:
    id: GO:0006878
    label: intracellular copper ion homeostasis
  evidence_type: TAS
  original_reference_id: PMID:16554302
  review:
    summary: >-
      TAS from DCTN4 interaction study, which discusses ATP7B role in
      copper homeostasis.
    action: KEEP_AS_NON_CORE
    reason: Redundant with IBA annotation for same term.

# --- Cellular detoxification of copper ion ---
- term:
    id: GO:1990880
    label: cellular detoxification of copper ion
  evidence_type: IDA
  original_reference_id: PMID:16472602
  review:
    summary: >-
      IDA from Cater et al. (2006) demonstrating ATP7B mediates vesicular
      sequestration of excess copper for subsequent exocytosis.
    action: ACCEPT
    reason: >-
      Directly demonstrated by immunofluorescence and copper accumulation
      studies in hepatoma cells. The vesicular sequestration mechanism
      specifically serves copper detoxification.
    supported_by:
      - reference_id: PMID:16472602
        supporting_text: >-
          Expression of wild-type and mutant ATP7B caused Chinese hamster
          ovary cells to accumulate copper in vesicles, which subsequently
          undergo exocytosis, releasing copper across the plasma membrane.

# --- Xenobiotic detoxification by transmembrane export across PM (INCORRECT) ---
- term:
    id: GO:1990961
    label: xenobiotic detoxification by transmembrane export across the plasma membrane
  evidence_type: IC
  original_reference_id: PMID:9837819
  review:
    summary: >-
      INCORRECT mechanism. ATP7B does NOT export copper directly across the
      plasma membrane. Per PMID:16472602, ATP7B mediates vesicular
      sequestration of copper, which subsequently undergoes exocytosis.
      Furthermore, copper is an essential element, not a xenobiotic.
    action: REMOVE
    reason: >-
      Two errors: (1) ATP7B uses vesicular sequestration, not direct plasma
      membrane export. Cater et al. (2006) explicitly showed ATP7B
      traffics to pericanalicular vesicles, NOT the canalicular membrane.
      (2) Copper is an endogenous essential metal, not a xenobiotic. The
      correct term is GO:1990880 (cellular detoxification of copper ion)
      which is already annotated with IDA evidence.
    supported_by:
      - reference_id: PMID:16472602
        supporting_text: >-
          In HepG2 cells, elevated copper levels stimulated trafficking of
          ATP7B to pericanalicular vesicles and not to the canalicular
          membrane as previously reported.
      - reference_id: file:human/ATP7B/ATP7B-deep-research-falcon.md
        supporting_text: >-
          Evidence supports copper-stimulated redistribution toward
          apical/canalicular regions, but stable canalicular plasma membrane
          residence is **variable across systems**; some studies support
          vesicular sequestration/exocytosis without clear canalicular
          membrane labeling, while others report canalicular fractions and/or
          tight junction pools.

# --- Monoatomic cation transport ---
- term:
    id: GO:0006812
    label: monoatomic cation transport
  evidence_type: IEA
  original_reference_id: GO_REF:0000002
  review:
    summary: >-
      Overly general parent of copper ion transport.
    action: MARK_AS_OVER_ANNOTATED
    reason: >-
      Too general. The specific copper ion transport term (GO:0006825)
      with IDA evidence is preferred.

# --- Ion transmembrane transport ---
- term:
    id: GO:0034220
    label: monoatomic ion transmembrane transport
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-936837
  review:
    summary: >-
      Reactome pathway annotation for ion transport by P-type ATPases.
      General term.
    action: KEEP_AS_NON_CORE
    reason: >-
      Correct but overly general. Subsumed by more specific copper
      transport annotations.

# --- Response to copper ion ---
- term:
    id: GO:0046688
    label: response to copper ion
  evidence_type: IDA
  original_reference_id: PMID:16472602
  review:
    summary: >-
      IDA showing ATP7B undergoes copper-responsive trafficking from TGN
      to pericanalicular vesicles in HepG2 cells.
    action: ACCEPT
    reason: >-
      The copper-responsive trafficking of ATP7B is a well-established
      phenomenon central to its homeostatic function. Elevated copper
      triggers relocalization from TGN to vesicles.
    supported_by:
      - reference_id: PMID:16472602
        supporting_text: >-
          In HepG2 cells, elevated copper levels stimulated trafficking of
          ATP7B to pericanalicular vesicles and not to the canalicular
          membrane as previously reported.

