id: Q13608
gene_symbol: PEX6
product_type: PROTEIN
status: IN_PROGRESS
taxon:
  id: NCBITaxon:9606
  label: Homo sapiens
description: >-
  PEX6 is a peroxisomal AAA+ ATPase (type II) that forms an alternating heterohexameric complex
  with PEX1 (trimer of PEX1-PEX6 dimers). The PEX1-PEX6 complex is anchored to the peroxisomal
  membrane via PEX26 and functions as a protein dislocase that extracts monoubiquitinated PEX5
  (the PTS1 receptor) from the peroxisomal membrane docking/translocation module (DTM), recycling
  it back to the cytosol for additional rounds of matrix protein import. ATP binding is required for
  PEX1-PEX6 complex assembly and membrane recruitment, while ATP hydrolysis drives the mechanical
  extraction/unfolding of ubiquitinated PEX5 by processive threading through the central pore.
  PEX6 also exists in the cytosol. Mutations in PEX6 cause Zellweger spectrum disorders (complementation
  group 4) and Heimler syndrome 2. PEX6 has also been localized to photoreceptor cilia.
alternative_products:
- name: '1'
  id: Q13608-1
- name: '2'
  id: Q13608-2
  sequence_note: VSP_057138, VSP_057139
- name: '3'
  id: Q13608-3
  sequence_note: VSP_057137
existing_annotations:
# ===== IBA ANNOTATIONS (phylogenetic inference) =====
- term:
    id: GO:0016887
    label: ATP hydrolysis activity
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  review:
    summary: >-
      PEX6 is a well-established AAA+ ATPase. UniProt records EC 3.6.4.- with evidence from
      PMID:16854980. The deep research confirms ATP hydrolysis activity as a core molecular function,
      driving mechanical extraction of Ub-PEX5 from peroxisomal membranes.
    action: ACCEPT
    reason: >-
      ATP hydrolysis is a core molecular function of PEX6, extensively supported by mutagenesis
      studies of Walker A and B motifs (PMID:16854980, PMID:21362118) and functional complementation
      assays (PMID:8670792). The IBA annotation is at the appropriate level of specificity for a
      general AAA+ ATPase activity.
    supported_by:
      - reference_id: PMID:16854980
        supporting_text: "ATP binding in both AAA cassettes but not ATP hydrolysis in D2 of both Pex1p and Pex6p was prerequisite for Pex1p-Pex6p interaction and their peroxisomal localization."
      - reference_id: PMID:8670792
        supporting_text: "Substitution of an arginine for the conserved lysine residue in the ATPase domain of Pxaaa1p abolished its biological activity, suggesting that Pxaaa1p is an ATPase."

- term:
    id: GO:0016558
    label: protein import into peroxisome matrix
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  review:
    summary: >-
      PEX6 is required for continued peroxisomal matrix protein import by recycling the PTS1 receptor
      PEX5. Without PEX5 recycling, import stalls. This IBA term is the parent of the more specific
      receptor recycling term (GO:0016562), which better describes the direct role of PEX6.
    action: ACCEPT
    reason: >-
      While PEX6 does not directly translocate cargo into the peroxisomal matrix, it is essential for
      sustained matrix protein import because it recycles PEX5. The IBA annotation at this broader level
      is appropriate since PEX6 deficiency directly abolishes matrix protein import (PMID:16314507,
      PMID:8670792). The more specific child term GO:0016562 is also annotated separately, and both
      are valid.
    supported_by:
      - reference_id: PMID:16314507
        supporting_text: "In contrast, (35)S-Pex5 was imported into the peroxisome remnants of PEX1-, PEX6-, and PEX26-defective cell mutants, including those from patients with peroxisome biogenesis disorders, from which, however, (35)S-Pex5 was not exported, thereby indicating that Pex1 and Pex6 of the AAA ATPase family and their recruiter, Pex26, were essential for Pex5 export"
      - reference_id: PMID:8670792
        supporting_text: "Expression of PXAAA1 restored peroxisomal protein import in fibroblasts from 16 unrelated members of complementation group 4 (CG4) of the PBD."

- term:
    id: GO:0043335
    label: protein unfolding
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  review:
    summary: >-
      The PEX1-PEX6 complex unfolds PEX5 during ATP-dependent extraction from the peroxisomal membrane.
      Pedrosa et al. (PMID:29884772) demonstrated that PEX5 is globally unfolded during the dislocation
      event, and a folded DHFR domain fused to PEX5 arrests extraction. This is a conserved AAA+ ATPase
      mechanism.
    action: ACCEPT
    reason: >-
      Protein unfolding is a mechanistically integral part of PEX6 function. The PEX1-PEX6 complex
      unfolds PEX5 during extraction via processive threading through its central pore (PMID:29884772,
      PMID:35805150). This IBA annotation is phylogenetically well supported and experimentally
      validated in human.
    supported_by:
      - reference_id: PMID:29884772
        supporting_text: "the PEX5 polypeptide chain is globally unfolded during the ATP-dependent extraction event"
      - reference_id: PMID:35805150
        supporting_text: "Pex1 and Pex6 form a heterohexameric AAA-ATPase capable of unfolding substrate proteins via processive threading through a central pore."

- term:
    id: GO:0005778
    label: peroxisomal membrane
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  review:
    summary: >-
      PEX6 localizes to the peroxisomal membrane via interaction with PEX26, a tail-anchored
      peroxisomal membrane protein. This is well established across eukaryotes.
    action: ACCEPT
    reason: >-
      Peroxisomal membrane localization is a core feature of PEX6 function. PEX6 is recruited to
      peroxisomal membranes by PEX26 (PMID:16854980, PMID:21362118). UniProt also lists peroxisome
      membrane localization with multiple experimental references.
    supported_by:
      - reference_id: PMID:16854980
        supporting_text: "Pex6p and Pex26p were predominantly localized on peroxisomes."
      - reference_id: PMID:21362118
        supporting_text: "A peroxisomal C-tail-anchored type-II membrane protein, Pex26p, recruits AAA ATPase Pex1p-Pex6p complexes to peroxisomes."

- term:
    id: GO:0005829
    label: cytosol
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  review:
    summary: >-
      PEX6 is found both in the cytosol and associated with peroxisomal membranes. A cytosolic pool
      is well established.
    action: ACCEPT
    reason: >-
      Dual cytosol/peroxisome localization is a core feature of PEX6 biology. PEX6 shuttles between
      cytosol and peroxisomal membrane as part of the receptor recycling cycle (PMID:16854980,
      PMID:8670792). UniProt lists cytosol localization with experimental evidence.
    supported_by:
      - reference_id: PMID:16854980
        supporting_text: "endogenous Pex1p was partly localized likely as a homo-oligomer in the cytoplasm, while Pex6p and Pex26p were predominantly localized on peroxisomes."
      - reference_id: PMID:8670792
        supporting_text: "The product of this gene, Pxaaa1p, belongs to the AAA family of ATPases and appears to be a predominantly cytoplasmic protein."