- term:
    id: GO:0046688
    label: response to copper ion
  evidence_type: IDA
  original_reference_id: PMID:16939419
  review:
    summary: >-
      IDA from Cater et al. (2006) showing copper-induced trafficking
      occurs even without N-terminal metal-binding sites or CPC motif.
    action: KEEP_AS_NON_CORE
    reason: >-
      Provides mechanistic insight but redundant with PMID:16472602 IDA
      for the same term.
    supported_by:
      - reference_id: PMID:16939419
        supporting_text: >-
          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).

- term:
    id: GO:0046688
    label: response to copper ion
  evidence_type: IEA
  original_reference_id: GO_REF:0000117
  review:
    summary: Electronic annotation redundant with IDA evidence.
    action: KEEP_AS_NON_CORE
    reason: Redundant with IDA from PMID:16472602.

- term:
    id: GO:0046688
    label: response to copper ion
  evidence_type: IDA
  original_reference_id: PMID:15269005
  review:
    summary: >-
      WRONG GENE. PMID:15269005 (Greenough et al. 2004) is about ATP7A
      (Menkes protein) trafficking in MDCK cells, NOT ATP7B. This annotation
      has been mis-attributed.
    action: REMOVE
    reason: >-
      PMID:15269005 studied ATP7A (Menkes), not ATP7B. The paper title
      explicitly states "Signals regulating trafficking of Menkes (MNK;
      ATP7A) copper-translocating P-type ATPase in polarized MDCK cells."
      This is a mis-annotation error.

# ============================================================
# CELLULAR COMPONENT ANNOTATIONS
# ============================================================

# --- Trans-Golgi network membrane ---
- term:
    id: GO:0032588
    label: trans-Golgi network membrane
  evidence_type: IDA
  original_reference_id: PMID:9837819
  review:
    summary: >-
      IDA from Forbes & Cox (1998) showing ATP7B localizes to TGN membrane
      under basal copper conditions.
    action: ACCEPT
    reason: >-
      Well-established primary localization of ATP7B. The TGN is where
      ATP7B performs its biosynthetic role of loading copper into
      ceruloplasmin and other cuproenzymes.
    supported_by:
      - reference_id: PMID:9837819
        supporting_text: >-
          Wilson disease is an autosomal recessive disorder of copper
          transport that causes hepatic and/or neurological disease
          resulting from copper accumulation in the liver and brain. The
          protein defective in this disorder is a putative
          copper-transporting P-type ATPase, ATP7B.
      - reference_id: file:human/ATP7B/ATP7B-deep-research-falcon.md
        supporting_text: >-
          At **basal/low copper**, ATP7B localizes predominantly to the
          **trans-Golgi network** (TGN), consistent with its biosynthetic role
          in delivering Cu into the secretory pathway.

- term:
    id: GO:0032588
    label: trans-Golgi network membrane
  evidence_type: IEA
  original_reference_id: GO_REF:0000117
  review:
    summary: Electronic annotation redundant with IDA evidence.
    action: KEEP_AS_NON_CORE
    reason: Redundant with IDA from PMID:9837819.

# --- Trans-Golgi network ---
- term:
    id: GO:0005802
    label: trans-Golgi network
  evidence_type: IDA
  original_reference_id: PMID:16472602
  review:
    summary: >-
      IDA from Cater et al. (2006) showing ATP7B localizes to TGN in HepG2
      hepatoma cells under basal conditions.
    action: ACCEPT
    reason: >-
      Confirmed TGN localization using endogenous ATP7B in hepatoma cells,
      which is more physiologically relevant than overexpression systems.
    supported_by:
      - reference_id: PMID:16472602
        supporting_text: >-
          Immunofluorescence microscopy was used to investigate the effect
          of copper concentration on the localization of endogenous ATP7B
          in HepG2 cells.

- term:
    id: GO:0005802
    label: trans-Golgi network
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  review:
    summary: Electronic annotation from Ensembl Compara orthology transfer.
    action: KEEP_AS_NON_CORE
    reason: Redundant with IDA from PMID:16472602.

- term:
    id: GO:0005802
    label: trans-Golgi network
  evidence_type: IDA
  original_reference_id: PMID:15269005
  review:
    summary: >-
      WRONG GENE. PMID:15269005 is about ATP7A (Menkes), not ATP7B.
      Mis-attributed annotation.
    action: REMOVE
    reason: >-
      PMID:15269005 studied ATP7A trafficking in MDCK cells. While ATP7B
      does localize to TGN (confirmed by other papers), this specific
      evidence is incorrectly attributed.

# --- Golgi apparatus ---
- term:
    id: GO:0005794
    label: Golgi apparatus
  evidence_type: IDA
  original_reference_id: GO_REF:0000052
  review:
    summary: >-
      IDA from immunofluorescence curation. Less specific than TGN membrane.
    action: KEEP_AS_NON_CORE
    reason: >-
      Correct but less specific than GO:0032588 (trans-Golgi network
      membrane). Acceptable as supporting evidence.

- term:
    id: GO:0005794
    label: Golgi apparatus
  evidence_type: IEA
  original_reference_id: GO_REF:0000044
  review:
    summary: Electronic annotation, less specific than TGN.
    action: KEEP_AS_NON_CORE
    reason: Redundant with more specific TGN annotations.

# --- Golgi membrane ---
- term:
    id: GO:0000139
    label: Golgi membrane
  evidence_type: IEA
  original_reference_id: GO_REF:0000044
  review:
    summary: >-
      Electronic annotation. Less specific than GO:0032588 (TGN membrane).
    action: KEEP_AS_NON_CORE
    reason: >-
      Redundant with the more specific GO:0032588 (trans-Golgi network
      membrane) which has IDA support.

- term:
    id: GO:0000139
    label: Golgi membrane
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-936895
  review:
    summary: Reactome annotation. Less specific than TGN membrane.
    action: KEEP_AS_NON_CORE
    reason: Redundant with more specific TGN membrane annotation.

# --- Cytoplasmic vesicle ---
- term:
    id: GO:0031410
    label: cytoplasmic vesicle
  evidence_type: IDA
  original_reference_id: PMID:16472602
  review:
    summary: >-
      IDA showing ATP7B traffics to pericanalicular cytoplasmic vesicles
      under elevated copper conditions.
    action: ACCEPT
    reason: >-
      Copper-induced vesicular localization is essential for the biliary
      excretion function of ATP7B. Well demonstrated in HepG2 cells.
    supported_by:
      - reference_id: PMID:16472602
        supporting_text: >-
          Mutation of an endocytic retrieval signal in ATP7B caused the
          protein to constitutively localize to vesicles and not to the
          plasma membrane, suggesting that a vesicular compartment(s) is
          the final trafficking destination for ATP7B.
      - reference_id: file:human/ATP7B/ATP7B-deep-research-falcon.md
        supporting_text: >-
          Upon **copper elevation**, ATP7B exits the TGN and redistributes to
          **cytosolic vesicles/pericanalicular vesicles** and subapical
          compartments in hepatocyte-derived polarized models; this
          trafficking is reversible upon copper chelation.

# --- Late endosome ---
- term:
    id: GO:0005770
    label: late endosome
  evidence_type: IDA
  original_reference_id: PMID:15681833
  review:
    summary: >-
      IDA from Harada et al. (2005) reporting ATP7B co-localizes with Rab7
      and NPC1 in late endosomes. This represents a minority view in the
      field; most groups report TGN as the primary compartment.
    action: KEEP_AS_NON_CORE
    reason: >-
      While experimentally supported, this may represent a post-Golgi
      trafficking intermediate rather than the primary steady-state
      compartment. The TGN model is more widely accepted and consistent
      with the ceruloplasmin biosynthesis role.
    supported_by:
      - reference_id: PMID:15681833
        supporting_text: >-
          We have confirmed that ATP7B is a late endosome-associated
          membrane protein.

- term:
    id: GO:0005770
    label: late endosome
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  review:
    summary: Electronic annotation consistent with Harada study.
    action: KEEP_AS_NON_CORE
    reason: See IDA late endosome annotation above.

# --- Perinuclear region of cytoplasm ---
- term:
    id: GO:0048471
    label: perinuclear region of cytoplasm
  evidence_type: IDA
  original_reference_id: PMID:16939419
  review:
    summary: >-
      IDA showing ATP7B at the perinuclear region, consistent with TGN
      localization.
    action: KEEP_AS_NON_CORE
    reason: >-
      The TGN is perinuclear, so this is consistent but less informative
      than the TGN annotation. Acceptable as supporting.

# --- Plasma membrane (QUESTIONABLE) ---
- term:
    id: GO:0005886
    label: plasma membrane
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  review:
    summary: >-
      IBA phylogenetic inference. QUESTIONABLE for ATP7B. Unlike ATP7A which
      traffics to the basolateral plasma membrane, ATP7B traffics to
      pericanalicular vesicles, NOT the plasma membrane.
    action: REMOVE
    reason: >-
      ATP7B does not localize to the plasma membrane. Per PMID:16472602,
      ATP7B traffics to pericanalicular vesicles and NOT to the canalicular
      membrane. Mutation of the endocytic retrieval signal causes
      constitutive vesicular localization, not PM localization. The IBA
      inference likely transferred from ATP7A which does traffic to PM.
    supported_by:
      - reference_id: PMID:16472602
        supporting_text: >-
          Mutation of an endocytic retrieval signal in ATP7B caused the
          protein to constitutively localize to vesicles and not to the
          plasma membrane, suggesting that a vesicular compartment(s) is
          the final trafficking destination for ATP7B.
      - reference_id: file:human/ATP7B/ATP7B-deep-research-falcon.md
        supporting_text: >-
          A cautious annotation should emphasize **copper-induced
          apical/canalicular-associated trafficking** and/or “TGN →
          pericanalicular vesicles” rather than constitutive “plasma
          membrane.”