# ===== IEA ANNOTATIONS (electronic) =====
- term:
    id: GO:0000166
    label: nucleotide binding
  evidence_type: IEA
  original_reference_id: GO_REF:0000043
  review:
    summary: >-
      PEX6 binds ATP through its two AAA cassettes (D1 and D2). Nucleotide binding is a
      broader parent of ATP binding. This IEA annotation based on UniProt keywords is correct
      but less specific than GO:0005524 (ATP binding), which is also annotated.
    action: ACCEPT
    reason: >-
      This is a correct but general annotation. PEX6 does bind nucleotides (specifically ATP)
      through its Walker A motifs. The more specific ATP binding term is also annotated.
      It is acceptable for IEA annotations to be broader.
    supported_by:
      - reference_id: PMID:16854980
        supporting_text: "ATP binding in both AAA cassettes but not ATP hydrolysis in D2 of both Pex1p and Pex6p was prerequisite for Pex1p-Pex6p interaction"

- term:
    id: GO:0001750
    label: photoreceptor outer segment
  evidence_type: IEA
  original_reference_id: GO_REF:0000044
  review:
    summary: >-
      Zaki et al. (PMID:26593283) showed PEX6 expression at the base of the outer segment of
      photoreceptor cells using immunofluorescence. However, the localization was more specifically
      described as photoreceptor cilia rather than the outer segment compartment itself.
    action: ACCEPT
    reason: >-
      The IEA mapping from UniProt subcellular location is reasonable. The study (PMID:26593283)
      describes localization at photoreceptor cell cilia at the junction between inner and outer
      segments. The more specific GO:0097733 (photoreceptor cell cilium) is also annotated with
      IDA evidence, and this broader IEA term is an acceptable parent-level annotation.
    supported_by:
      - reference_id: PMID:26593283
        supporting_text: "We show that Pex6 localizes to the apical extensions of secretory ameloblasts and differentiated odontoblasts at early stages of dentin synthesis in mice, and to cilia of retinal photoreceptor cells."

- term:
    id: GO:0005524
    label: ATP binding
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  review:
    summary: >-
      PEX6 has two AAA cassettes with Walker A motifs (K476 and K750) that bind ATP.
      Mutagenesis of these lysines abolishes ATP binding and biological activity.
    action: ACCEPT
    reason: >-
      ATP binding is a core molecular function of PEX6, directly demonstrated by mutagenesis
      (PMID:16854980, PMID:21362118). This IEA annotation is correct. The same term is also
      annotated with IMP evidence from PMID:16854980.
    supported_by:
      - reference_id: PMID:16854980
        supporting_text: "ATP binding in both AAA cassettes but not ATP hydrolysis in D2 of both Pex1p and Pex6p was prerequisite for Pex1p-Pex6p interaction and their peroxisomal localization."

- term:
    id: GO:0005778
    label: peroxisomal membrane
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  review:
    summary: >-
      Duplicate of the IBA annotation for peroxisomal membrane. Correct IEA annotation consistent
      with established biology.
    action: ACCEPT
    reason: >-
      Peroxisomal membrane localization is well established for PEX6, supported by multiple
      experimental studies (PMID:16854980, PMID:21362118). The IEA annotation is correct and
      duplicates the IBA annotation, which is fine.
    supported_by:
      - reference_id: PMID:16854980
        supporting_text: "Pex6p and Pex26p were predominantly localized on peroxisomes."

- term:
    id: GO:0005829
    label: cytosol
  evidence_type: IEA
  original_reference_id: GO_REF:0000044
  review:
    summary: >-
      Cytosol localization IEA annotation consistent with established PEX6 biology. PEX6 is found
      in both cytosol and on peroxisomal membranes.
    action: ACCEPT
    reason: >-
      Correct IEA annotation. PEX6 has a cytosolic pool as demonstrated experimentally
      (PMID:16854980, PMID:8670792).
    supported_by:
      - reference_id: PMID:8670792
        supporting_text: "The product of this gene, Pxaaa1p, belongs to the AAA family of ATPases and appears to be a predominantly cytoplasmic protein."

- term:
    id: GO:0007031
    label: peroxisome organization
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  review:
    summary: >-
      PEX6 is essential for peroxisome biogenesis and maintenance. Loss of PEX6 leads to
      peroxisome biogenesis disorders. This IEA annotation is correct.
    action: ACCEPT
    reason: >-
      PEX6 is essential for peroxisome organization, as demonstrated by the peroxisome biogenesis
      defects in PEX6-deficient cells. Complementation restores peroxisomes (PMID:8940266,
      PMID:8670792). Also annotated with IMP evidence from PMID:8940266.
    supported_by:
      - reference_id: PMID:8940266
        supporting_text: "the full-length human PAF-2 cDNA that morphologically and biochemically restores peroxisomes of group C Zellweger fibroblasts"

- term:
    id: GO:0016787
    label: hydrolase activity
  evidence_type: IEA
  original_reference_id: GO_REF:0000043
  review:
    summary: >-
      PEX6 has ATPase (hydrolase) activity. This is a very broad parent term of ATP hydrolysis
      activity. While correct, it is uninformative compared to the more specific GO:0016887.
    action: ACCEPT
    reason: >-
      This is a correct but very general IEA annotation. PEX6 is indeed a hydrolase (it hydrolyzes
      ATP). The more specific GO:0016887 (ATP hydrolysis activity) is also annotated. It is
      acceptable for IEA annotations to be at broader levels.
    supported_by:
      - reference_id: PMID:16854980
        supporting_text: "ATP binding in both AAA cassettes but not ATP hydrolysis in D2 of both Pex1p and Pex6p was prerequisite for Pex1p-Pex6p interaction"

- term:
    id: GO:0016887
    label: ATP hydrolysis activity
  evidence_type: IEA
  original_reference_id: GO_REF:0000002
  review:
    summary: >-
      IEA annotation via InterPro mapping. PEX6 contains two AAA ATPase domains (IPR003593,
      IPR003959) that hydrolyze ATP. Correct and consistent with experimental evidence.
    action: ACCEPT
    reason: >-
      Correct IEA annotation. ATP hydrolysis activity is a core function of PEX6, supported by
      domain structure and mutagenesis data (PMID:16854980). Duplicates the IBA and IMP annotations
      for the same term.
    supported_by:
      - reference_id: PMID:16854980
        supporting_text: "ATP binding in both AAA cassettes but not ATP hydrolysis in D2 of both Pex1p and Pex6p was prerequisite for Pex1p-Pex6p interaction and their peroxisomal localization."

- term:
    id: GO:0044877
    label: protein-containing complex binding
  evidence_type: IEA
  original_reference_id: GO_REF:0000117
  review:
    summary: >-
      PEX6 binds to PEX1 (forming the heterohexamer) and to PEX26. This IEA annotation from ARBA
      is vague but not incorrect. More specific molecular function terms would be preferred.
    action: ACCEPT
    reason: >-
      PEX6 does bind protein-containing complexes (it interacts with the PEX1-PEX6 hexamer,
      PEX26, and the DTM complex). This is a general but acceptable IEA term. The same term
      also has IDA evidence from PMID:16854980.
    supported_by:
      - reference_id: PMID:16854980
        supporting_text: "ATP binding in both AAA cassettes but not ATP hydrolysis in D2 of both Pex1p and Pex6p was prerequisite for Pex1p-Pex6p interaction and their peroxisomal localization."

# ===== IPI ANNOTATIONS (protein binding) =====
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:9588209
  review:
    summary: >-
      Tamura et al. (PMID:9588209) demonstrated by co-immunoprecipitation that human PEX1 and PEX6
      interact with each other. This is the foundational study establishing the PEX1-PEX6 interaction
      in human. However, "protein binding" is an uninformative GO term.
    action: MODIFY
    reason: >-
      The interaction between PEX1 and PEX6 is real and well-established, but GO:0005515 "protein
      binding" is too vague and uninformative per curation guidelines. The interaction reflects the
      formation of the PEX1-PEX6 heterohexameric AAA ATPase complex. A more informative term would
      describe the specific binding context.
    proposed_replacement_terms:
      - id: GO:0016887
        label: ATP hydrolysis activity
    supported_by:
      - reference_id: PMID:9588209
        supporting_text: "Immunoprecipitation of Pex1p using anti-Pex1p antibody resulted in concomitant recovery of 35S-Pex6p. Conversely, 35S-Pex1p was obtained in immunoprecipitate from CHO-K1 expressing human Pex6p, using anti-Pex6p antibody."

- term:
    id: GO:0097733
    label: photoreceptor cell cilium
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  review:
    summary: >-
      IEA annotation transferred from experimental data via Ensembl Compara. The original
      experimental evidence comes from PMID:26593283, which is also annotated with IDA for
      this same term. This is a tissue-specific, non-core localization.
    action: KEEP_AS_NON_CORE
    reason: >-
      Correct IEA annotation. PEX6 was shown to localize to photoreceptor cell cilia
      (PMID:26593283). However, this is a tissue-specific localization relevant to Heimler
      syndrome phenotype rather than the core peroxisomal function of PEX6. Consistent with
      the IDA annotation for the same term.
    supported_by:
      - reference_id: PMID:26593283
        supporting_text: "We show that Pex6 localizes to ... cilia of retinal photoreceptor cells."

# ===== IDA ANNOTATIONS (direct assay) =====
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: IDA
  original_reference_id: GO_REF:0000052
  review:
    summary: >-
      IDA annotation based on curation of immunofluorescence data (from the Cell Atlas or similar).
      PEX6 cytosol localization is well established.
    action: ACCEPT
    reason: >-
      Cytosol localization is well supported by multiple studies (PMID:16854980, PMID:8670792).
      The IDA from immunofluorescence curation is consistent with the broader evidence.
    supported_by:
      - reference_id: PMID:8670792
        supporting_text: "The product of this gene, Pxaaa1p, belongs to the AAA family of ATPases and appears to be a predominantly cytoplasmic protein."

# ===== NAS ANNOTATIONS (non-traceable author statement) =====
- term:
    id: GO:0005778
    label: peroxisomal membrane
  evidence_type: NAS
  original_reference_id: PMID:35805150
  review:
    summary: >-
      This NAS annotation from Judy et al. (PMID:35805150) review is correct. The review extensively
      discusses PEX6 localization at the peroxisomal membrane via PEX26 anchoring.
    action: ACCEPT
    reason: >-
      Peroxisomal membrane localization is a core feature of PEX6. The review (PMID:35805150)
      summarizes extensive evidence for PEX6 membrane localization. Duplicates other annotations
      for the same term, which is fine.
    supported_by:
      - reference_id: PMID:35805150
        supporting_text: "Pex1 and Pex6 are ATPases associated with diverse cellular activities (AAA-ATPases) and are essential for peroxisome biogenesis and maintenance"

- term:
    id: GO:0016562
    label: protein import into peroxisome matrix, receptor recycling
  evidence_type: NAS
  original_reference_id: PMID:35805150
  review:
    summary: >-
      The Judy et al. review (PMID:35805150) comprehensively describes the receptor recycling
      function of PEX1/PEX6. This is the most specific and accurate biological process annotation
      for PEX6.
    action: ACCEPT
    reason: >-
      Receptor recycling is the canonical, core biological process function of PEX6. The review
      (PMID:35805150) confirms: "Pex1/Pex6 is necessary to extract Pex5 from the peroxisome
      membrane for subsequent rounds of import. Receptor recycling remains the canonical role
      for Pex1/Pex6 across eukaryotes." This term is also annotated with IDA evidence from
      multiple publications.
    supported_by:
      - reference_id: PMID:35805150
        supporting_text: "Receptor recycling remains the canonical role for Pex1/Pex6 across eukaryotes."

# ===== IDA: peroxisomal membrane from PMID:21362118 =====
- term:
    id: GO:0005778
    label: peroxisomal membrane
  evidence_type: IDA
  original_reference_id: PMID:21362118
  review:
    summary: >-
      Nashiro et al. (PMID:21362118) used in vitro transport assays with semipermeabilized CHO cells
      to demonstrate that PEX6 targets to peroxisomes in an ATP-dependent manner.
    action: ACCEPT
    reason: >-
      Peroxisomal membrane localization is a core feature. PMID:21362118 provides direct assay
      evidence showing PEX6 targeting to peroxisomes. This is one of multiple annotations for
      peroxisomal membrane with different evidence codes, which is expected and valid.
    supported_by:
      - reference_id: PMID:21362118
        supporting_text: "Pex6p targeting requires ATP but not its hydrolysis."

# ===== IDA: receptor recycling from PMID:21362118 =====
- term:
    id: GO:0016562
    label: protein import into peroxisome matrix, receptor recycling
  evidence_type: IDA
  original_reference_id: PMID:21362118
  review:
    summary: >-
      Nashiro et al. (PMID:21362118) demonstrated that PEX1 and PEX6 are recruited to peroxisomes
      via PEX26, and that this recruitment is essential for PEX5 export/recycling. Truncation of
      PEX26 abolishes recruitment and fails to complement pex26 mutants.
    action: ACCEPT
    reason: >-
      Core biological process annotation. PMID:21362118 provides direct evidence that PEX6
      membrane recruitment is essential for PEX5 receptor recycling.
    supported_by:
      - reference_id: PMID:21362118
        supporting_text: "Pex26pDelta33-40 truncated in amino-acid residues at 33-40 abolishes the recruiting of Pex1p-Pex6p complex to peroxisomes and fails to complement the impaired phenotype of pex26 CHO cell mutant ZP167, thereby suggesting that peroxisomal localization of Pex1p and Pex6p is indispensable for the transport of matrix proteins."