- term:
    id: GO:0005886
    label: plasma membrane
  evidence_type: TAS
  original_reference_id: PMID:8298641
  review:
    summary: >-
      TAS from the original 1993 Wilson disease gene cloning paper (Tanzi
      et al.). This predates the detailed trafficking studies and was based
      on the assumption that a transmembrane transporter must be at the PM.
    action: REMOVE
    reason: >-
      Outdated annotation from 1993 before ATP7B trafficking was understood.
      Subsequent studies (PMID:16472602, PMID:16939419) have definitively
      shown ATP7B traffics to TGN and vesicles, not the plasma membrane.

# --- Basolateral plasma membrane (WRONG GENE) ---
- term:
    id: GO:0016323
    label: basolateral plasma membrane
  evidence_type: IDA
  original_reference_id: PMID:15269005
  review:
    summary: >-
      WRONG GENE. PMID:15269005 is about ATP7A (Menkes protein) in polarized
      MDCK cells. ATP7A traffics to the basolateral membrane; ATP7B traffics
      to the apical/canalicular side via vesicular intermediates.
    action: REMOVE
    reason: >-
      Mis-attributed annotation. PMID:15269005 studied ATP7A (Menkes), not
      ATP7B. The paper explicitly describes "Menkes (MNK; ATP7A)" in the
      title. Basolateral PM is the correct localization for ATP7A but
      incorrect for ATP7B, which traffics to apical/pericanalicular vesicles.

# --- Membrane (generic) ---
- term:
    id: GO:0016020
    label: membrane
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  review:
    summary: Very generic membrane annotation.
    action: MARK_AS_OVER_ANNOTATED
    reason: >-
      Too general. More specific membrane annotations (TGN membrane,
      cytoplasmic vesicle) are available with IDA support.

- term:
    id: GO:0016020
    label: membrane
  evidence_type: HDA
  original_reference_id: PMID:19946888
  review:
    summary: >-
      HDA from NK cell membrane proteome study. Identifies ATP7B as a
      membrane protein, which is correct but uninformative.
    action: KEEP_AS_NON_CORE
    reason: >-
      Generic membrane annotation. The HDA from an NK cell proteomics study
      is not informative for ATP7B's specific subcellular localization.

# --- Cytoplasm ---
- term:
    id: GO:0005737
    label: cytoplasm
  evidence_type: IEA
  original_reference_id: GO_REF:0000044
  review:
    summary: >-
      Electronic annotation mapping from UniProt subcellular location. May
      relate to isoform 2 which is cytoplasmic.
    action: KEEP_AS_NON_CORE
    reason: >-
      This may refer to isoform 2 (P35670-2) which lacks transmembrane
      domains and is cytoplasmic. Acceptable as a general annotation but
      isoform-specificity should be noted.

# --- Mitochondrion (DUBIOUS) ---
- term:
    id: GO:0005739
    label: mitochondrion
  evidence_type: IEA
  original_reference_id: GO_REF:0000044
  review:
    summary: >-
      Electronic annotation from UniProt mapping. Based on the WND/140 kDa
      proteolytic fragment reported by one group (PMID:9600907). Not the
      primary localization of full-length ATP7B.
    action: MARK_AS_OVER_ANNOTATED
    reason: >-
      The mitochondrial localization was reported for a 140 kDa N-terminally
      cleaved fragment, not full-length ATP7B. This finding (PMID:9600907)
      has not been widely reproduced and does not reflect the primary
      subcellular localization of the protein.

- term:
    id: GO:0005739
    label: mitochondrion
  evidence_type: HTP
  original_reference_id: PMID:34800366
  review:
    summary: >-
      HTP from large-scale mitochondrial proteomics study. May represent
      contamination or the cleaved fragment.
    action: MARK_AS_OVER_ANNOTATED
    reason: >-
      High-throughput proteomics can detect contaminating proteins or
      low-abundance fragments. The primary localization of ATP7B is TGN,
      not mitochondria. This HTP finding is inconsistent with the
      extensive cell biology literature.

references:
- id: file:human/ATP7B/ATP7B-deep-research-falcon.md
  title: Falcon deep research report for human ATP7B
  findings:
    - statement: >-
        ATP7B is a P1B-type ATP-dependent Cu(I) transporter with core
        functions in TGN copper loading and copper-induced vesicular export.
      supporting_text: >-
        ATP7B encodes the Wilson disease copper transporter, a **P1B-type
        (P-type) Cu(I)-transporting ATPase** whose well-supported
        GO-relevant biology centers on: (i) **ATP-driven Cu(I) export from
        the cytosol into the trans-Golgi network (TGN) lumen** for
        metallation of secretory cuproproteins, and (ii) **copper-induced
        trafficking** to post-Golgi vesicles/pericanalicular compartments to
        enable **cellular copper detoxification and biliary copper
        excretion** in hepatocytes.
      reference_section_type: ABSTRACT
      full_text_unavailable: false
    - statement: >-
        ATOX1-mediated copper transfer is the informative protein interaction
        for ATP7B.
      supporting_text: >-
        The cytosolic copper chaperone **ATOX1** delivers Cu(I) to ATP7B by
        forming **transient Cu-bridged protein–protein complexes**, stabilized
        largely by the copper-coordinating cysteines, transferring Cu(I) to
        ATP7B’s N-terminal MBDs and (directly or indirectly) onward to the
        transmembrane transport site.
      reference_section_type: ABSTRACT
      full_text_unavailable: false
    - statement: >-
        ATP7B plasma membrane and late endosome annotations require caution.
      supporting_text: >-
        The exact identity of the vesicular carriers and whether ATP7B
        transiently resides at the canalicular membrane remain debated.
      reference_section_type: ABSTRACT
      full_text_unavailable: false
- id: GO_REF:0000002
  title: Gene Ontology annotation through association of InterPro records with GO terms
  findings: []
- id: GO_REF:0000033
  title: Annotation inferences using phylogenetic trees
  findings: []
- id: GO_REF:0000044
  title: >-
    Gene Ontology annotation based on UniProtKB/Swiss-Prot Subcellular Location
    vocabulary mapping, accompanied by conservative changes to GO terms applied
    by UniProt
  findings: []
- id: GO_REF:0000052
  title: Gene Ontology annotation based on curation of immunofluorescence data
  findings: []
- id: GO_REF:0000107
  title: >-
    Automatic transfer of experimentally verified manual GO annotation data
    to orthologs using Ensembl Compara
  findings: []
- id: GO_REF:0000117
  title: Electronic Gene Ontology annotations created by ARBA machine learning models
  findings: []
- id: GO_REF:0000120
  title: Combined Automated Annotation using Multiple IEA Methods
  findings: []
- id: PMID:8298641
  title: >-
    The Wilson disease gene is a copper transporting ATPase with homology to
    the Menkes disease gene.
  findings:
    - statement: >-
        Original identification of ATP7B as the Wilson disease gene with 76%
        amino acid homology to ATP7A (Menkes disease gene).
      supporting_text: >-
        The predicted functional properties of the pWD gene together with its
        strong homology to Mc1, genetic mapping data and identification of four
        independent disease-specific mutations, provide convincing evidence that
        pWD is the Wilson disease gene.
      reference_section_type: ABSTRACT
      full_text_unavailable: true
- id: PMID:9837819
  title: >-
    Functional characterization of missense mutations in ATP7B: Wilson disease
    mutation or normal variant?
  findings:
    - statement: >-
        CPC motif is essential for ATP7B copper transport activity.
      supporting_text: >-
        Mutation of the CPC motif resulted in a nonfunctional protein, which
        demonstrates that this motif is essential for copper transport by ATP7B.
      reference_section_type: ABSTRACT
      full_text_unavailable: false
- id: PMID:12029094
  title: >-
    Metallochaperone Atox1 transfers copper to the NH2-terminal domain of the
    Wilson's disease protein and regulates its catalytic activity.
  findings:
    - statement: >-
        ATOX1 transfers copper to ATP7B and stimulates its catalytic activity.
      supporting_text: >-
        We demonstrate that Atox1 transfers copper to the purified amino-terminal
        domain of WNDP (N-WNDP) in a dose-dependent and saturable manner.
      reference_section_type: ABSTRACT
      full_text_unavailable: true
- id: PMID:12572677
  title: >-
    Copper-induced trafficking of the cU-ATPases: a key mechanism for copper
    homeostasis.
  findings:
    - statement: >-
        Copper-induced trafficking of Cu-ATPases is a key homeostatic mechanism.
      supporting_text: >-
        In cells cultured in low copper concentration MNK and WND localize to
        the transGolgi network but in high copper relocalize either to the