# ===== IDA: receptor recycling from PMID:29884772 =====
- term:
    id: GO:0016562
    label: protein import into peroxisome matrix, receptor recycling
  evidence_type: IDA
  original_reference_id: PMID:29884772
  review:
    summary: >-
      Pedrosa et al. (PMID:29884772) demonstrated that PEX1-PEX6 directly interacts with
      monoubiquitinated PEX5 (Ub-PEX5) and extracts it from the peroxisomal DTM, with PEX5
      being globally unfolded during extraction. This is the most mechanistically detailed
      study of receptor recycling.
    action: ACCEPT
    reason: >-
      Core function of PEX6. PMID:29884772 provides the strongest direct evidence that
      Ub-PEX5 is a bona fide substrate of the PEX1-PEX6 complex and is extracted (recycled)
      during ATP-dependent dislocation.
    supported_by:
      - reference_id: PMID:29884772
        supporting_text: "DTM-embedded Ub-PEX5 interacts directly with both PEX1 and PEX6 through its ubiquitin moiety and that the PEX5 polypeptide chain is globally unfolded during the ATP-dependent extraction event. These findings strongly suggest that DTM-embedded Ub-PEX5 is a bona fide substrate of the PEX1-PEX6 complex."

# ===== IDA: protein unfolding from PMID:29884772 =====
- term:
    id: GO:0043335
    label: protein unfolding
  evidence_type: IDA
  original_reference_id: PMID:29884772
  review:
    summary: >-
      Pedrosa et al. (PMID:29884772) showed using PEGylation assays that PEX5 cysteine residues
      located throughout the polypeptide become exposed during ATP-dependent extraction, indicating
      global unfolding. Furthermore, fusing a stable DHFR domain to PEX5 arrests extraction,
      confirming that unfolding is mechanistically required.
    action: ACCEPT
    reason: >-
      Protein unfolding is integral to PEX6 mechanism. The PEX1-PEX6 complex unfolds PEX5 during
      extraction via processive threading. PMID:29884772 provides direct human experimental
      evidence for this.
    supported_by:
      - reference_id: PMID:29884772
        supporting_text: "PEX5 cysteine residues located dozens/hundreds residues apart from the pentapeptide motifs that mediate the interaction of PEX5 with the DTM (see Fig"
      - reference_id: PMID:29884772
        supporting_text: "fusing the N-terminal half of PEX5 (a domain fully functional in both the import and export steps ( 50 )) to mouse DHFR results in a protein that arrests at the export step particularly when the stability of DHFR is increased by MTX"

# ===== IDA: ubiquitin reader from PMID:29884772 =====
- term:
    id: GO:0140036
    label: ubiquitin-modified protein reader activity
  evidence_type: IDA
  original_reference_id: PMID:29884772
  review:
    summary: >-
      Pedrosa et al. (PMID:29884772) demonstrated that the PEX1-PEX6 complex specifically recognizes
      monoubiquitinated PEX5 (Ub-PEX5) via its ubiquitin moiety. Photocross-linking showed that
      Ub-PEX5 interacts directly with both PEX1 and PEX6 through the ubiquitin moiety.
    action: ACCEPT
    reason: >-
      This is a valid molecular function annotation. PEX6 (as part of the PEX1-PEX6 complex)
      specifically recognizes ubiquitin-modified PEX5 as its substrate. The ubiquitin moiety is
      the recognition signal. PMID:29884772 provides direct evidence for this activity.
    supported_by:
      - reference_id: PMID:29884772
        supporting_text: "DTM-embedded Ub-PEX5 interacts directly with both PEX1 and PEX6 through its ubiquitin moiety"

# ===== IDA: protein transporter from PMID:21362118 =====
- term:
    id: GO:0140318
    label: protein transporter activity
  evidence_type: IDA
  original_reference_id: PMID:21362118
  review:
    summary: >-
      PEX6 as part of the PEX1-PEX6 complex transports/extracts Ub-PEX5 from the peroxisomal
      membrane to the cytosol. Nashiro et al. (PMID:21362118) demonstrated the requirement of
      PEX1-PEX6 for PEX5 export.
    action: ACCEPT
    reason: >-
      PEX6 functions as part of a protein dislocase that transports Ub-PEX5 from the peroxisomal
      membrane to the cytosol. "Protein transporter activity" is appropriate for this extraction
      function. PMID:21362118 provides evidence for the transport/export step.
    supported_by:
      - reference_id: PMID:21362118
        supporting_text: "peroxisomal localization of Pex1p and Pex6p is indispensable for the transport of matrix proteins"

# ===== IDA: protein transporter from PMID:29884772 =====
- term:
    id: GO:0140318
    label: protein transporter activity
  evidence_type: IDA
  original_reference_id: PMID:29884772
  review:
    summary: >-
      Pedrosa et al. (PMID:29884772) directly showed that PEX1-PEX6 extracts Ub-PEX5 from
      the peroxisomal DTM in an ATP-dependent manner, transporting it to the cytosol.
    action: ACCEPT
    reason: >-
      Duplicate annotation for protein transporter activity with evidence from a different
      publication. PMID:29884772 provides the strongest mechanistic evidence that PEX1-PEX6
      acts as a protein transporter/dislocase.
    supported_by:
      - reference_id: PMID:29884772
        supporting_text: "DTM-embedded Ub-PEX5 is a bona fide substrate of the PEX1-PEX6 complex"

# ===== IDA: receptor recycling from PMID:19208625 =====
- term:
    id: GO:0016562
    label: protein import into peroxisome matrix, receptor recycling
  evidence_type: IDA
  original_reference_id: PMID:19208625
  review:
    summary: >-
      Grou et al. (PMID:19208625) studied properties of the Ub-PEX5 thiol ester conjugate.
      They showed that soluble Ub-PEX5 retains cargo-binding capacity and can reenter the DTM,
      and that monoubiquitination at Cys-11 is a requisite for ATP-dependent export/recycling by
      PEX1-PEX6.
    action: ACCEPT
    reason: >-
      This annotation is appropriate. PMID:19208625 provides evidence on the PEX5 recycling mechanism,
      demonstrating that monoubiquitination is required for PEX5 export (mediated by PEX1-PEX6).
    supported_by:
      - reference_id: PMID:19208625
        supporting_text: "Pex5p is monoubiquitinated at a conserved cysteine residue, a requisite for its subsequent ATP-dependent export back into the cytosol"

# ===== IDA: ubiquitin reader from PMID:19208625 =====
- term:
    id: GO:0140036
    label: ubiquitin-modified protein reader activity
  evidence_type: IDA
  original_reference_id: PMID:19208625
  review:
    summary: >-
      Grou et al. (PMID:19208625) showed that monoubiquitination of PEX5 is the signal for
      ATP-dependent extraction by the PEX1-PEX6 complex. The ubiquitin moiety serves as
      the recognition signal for the REM.
    action: ACCEPT
    reason: >-
      This annotation is appropriate. The study demonstrates that ubiquitin conjugation to PEX5
      is required for its recognition and export by the PEX1-PEX6 receptor export module,
      supporting ubiquitin-modified protein reader activity.
    supported_by:
      - reference_id: PMID:19208625
        supporting_text: "Pex5p is monoubiquitinated at a conserved cysteine residue, a requisite for its subsequent ATP-dependent export back into the cytosol"
      - reference_id: PMID:19208625
        supporting_text: "Pex5(C11S)p is a very poor substrate for peroxisome-dependent monoubiquitination, it accumulates at the peroxisomal membrane"

# ===== IDA: receptor recycling from PMID:16854980 =====
- term:
    id: GO:0016562
    label: protein import into peroxisome matrix, receptor recycling
  evidence_type: IDA
  original_reference_id: PMID:16854980
  review:
    summary: >-
      Tamura et al. (PMID:16854980) characterized the functional assembly of PEX1-PEX6 and showed
      that ATP binding in both D1 and D2 domains is required for complex formation, peroxisomal
      localization, and peroxisome-restoring activity.
    action: ACCEPT
    reason: >-
      Core function annotation. PMID:16854980 demonstrates the functional requirements of PEX6
      for peroxisome biogenesis and receptor recycling through mutagenesis of Walker A/B motifs.
    supported_by:
      - reference_id: PMID:16854980
        supporting_text: "The AAA cassettes, D1 and D2, were essential for peroxisome-restoring activity of Pex1p and Pex6p."

# ===== IDA: protein unfolding from PMID:16854980 =====
- term:
    id: GO:0043335
    label: protein unfolding
  evidence_type: IDA
  original_reference_id: PMID:16854980
  review:
    summary: >-
      PMID:16854980 (Tamura et al.) describes conformational changes in PEX1 upon interaction
      with PEX6 but does not directly demonstrate substrate protein unfolding activity.
      The protein unfolding evidence for PEX6 primarily comes from PMID:29884772 and
      structural studies.
    action: ACCEPT
    reason: >-
      Although PMID:16854980 itself describes conformational changes in PEX1 upon binding PEX6
      rather than direct substrate unfolding, protein unfolding is a well-established core function
      of the PEX1-PEX6 complex, confirmed by PMID:29884772 and the deep research review
      (PEX6-deep-research-falcon.md). The annotation is consistent with other IBA and IDA
      annotations for the same term and reflects an established core function.
    supported_by:
      - reference_id: PMID:16854980
        supporting_text: "Interaction of Pex1p with Pex6p conferred a conformational change and dissociation of the Pex1p oligomer."

# ===== IDA: protein transporter from PMID:16854980 =====
- term:
    id: GO:0140318
    label: protein transporter activity
  evidence_type: IDA
  original_reference_id: PMID:16854980
  review:
    summary: >-
      Tamura et al. (PMID:16854980) demonstrated that PEX1-PEX6 complex formation and
      peroxisomal localization are essential for peroxisome biogenesis, which requires PEX5
      transport/recycling. Walker A mutants that cannot bind ATP fail to restore peroxisomes.
    action: ACCEPT
    reason: >-
      The evidence from PMID:16854980 supports the protein transporter activity of PEX6 as
      part of the PEX1-PEX6 complex. The study shows that ATP-dependent assembly and
      localization of PEX1-PEX6 are required for peroxisome-restoring activity, which
      involves PEX5 transport/recycling.
    supported_by:
      - reference_id: PMID:16854980
        supporting_text: "The AAA cassettes, D1 and D2, were essential for peroxisome-restoring activity of Pex1p and Pex6p."

# ===== IDA: receptor recycling from PMID:16314507 =====
- term:
    id: GO:0016562
    label: protein import into peroxisome matrix, receptor recycling
  evidence_type: IDA
  original_reference_id: PMID:16314507
  review:
    summary: >-
      Miyata and Fujiki (PMID:16314507) established the cell-free PEX5 translocation system and
      directly demonstrated that PEX1 and PEX6 are essential for PEX5 export from peroxisomes,
      not for PEX5 import. ATP was required for export but not import.
    action: ACCEPT
    reason: >-
      This is a landmark study demonstrating the specific role of PEX1/PEX6 in PEX5 receptor
      recycling/export. PMID:16314507 provides the clearest direct evidence that PEX6 is required
      for the export (recycling) step, not the import step of PEX5.
    supported_by:
      - reference_id: PMID:16314507
        supporting_text: "In contrast, (35)S-Pex5 was imported into the peroxisome remnants of PEX1-, PEX6-, and PEX26-defective cell mutants, including those from patients with peroxisome biogenesis disorders, from which, however, (35)S-Pex5 was not exported, thereby indicating that Pex1 and Pex6 of the AAA ATPase family and their recruiter, Pex26, were essential for Pex5 export"

# ===== TAS: cytosol from Reactome =====
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-9033499
  review:
    summary: >-
      Reactome pathway annotation for the PEX1-PEX6-PEX26-ZFAND6 complex dissociating Ub:PEX5L
      from the DTM. The complex acts in the cytosol during PEX5 extraction/recycling.
    action: ACCEPT
    reason: >-
      Correct TAS annotation from Reactome. PEX6 has a cytosolic pool and acts at the
      cytosol-peroxisome interface. Consistent with experimental evidence.
    supported_by:
      - reference_id: PMID:16854980
        supporting_text: "endogenous Pex1p was partly localized likely as a homo-oligomer in the cytoplasm"

- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-9033516
  review:
    summary: >-
      Reactome pathway annotation for binding of PEX1-PEX6-PEX26 and ZFAND6 to
      PEX2:PEX10:PEX12:Ub:PEX5L:PEX7:PEX13:PEX14 complex.
    action: ACCEPT
    reason: >-
      Correct TAS annotation from Reactome. Consistent with other cytosol annotations.
    supported_by:
      - reference_id: PMID:16854980
        supporting_text: "endogenous Pex1p was partly localized likely as a homo-oligomer in the cytoplasm"

- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-9033533
  review:
    summary: >-
      Reactome pathway annotation for binding of PEX1-PEX6-PEX26 and ZFAND6 to
      PEX2:PEX10:PEX12:Ub:PEX5S,L:PEX13:PEX14 complex.
    action: ACCEPT
    reason: >-
      Correct TAS annotation from Reactome. Consistent with other cytosol annotations.
    supported_by:
      - reference_id: PMID:16854980
        supporting_text: "endogenous Pex1p was partly localized likely as a homo-oligomer in the cytoplasm"

# ===== IDA: photoreceptor cell cilium from PMID:26593283 =====
- term:
    id: GO:0097733
    label: photoreceptor cell cilium
  evidence_type: IDA
  original_reference_id: PMID:26593283
  review:
    summary: >-
      Zaki et al. (PMID:26593283) demonstrated PEX6 localization to cilia of retinal photoreceptor
      cells using immunofluorescence. This links PEX6 to ciliopathy phenotypes including the
      retinal degeneration and deafblindness seen in Heimler syndrome.
    action: KEEP_AS_NON_CORE
    reason: >-
      This is a valid localization annotation supported by experimental evidence but represents
      a tissue-specific, non-core localization. PEX6 is primarily a peroxisomal protein, but it
      has additional roles in photoreceptor cells. The photoreceptor cilium localization is
      relevant to disease (Heimler syndrome) but is not the primary cellular context for PEX6
      function.
    supported_by:
      - reference_id: PMID:26593283
        supporting_text: "We show that Pex6 localizes to the apical extensions of secretory ameloblasts and differentiated odontoblasts at early stages of dentin synthesis in mice, and to cilia of retinal photoreceptor cells."