        plasma membrane (MNK) or a vesicular compartment (WND).
      reference_section_type: ABSTRACT
      full_text_unavailable: true
- id: PMID:12763797
  title: >-
    Functional properties of the human copper-transporting ATPase ATP7B (the
    Wilson's disease protein) and regulation by metallochaperone Atox1.
  findings:
    - statement: >-
        ATP7B catalytic activity is stimulated by copper and ATOX1.
      supporting_text: >-
        Wilson's disease protein (WNDP) is a copper-transporting P(1)-type
        ATPase which plays a key role in normal distribution of copper in a
        number of tissues, particularly in the liver and the brain.
      reference_section_type: ABSTRACT
      full_text_unavailable: true
- id: PMID:12968035
  title: >-
    The copper toxicosis gene product Murr1 directly interacts with the Wilson
    disease protein.
  findings:
    - statement: >-
        COMMD1 (Murr1) directly interacts with ATP7B.
      supporting_text: >-
        the Wilson disease protein directly interacts with the human homologue
        of Murr1 in vitro and in vivo and that this interaction is mediated via
        the copper binding, amino terminus of this ATPase.
      reference_section_type: ABSTRACT
      full_text_unavailable: true
- id: PMID:14709553
  title: Binding of copper(I) by the Wilson disease protein and its copper chaperone.
  findings:
    - statement: >-
        ATP7B binds Cu(I) via six N-terminal HMA domains with CXXC motifs.
      supporting_text: >-
        The WND and Menkes proteins are distinguished from other P-type ATPases
        by the presence of six soluble N-terminal metal-binding domains
        containing a conserved CXXC metal-binding motif.
      reference_section_type: ABSTRACT
      full_text_unavailable: true
- id: PMID:15205462
  title: "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."
  findings:
    - statement: >-
        Wilson disease mutations affect ATP binding and catalytic activity.
      supporting_text: >-
        Mutations of the invariant WNDP residues E1064A and H1069Q drastically
        reduce nucleotide affinities, pointing to the likely role of these
        residues in nucleotide coordination.
      reference_section_type: ABSTRACT
      full_text_unavailable: true
- id: PMID:15269005
  title: >-
    Signals regulating trafficking of Menkes (MNK; ATP7A) copper-translocating
    P-type ATPase in polarized MDCK cells.
  findings:
    - statement: >-
        This paper is about ATP7A (Menkes), NOT ATP7B. Annotations attributed
        to ATP7B from this paper are mis-annotations.
      supporting_text: >-
        we demonstrate that MNK relocalizes from the Golgi to the basolateral
        (BL) membrane under elevated copper conditions.
      reference_section_type: ABSTRACT
      full_text_unavailable: true
- id: PMID:15681833
  title: >-
    The Wilson disease protein ATP7B resides in the late endosomes with Rab7
    and the Niemann-Pick C1 protein.
  findings:
    - statement: >-
        ATP7B co-localizes with Rab7 and NPC1 in late endosomes (minority view).
      supporting_text: >-
        We have confirmed that ATP7B is a late endosome-associated membrane
        protein.
      reference_section_type: ABSTRACT
      full_text_unavailable: false
- id: PMID:16472602
  title: >-
    ATP7B mediates vesicular sequestration of copper: insight into biliary
    copper excretion.
  findings:
    - statement: >-
        ATP7B mediates copper excretion via vesicular sequestration, not
        direct plasma membrane transport.
      supporting_text: >-
        In HepG2 cells, elevated copper levels stimulated trafficking of ATP7B
        to pericanalicular vesicles and not to the canalicular membrane as
        previously reported.
      reference_section_type: RESULTS
      full_text_unavailable: true
    - statement: >-
        Vesicles, not plasma membrane, are the final trafficking destination
        for ATP7B.
      supporting_text: >-
        Mutation of an endocytic retrieval signal in ATP7B caused the protein
        to constitutively localize to vesicles and not to the plasma membrane,
        suggesting that a vesicular compartment(s) is the final trafficking
        destination for ATP7B.
      reference_section_type: RESULTS
      full_text_unavailable: true
- id: PMID:16554302
  title: >-
    Copper-dependent interaction of dynactin subunit p62 with the N terminus
    of ATP7B but not ATP7A.
  findings:
    - statement: >-
        DCTN4 (p62) interacts specifically with ATP7B N-terminus in a
        copper-dependent manner.
      supporting_text: >-
        The dynactin complex binds cargo, such as vesicles and organelles, to
        cytoplasmic dynein for retrograde microtubule-mediated trafficking and
        could feasibly be involved in the copper-regulated trafficking of ATP7B.
      reference_section_type: ABSTRACT
      full_text_unavailable: true
- id: PMID:16567646
  title: >-
    Solution structure of the N-domain of Wilson disease protein: distinct
    nucleotide-binding environment and effects of disease mutations.
  findings:
    - statement: >-
        NMR structure reveals distinct nucleotide-binding environment in
        ATP7B N-domain.
      supporting_text: >-
        the nucleotide coordination environment of ATP7B within this fold is
        different. The residues H1069, G1099, G1101, I1102, G1149, and N1150