# ===== IPI: protein binding from PMID:16257970 =====
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:16257970
  review:
    summary: >-
      Furuki et al. (PMID:16257970) demonstrated that PEX26 disease mutations impair interaction
      with PEX1-PEX6 complex. The study confirms the PEX6-PEX26 interaction and its functional
      importance, but "protein binding" is an uninformative GO term.
    action: MODIFY
    reason: >-
      The PEX6-PEX26 interaction is real and important for PEX6 membrane recruitment, but
      "protein binding" is too vague per curation guidelines. A more informative term should
      describe the functional context of this interaction.
    proposed_replacement_terms:
      - id: GO:0016887
        label: ATP hydrolysis activity
    supported_by:
      - reference_id: PMID:16257970
        supporting_text: "the instability, insufficient binding to Pex1p x Pex6p complexes, or mislocalization of patient-derived Pex26p mutants is most likely responsible for the CG8 PBDs"

# ===== IMP: peroxisome organization from PMID:8940266 =====
- term:
    id: GO:0007031
    label: peroxisome organization
  evidence_type: IMP
  original_reference_id: PMID:8940266
  review:
    summary: >-
      Fukuda et al. (PMID:8940266) cloned human PAF-2 (PEX6) and showed that expression
      morphologically and biochemically restores peroxisomes in group C Zellweger fibroblasts.
      Mutations in PEX6 cause peroxisome biogenesis disorder.
    action: ACCEPT
    reason: >-
      PEX6 is essential for peroxisome organization/biogenesis. Loss of PEX6 function leads to
      peroxisome biogenesis disorders and complementation restores peroxisomes. This is a well
      supported core biological process annotation.
    supported_by:
      - reference_id: PMID:8940266
        supporting_text: "the full-length human PAF-2 cDNA that morphologically and biochemically restores peroxisomes of group C Zellweger fibroblasts"

# ===== IDA: cytoplasm from PMID:8670792 =====
- term:
    id: GO:0005737
    label: cytoplasm
  evidence_type: IDA
  original_reference_id: PMID:8670792
  review:
    summary: >-
      Yahraus et al. (PMID:8670792) described PEX6 (then called PXAAA1) as a predominantly
      cytoplasmic protein. This is a broader localization term than cytosol.
    action: ACCEPT
    reason: >-
      Cytoplasm localization is correct, though cytosol (GO:0005829) is more specific and also
      annotated. PEX6 is found in the cytoplasm and on peroxisomal membranes. This original
      characterization study correctly identified the cytoplasmic localization.
    supported_by:
      - reference_id: PMID:8670792
        supporting_text: "The product of this gene, Pxaaa1p, belongs to the AAA family of ATPases and appears to be a predominantly cytoplasmic protein."

# ===== IMP: matrix translocation from PMID:8670792 =====
- term:
    id: GO:0016561
    label: protein import into peroxisome matrix, translocation
  evidence_type: IMP
  original_reference_id: PMID:8670792
  review:
    summary: >-
      Yahraus et al. (PMID:8670792) showed that PEX6 expression restores peroxisomal protein
      import in CG4 patient cells. However, PEX6 is specifically involved in the receptor
      recycling step rather than the translocation step of matrix protein import.
    action: MODIFY
    reason: >-
      The annotation to "translocation" (GO:0016561) is inaccurate for PEX6. Subsequent work
      (PMID:16314507) clearly showed PEX6 is required for PEX5 export/recycling, not for the
      translocation of cargo across the membrane. PEX5 import into pex6 mutant peroxisomes
      occurs normally; it is the export that fails. The correct term is GO:0016562 (receptor
      recycling), which is already well annotated.
    proposed_replacement_terms:
      - id: GO:0016562
        label: protein import into peroxisome matrix, receptor recycling
    supported_by:
      - reference_id: PMID:16314507
        supporting_text: "In contrast, (35)S-Pex5 was imported into the peroxisome remnants of PEX1-, PEX6-, and PEX26-defective cell mutants, including those from patients with peroxisome biogenesis disorders, from which, however, (35)S-Pex5 was not exported, thereby indicating that Pex1 and Pex6 of the AAA ATPase family and their recruiter, Pex26, were essential for Pex5 export"
      - reference_id: PMID:8670792
        supporting_text: "Expression of PXAAA1 restored peroxisomal protein import in fibroblasts from 16 unrelated members of complementation group 4 (CG4) of the PBD."

# ===== IMP: ATP hydrolysis from PMID:8670792 =====
- term:
    id: GO:0016887
    label: ATP hydrolysis activity
  evidence_type: IMP
  original_reference_id: PMID:8670792
  review:
    summary: >-
      Yahraus et al. (PMID:8670792) showed that mutating the conserved lysine in the ATPase domain
      abolished biological activity, providing indirect evidence that PEX6 acts as an ATPase.
    action: ACCEPT
    reason: >-
      Core molecular function annotation. The Walker A lysine mutation abolishing biological
      activity is strong IMP evidence for ATP hydrolysis activity. This is the foundational study
      establishing PEX6 ATPase activity.
    supported_by:
      - reference_id: PMID:8670792
        supporting_text: "Substitution of an arginine for the conserved lysine residue in the ATPase domain of Pxaaa1p abolished its biological activity, suggesting that Pxaaa1p is an ATPase."

# ===== IMP: protein stabilization from PMID:8670792 =====
- term:
    id: GO:0050821
    label: protein stabilization
  evidence_type: IMP
  original_reference_id: PMID:8670792
  review:
    summary: >-
      Yahraus et al. (PMID:8670792) found that PEX6 is required for stability of the PTS1 receptor
      (PEX5, then called Pxr1p). In PEX6-deficient cells, PEX5 is destabilized.
    action: KEEP_AS_NON_CORE
    reason: >-
      The observation that PEX6 is required for PEX5 stability is correct but represents an indirect
      consequence of PEX6 function in receptor recycling rather than a direct molecular activity.
      When PEX5 cannot be recycled (due to PEX6 loss), it accumulates at the membrane and is
      targeted for proteasomal degradation (polyubiquitination), leading to instability. This is
      a downstream phenotypic consequence, not a direct protein stabilization function.
    supported_by:
      - reference_id: PMID:8670792
        supporting_text: "Pxaaa1p is required for stability of the predominantly cytoplasmic PTS1 receptor, Pxr1p."
      - reference_id: PMID:35805150
        supporting_text: "cells deficient in Pex1 or Pex6 have fewer peroxisomes than wildtype cells, which was eventually attributed to pexophagy"

# ===== IPI: protein binding from PMID:16854980 =====
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:16854980
  review:
    summary: >-
      Tamura et al. (PMID:16854980) demonstrated interactions between PEX6 and PEX1 and PEX26
      through co-immunoprecipitation and functional assays. "Protein binding" is too vague.
    action: MODIFY
    reason: >-
      Per curation guidelines, "protein binding" is an uninformative term. The interactions
      described (PEX6-PEX1 and PEX6-PEX26) reflect the functional assembly of the AAA ATPase
      complex and its membrane recruitment. A more specific molecular function term is preferred.
    proposed_replacement_terms:
      - id: GO:0016887
        label: ATP hydrolysis activity
    supported_by:
      - reference_id: PMID:16854980
        supporting_text: "ATP binding in both AAA cassettes but not ATP hydrolysis in D2 of both Pex1p and Pex6p was prerequisite for Pex1p-Pex6p interaction and their peroxisomal localization."

# ===== IMP: ATP binding from PMID:16854980 =====
- term:
    id: GO:0005524
    label: ATP binding
  evidence_type: IMP
  original_reference_id: PMID:16854980
  review:
    summary: >-
      Tamura et al. (PMID:16854980) showed that Walker A mutations (K476E in D1, K750E in D2)
      abolished ATP binding and decreased interactions with PEX1 and PEX26, providing mutant
      phenotype evidence for ATP binding.
    action: ACCEPT
    reason: >-
      Core molecular function annotation. Walker A lysine mutations that abolish ATP binding
      also abolish PEX6 function, providing strong IMP evidence. PEX6 has two ATP-binding
      sites (D1 and D2 domains).
    supported_by:
      - reference_id: PMID:16854980
        supporting_text: "ATP binding in both AAA cassettes but not ATP hydrolysis in D2 of both Pex1p and Pex6p was prerequisite for Pex1p-Pex6p interaction and their peroxisomal localization."

# ===== IDA: peroxisome from PMID:11439091 =====
- term:
    id: GO:0005777
    label: peroxisome
  evidence_type: IDA
  original_reference_id: PMID:11439091
  review:
    summary: >-
      Tamura et al. (PMID:11439091) studied PEX1-PEX6 interaction in the context of peroxisome
      biogenesis disorders and showed PEX6 localization at peroxisomes through interaction
      with PEX1.
    action: ACCEPT
    reason: >-
      Peroxisome localization is a core feature of PEX6. The broader term "peroxisome"
      (GO:0005777) is a parent of "peroxisomal membrane" (GO:0005778), both of which are valid.
      PEX6 associates with peroxisomes via PEX26 anchoring.
    supported_by:
      - reference_id: PMID:11439091
        supporting_text: "Pex1p-G843D interacted with Pex6p at approx. 50% of the level of normal Pex1p, whereas Pex1p from ZS patients mostly showing non-temperature-sensitive peroxisome biogenesis hardly bound to Pex6p."

# ===== IDA: peroxisome from PMID:16854980 =====
- term:
    id: GO:0005777
    label: peroxisome
  evidence_type: IDA
  original_reference_id: PMID:16854980
  review:
    summary: >-
      Tamura et al. (PMID:16854980) showed PEX6 localization to peroxisomes in HEK293 cells,
      with PEX6 and PEX26 predominantly on peroxisomes.
    action: ACCEPT
    reason: >-
      Correct localization annotation. PEX6 localizes to peroxisomes. Duplicate with different
      reference but same term, which is valid.
    supported_by:
      - reference_id: PMID:16854980
        supporting_text: "Pex6p and Pex26p were predominantly localized on peroxisomes."

# ===== IDA: cytosol from PMID:16854980 =====
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: IDA
  original_reference_id: PMID:16854980
  review:
    summary: >-
      Tamura et al. (PMID:16854980) detected PEX6 in the cytosol in addition to peroxisomal
      membranes.
    action: ACCEPT
    reason: >-
      Correct cytosol localization. PEX6 is found in both the cytosol and on peroxisomal
      membranes. This dual localization is a core feature of PEX6 biology.
    supported_by:
      - reference_id: PMID:16854980
        supporting_text: "endogenous Pex1p was partly localized likely as a homo-oligomer in the cytoplasm, while Pex6p and Pex26p were predominantly localized on peroxisomes."

# ===== IMP: protein targeting to peroxisome from PMID:16854980 =====
- term:
    id: GO:0006625
    label: protein targeting to peroxisome
  evidence_type: IMP
  original_reference_id: PMID:16854980
  review:
    summary: >-
      Tamura et al. (PMID:16854980) showed that functional PEX6 (with intact AAA cassettes) is
      required for peroxisome-restoring activity, which involves the targeting of matrix proteins
      to peroxisomes via PEX5 recycling.
    action: ACCEPT
    reason: >-
      PEX6 is essential for protein targeting to peroxisomes by recycling the PTS1 receptor PEX5.
      Loss of PEX6 function abolishes matrix protein import (PMID:16854980, PMID:8670792). While
      receptor recycling (GO:0016562) is the more specific mechanistic annotation, protein targeting
      to peroxisome captures the broader biological consequence of PEX6 function.
    supported_by:
      - reference_id: PMID:16854980
        supporting_text: "The AAA cassettes, D1 and D2, were essential for peroxisome-restoring activity of Pex1p and Pex6p."

# ===== IMP: ATP hydrolysis from PMID:16854980 =====
- term:
    id: GO:0016887
    label: ATP hydrolysis activity
  evidence_type: IMP
  original_reference_id: PMID:16854980
  review:
    summary: >-
      Tamura et al. (PMID:16854980) performed extensive mutagenesis of Walker A (K476E, K750E)
      and Walker B (D532N, D803N) motifs in both D1 and D2 domains of PEX6, demonstrating that
      ATP binding and hydrolysis are required for biological function.
    action: ACCEPT
    reason: >-
      Strong IMP evidence for ATP hydrolysis activity. Both ATP binding (Walker A) and hydrolysis
      (Walker B) mutations in PEX6 impair function. This is the most detailed mutagenesis study
      of PEX6 ATPase activity.
    supported_by:
      - reference_id: PMID:16854980
        supporting_text: "ATP binding in both AAA cassettes but not ATP hydrolysis in D2 of both Pex1p and Pex6p was prerequisite for Pex1p-Pex6p interaction and their peroxisomal localization."