        conserved in the P(1B)-ATPase subfamily contribute to ATP binding.
      reference_section_type: ABSTRACT
      full_text_unavailable: false
- id: PMID:16676348
  title: >-
    A new hepatocytic isoform of PLZF lacking the BTB domain interacts with
    ATP7B, the Wilson disease protein, and positively regulates ERK signal
    transduction.
  findings:
    - statement: >-
        Hepatocytic ZBTB16/PLZF isoform interacts with ATP7B C-terminus.
      supporting_text: >-
        These data suggest the existence of a mechanism that regulates ERK
        signaling via the C-terminus of ATP7B and the ATP7B-interacting
        hepatocytic PLZF.
      reference_section_type: ABSTRACT
      full_text_unavailable: true
- id: PMID:16884690
  title: >-
    Copper-dependent interaction of glutaredoxin with the N termini of the
    copper-ATPases (ATP7A and ATP7B) defective in Menkes and Wilson diseases.
  findings:
    - statement: >-
        GRX1 interacts with ATP7B N-terminus in a copper-dependent manner.
      supporting_text: >-
        We propose that GRX1 is essential for ATPase function and catalyses
        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.
      reference_section_type: ABSTRACT
      full_text_unavailable: true
- id: PMID:16939419
  title: >-
    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).
  findings:
    - statement: >-
        ATP7B copper-induced trafficking is coupled to catalytic cycle, not
        direct copper binding.
      supporting_text: >-
        ATP7B trafficking is regulated with its copper-translocation cycle,
        with cytosolic vesicular localization associated with the
        acyl-phosphate intermediate.
      reference_section_type: ABSTRACT
      full_text_unavailable: false
- id: PMID:17919502
  title: >-
    Distinct Wilson's disease mutations in ATP7B are associated with enhanced
    binding to COMMD1 and reduced stability of ATP7B.
  findings:
    - statement: >-
        Wilson disease mutations enhance COMMD1 binding and reduce ATP7B
        stability.
      supporting_text: >-
        Four WD patient-derived mutations in this region of ATP7B
        significantly increased its binding to COMMD1. Two of these mutations
        also resulted in mislocalization and increased degradation rate of
        ATP7B.
      reference_section_type: RESULTS
      full_text_unavailable: false
- id: PMID:19946888
  title: Defining the membrane proteome of NK cells.
  findings:
    - statement: >-
        ATP7B detected in NK cell membrane proteomics.
      supporting_text: >-
        Mass spectrometric analysis identified 1843 proteins with high
        confidence scores.
      reference_section_type: ABSTRACT
      full_text_unavailable: true
- id: PMID:22240481
  title: Diverse functional properties of Wilson disease ATP7B variants.
  findings:
    - statement: >-
        Comprehensive functional characterization of 27 Wilson disease variants.
      supporting_text: >-
        Properties of ATP7B variants with pathogenic amino-acid substitution
        varied greatly even if substitutions were in the same functional
        domain. Some variants had complete loss of catalytic and transport
        activity, whereas others lost transport activity but retained
        phosphor-intermediate formation or had partial losses of activity.
      reference_section_type: RESULTS
      full_text_unavailable: false
- id: PMID:26004889
  title: >-
    Functional characterization of new mutations in Wilson disease gene (ATP7B)
    using the yeast model.
  findings:
    - statement: >-
        Yeast complementation demonstrates ATP7B copper transport activity.
      supporting_text: >-
        Expression of human wild type ATP7B gene in ccc2Δ mutant yeast restored
        the growth deficiency and copper transport activity; however, expression
        of the mutant forms did not restore the copper transport functions and
        only partially supported the cell growth.
      reference_section_type: ABSTRACT
      full_text_unavailable: true
- id: PMID:34800366
  title: >-
    Quantitative high-confidence human mitochondrial proteome and its dynamics
    in cellular context.
  findings:
    - statement: >-
        ATP7B detected in high-throughput mitochondrial proteomics.
      supporting_text: >-
        We classified >8,000 proteins in mitochondrial preparations of human
        cells and defined a mitochondrial high-confidence proteome of >1,100
        proteins (MitoCoP).
      reference_section_type: ABSTRACT
      full_text_unavailable: false
- id: Reactome:R-HSA-936837
  title: Ion transport by P-type ATPases
  findings:
    - statement: >-
        ATP7B is part of the P-type ATPase ion transport pathway.
      supporting_text: >-
        The P-type ATPases (E1-E2 ATPases) are a large group of evolutionarily
        related ion pumps that are found in bacteria, archaea  and eukaryotes.
      reference_section_type: ABSTRACT
      full_text_unavailable: false
- id: Reactome:R-HSA-936895
  title: ATP7B transports cytosolic Cu1+ to Golgi lumen
  findings:
    - statement: >-
        ATP7B transports Cu(I) from cytosol to Golgi lumen coupled to ATP
        hydrolysis.
      supporting_text: >-
        ATP7B resides on the trans-Golgi membrane where it it thought to
        sequester copper from the cytosol into the golgi (Yang et al, 1997).
      reference_section_type: ABSTRACT
      full_text_unavailable: false