# ===== IDA: protein-containing complex binding from PMID:16854980 =====
- term:
    id: GO:0044877
    label: protein-containing complex binding
  evidence_type: IDA
  original_reference_id: PMID:16854980
  review:
    summary: >-
      Tamura et al. (PMID:16854980) demonstrated PEX6 interactions with PEX1 (forming the
      heterohexamer) and PEX26, and identified binding regions between these proteins. PEX6
      binds to protein-containing complexes (PEX1-PEX6 hexamer, PEX26 recruitment complex).
    action: ACCEPT
    reason: >-
      PEX6 does bind protein-containing complexes. The term is somewhat general but the IDA
      evidence from PMID:16854980 directly demonstrates complex binding through
      co-immunoprecipitation and binding assays.
    supported_by:
      - reference_id: PMID:16854980
        supporting_text: "We herein assigned the binding regions between human Pex1p and Pex6p and elucidated pivotal roles of the AAA cassettes, called D1 and D2 domains, in Pex1p-Pex6p interaction and peroxisome biogenesis."

references:
- 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:0000043
  title: Gene Ontology annotation based on UniProtKB/Swiss-Prot keyword mapping
  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:11439091
  title: Phenotype-genotype relationships in peroxisome biogenesis disorders of PEX1-defective
    complementation group 1 are defined by Pex1p-Pex6p interaction.
  findings:
    - statement: PEX1-PEX6 interaction strength correlates with disease severity
    - statement: PEX1 mutants that cannot bind PEX6 cause the most severe Zellweger syndrome phenotype
- id: PMID:16257970
  title: Mutations in the peroxin Pex26p responsible for peroxisome biogenesis disorders
    of complementation group 8 impair its stability, peroxisomal localization, and
    interaction with the Pex1p x Pex6p complex.
  findings:
    - statement: PEX26 disease mutations impair interaction with PEX1-PEX6 complex
    - statement: PEX26 recruits PEX1-PEX6 to peroxisomes
- id: PMID:16314507
  title: 'Shuttling mechanism of peroxisome targeting signal type 1 receptor Pex5:
    ATP-independent import and ATP-dependent export.'
  findings:
    - statement: PEX5 import into peroxisomes is ATP-independent
    - statement: PEX5 export requires ATP and is dependent on PEX1, PEX6, and PEX26
    - statement: PEX5 recycling occurs through multiple rounds
- id: PMID:16854980
  title: Dynamic and functional assembly of the AAA peroxins, Pex1p and Pex6p, and
    their membrane receptor Pex26p.
  findings:
    - statement: ATP binding in both D1 and D2 is required for PEX1-PEX6 interaction
    - statement: Walker A and B mutagenesis defines functional requirements
    - statement: PEX6 and PEX26 are predominantly peroxisomal
    - statement: PEX1 exists as homo-oligomer in cytosol and hetero-oligomer on peroxisomes
- id: PMID:19208625
  title: Properties of the ubiquitin-pex5p thiol ester conjugate.
  findings:
    - statement: Monoubiquitination of PEX5 at Cys-11 is required for ATP-dependent export
    - statement: C11K mutant PEX5 is fully functional for import and export
    - statement: Soluble Ub-PEX5 retains cargo binding capacity
- id: PMID:21362118
  title: Recruiting mechanism of the AAA peroxins, Pex1p and Pex6p, to Pex26p on the
    peroxisomal membrane.
  findings:
    - statement: PEX26 residues 33-40 required for PEX1-PEX6 recruitment to peroxisomes
    - statement: PEX6 targeting requires ATP but not ATP hydrolysis
    - statement: PEX1 targeting requires ATP hydrolysis
    - statement: ATP binding induces conformational changes in PEX1 and PEX6
- id: PMID:26593283
  title: PEX6 is Expressed in Photoreceptor Cilia and Mutated in Deafblindness with
    Enamel Dysplasia and Microcephaly.
  findings:
    - statement: PEX6 localizes to cilia of retinal photoreceptor cells
    - statement: PEX6 localizes to ameloblasts and odontoblasts in mice
    - statement: PEX6 G413V mutation causes deafblindness with enamel dysplasia
    - statement: Links peroxisome biogenesis disorders to ciliopathies
- id: PMID:29884772
  title: Peroxisomal monoubiquitinated PEX5 interacts with the AAA ATPases PEX1 and
    PEX6 and is unfolded during its dislocation into the cytosol.
  findings:
    - statement: DTM-embedded Ub-PEX5 interacts directly with both PEX1 and PEX6 via ubiquitin moiety
    - statement: PEX5 polypeptide chain is globally unfolded during ATP-dependent extraction
    - statement: Fusion of stable DHFR domain to PEX5 arrests extraction
    - statement: Ub-PEX5 is a bona fide substrate of the PEX1-PEX6 complex
- id: PMID:35805150
  title: Insights into the Structure and Function of the Pex1/Pex6 AAA-ATPase in Peroxisome
    Homeostasis.
  findings:
    - statement: PEX1-PEX6 forms heterohexameric AAA-ATPase
    - statement: Functions in receptor recycling and prevention of pexophagy
    - statement: Unfolds substrates by processive threading through central pore
    - statement: PEX1/PEX6 mutations are most common cause of PBDs
- id: PMID:8670792
  title: The peroxisome biogenesis disorder group 4 gene, PXAAA1, encodes a cytoplasmic
    ATPase required for stability of the PTS1 receptor.
  findings:
    - statement: PEX6 (PXAAA1) is the CG4 PBD gene
    - statement: PEX6 is predominantly cytoplasmic
    - statement: Walker A lysine mutation abolishes biological activity
    - statement: PEX6 required for PEX5 (PTS1 receptor) stability
    - statement: Expression restores peroxisomal protein import in CG4 cells
- id: PMID:8940266
  title: 'Human peroxisome assembly factor-2 (PAF-2): a gene responsible for group
    C peroxisome biogenesis disorder in humans.'
  findings:
    - statement: Human PAF-2 (PEX6) cDNA restores peroxisomes in group C Zellweger cells
    - statement: Two pathogenic mutations identified
    - statement: Gene located on chromosome 6p21.1
- id: PMID:9588209
  title: A cytoplasmic AAA family peroxin, Pex1p, interacts with Pex6p.
  findings:
    - statement: PEX1 and PEX6 interact with each other by co-immunoprecipitation
    - statement: PEX1 is localized in the cytoplasm
- id: Reactome:R-HSA-9033499
  title: PEX1:PEX6:PEX26:ZFAND6 dissociates Ub:PEX5L and PEX7 from PEX14:PEX13:PEX2:PEX10:PEX12
    and translocates PEX5L and PEX7 from the peroxisomal membrane to the cytosol
  findings: []
- id: Reactome:R-HSA-9033516
  title: PEX2:PEX10:PEX12:Ub:PEX5L:PEX7:PEX13:PEX14 binds PEX1:PEX6:PEX26 and ZFAND6
  findings: []
- id: Reactome:R-HSA-9033533
  title: PEX2:PEX10:PEX12:Ub:PEX5S,L:PEX13:PEX14 binds PEX1:PEX6:PEX26 and ZFAND6
  findings: []