core_functions:
- molecular_function:
    id: GO:0140581
    label: P-type monovalent copper transporter activity
  description: >-
    ATP7B is an ATP-dependent P1B-type Cu(I) transporter that exports cytosolic
    copper into the trans-Golgi network lumen for secretory cuproenzyme
    metallation and traffics under elevated copper to vesicular/pericanalicular
    compartments for copper detoxification and biliary excretion.
  directly_involved_in:
  - id: GO:0006825
    label: copper ion transport
  - id: GO:0060003
    label: copper ion export
  - id: GO:0006878
    label: intracellular copper ion homeostasis
  - id: GO:1990880
    label: cellular detoxification of copper ion
  locations:
  - id: GO:0032588
    label: trans-Golgi network membrane
  - id: GO:0031410
    label: cytoplasmic vesicle
  supported_by:
  - reference_id: file:human/ATP7B/ATP7B-deep-research-falcon.md
    supporting_text: >-
      ATP7B encodes the Wilson disease copper transporter, a **P1B-type
      (P-type) Cu(I)-transporting ATPase** whose well-supported GO-relevant
      biology centers on: (i) **ATP-driven Cu(I) export from the cytosol into
      the trans-Golgi network (TGN) lumen** for metallation of secretory
      cuproproteins, and (ii) **copper-induced trafficking** to post-Golgi
      vesicles/pericanalicular compartments to enable **cellular copper
      detoxification and biliary copper excretion** in hepatocytes.
  - reference_id: file:human/ATP7B/ATP7B-deep-research-falcon.md
    supporting_text: >-
      The cytosolic copper chaperone **ATOX1** delivers Cu(I) to ATP7B by
      forming **transient Cu-bridged protein–protein complexes**, stabilized
      largely by the copper-coordinating cysteines, transferring Cu(I) to
      ATP7B’s N-terminal MBDs and (directly or indirectly) onward to the
      transmembrane transport site.
  - reference_id: file:human/ATP7B/ATP7B-deep-research-falcon.md
    supporting_text: >-
      At **basal/low copper**, ATP7B localizes predominantly to the
      **trans-Golgi network** (TGN), consistent with its biosynthetic role in
      delivering Cu into the secretory pathway.
  - reference_id: file:human/ATP7B/ATP7B-deep-research-falcon.md
    supporting_text: >-
      Upon **copper elevation**, ATP7B exits the TGN and redistributes to
      **cytosolic vesicles/pericanalicular vesicles** and subapical
      compartments in hepatocyte-derived polarized models; this trafficking is
      reversible upon copper chelation.
proposed_new_terms: []
suggested_questions:
- question: >-
    Should ATP7B cellular-component annotation distinguish copper-induced
    pericanalicular vesicles, transient canalicular membrane association, and
    late-endosome/endolysosomal intermediates by cell type and copper condition?
- question: >-
    Should generic protein-binding annotations for ATP7B be replaced by a more
    informative chaperone-mediated copper transfer annotation involving ATOX1
    if an appropriate GO molecular function or extension pattern is available?
suggested_experiments:
- description: >-
    Use endogenous ATP7B tagging in polarized human hepatocyte models with
    graded copper and chelation time courses, co-imaged with TGN,
    canalicular, vesicle, late-endosome, and lysosome markers, to resolve the
    compartments that should receive GO cellular-component annotation.
  experiment_type: endogenous tagging and copper-dependent live/immunofluorescence imaging
- description: >-
    Combine ATOX1 perturbation or copper-transfer-defective mutants with direct
    ATP7B copper transport, ATPase, ceruloplasmin metallation, and vesicular
    export assays to separate catalytic copper transport from regulatory
    chaperone interactions.
  experiment_type: genetic rescue and biochemical transport assay