id: O43933
gene_symbol: PEX1
product_type: PROTEIN
status: IN_PROGRESS
taxon:
  id: NCBITaxon:9606
  label: Homo sapiens
description: >-
  PEX1 is a peroxisomal AAA+ ATPase that forms a heterohexameric complex with PEX6,
  anchored to the peroxisomal membrane by PEX26. It is a core component of the receptor
  export module (REM) that mediates ATP-dependent extraction and recycling of the
  monoubiquitinated PTS1 receptor PEX5 from the peroxisomal docking/translocation module
  (DTM). PEX1 specifically recognizes PEX5 monoubiquitinated at Cys-11 through its
  ubiquitin moiety and unfolds PEX5 by processive threading through the central pore
  of the PEX1-PEX6 hexamer. PEX1 also exists as a homo-oligomer in the cytosol, which
  dissociates upon PEX6 binding. PEX1 is the most commonly mutated gene in Zellweger
  spectrum disorders, accounting for approximately 65% of cases. Mutations cause a
  spectrum of peroxisome biogenesis disorders from severe Zellweger syndrome to mild
  Heimler syndrome.
alternative_products:
- name: '1'
  id: O43933-1
- name: '2'
  id: O43933-2
  sequence_note: VSP_057136
existing_annotations:
# ===== IBA ANNOTATIONS =====
- term:
    id: GO:0016887
    label: ATP hydrolysis activity
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  review:
    summary: >-
      PEX1 is a well-established AAA+ ATPase with demonstrated ATP hydrolysis activity.
      UniProt records catalytic activity (EC 3.6.4.-) with experimental evidence from
      PMID:16854980. Walker motif mutagenesis (K605E, D662N, K887E, D940N) confirmed
      that both D1 and D2 AAA cassettes are functional ATPase domains.
    action: ACCEPT
    reason: >-
      ATP hydrolysis is a core molecular function of PEX1. IBA annotation is well-supported
      by phylogenetic conservation and direct experimental evidence showing that Walker motif
      mutations abolish ATP binding and hydrolysis (PMID:16854980, PMID:21362118).
    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:21362118
        supporting_text: "Pex1p is targeted to peroxisomes in a manner dependent on ATP hydrolysis"

- term:
    id: GO:0016558
    label: protein import into peroxisome matrix
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  review:
    summary: >-
      PEX1 is essential for peroxisomal matrix protein import. Loss of PEX1 function
      results in severe defects in matrix protein import (PMID:9398847). PEX1 specifically
      functions at the receptor recycling step, which is required for continuous import
      cycles (PMID:16314507, PMID:29884772).
    action: ACCEPT
    reason: >-
      Protein import into peroxisome matrix is a core biological process for PEX1. Although
      PEX1 acts specifically at the receptor recycling step rather than the import step per
      se, the broader term is appropriate since PEX1 is absolutely required for sustained
      import. IBA annotation is phylogenetically sound and well-supported experimentally.
    supported_by:
      - reference_id: PMID:9398847
        supporting_text: "Expression of human PEX1 restored peroxisomal protein import in fibroblasts from 30 CG1 patients"
      - reference_id: PMID:16314507
        supporting_text: "Pex1 and Pex6 of the AAA ATPase family and their recruiter, Pex26, were essential for Pex5 export"

- term:
    id: GO:0043335
    label: protein unfolding
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  review:
    summary: >-
      PEX1/PEX6 unfolds PEX5 during ATP-dependent extraction from the peroxisomal membrane.
      Pedrosa et al. (PMID:29884772) showed that the PEX5 polypeptide chain is globally
      unfolded during the dislocation event, and that fusing a stabilized DHFR domain to
      PEX5 arrests export. The PEX1-PEX6 hexamer processes substrates by processive
      threading through its central pore (PMID:35805150).
    action: ACCEPT
    reason: >-
      Protein unfolding is a core mechanistic activity of PEX1 as part of the PEX1-PEX6
      AAA ATPase complex. IBA annotation is consistent with direct experimental evidence
      showing global unfolding of PEX5 during extraction.
    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: >-
      PEX1 localizes to the peroxisomal membrane where it performs its receptor recycling
      function. It is recruited to peroxisomes via PEX26 in complex with PEX6 (PMID:16854980,
      PMID:21362118). Multiple studies confirm peroxisomal membrane localization.
    action: ACCEPT
    reason: >-
      Peroxisomal membrane is a core localization for PEX1 where it carries out its primary
      function. Well-supported by IBA and multiple experimental studies.
    supported_by:
      - reference_id: PMID:16854980
        supporting_text: "endogenous Pex1p was partly localized likely as a homo-oligomer in the cytoplasm"
      - 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: >-
      PEX1 is found in the cytosol as a homo-oligomer that dissociates upon interaction
      with PEX6 (PMID:16854980). UniProt confirms cytosol localization with experimental
      evidence.
    action: ACCEPT
    reason: >-
      Cytosol is a well-established localization for PEX1. The protein exists in two pools:
      a cytosolic homo-oligomeric form and a peroxisome membrane-associated heterohexamer
      with PEX6.
    supported_by:
      - reference_id: PMID:16854980
        supporting_text: "endogenous Pex1p was partly localized likely as a homo-oligomer in the cytoplasm"

# ===== IEA ANNOTATIONS =====
- term:
    id: GO:0000166
    label: nucleotide binding
  evidence_type: IEA
  original_reference_id: GO_REF:0000043
  review:
    summary: >-
      PEX1 contains two AAA cassettes (D1 and D2) each with Walker A and B motifs for
      nucleotide binding. UniProt annotates ATP binding sites at positions 599-606 and
      881-888. This IEA annotation is more general than the IBA/IMP annotations for
      ATP binding.
    action: ACCEPT
    reason: >-
      Nucleotide binding is a parent term of ATP binding and is correct for PEX1. While
      more specific terms exist (ATP binding), this IEA annotation based on keyword mapping
      is not incorrect and is acceptable as a broader electronic annotation.

- term:
    id: GO:0005524
    label: ATP binding
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  review:
    summary: >-
      PEX1 binds ATP via its two AAA cassettes. ATP binding is required for PEX1-PEX6
      interaction and peroxisomal localization (PMID:16854980). Walker A mutants (K605E,
      K887E) abolish ATP binding.
    action: ACCEPT
    reason: >-
      ATP binding is a core molecular function of PEX1. This IEA annotation is consistent
      with experimental 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"

- term:
    id: GO:0005777
    label: peroxisome
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  review:
    summary: >-
      PEX1 is associated with peroxisomes, specifically the peroxisomal membrane. This
      IEA annotation is broader than the more specific peroxisomal membrane annotation
      but is not incorrect.
    action: ACCEPT
    reason: >-
      Peroxisome localization is correct for PEX1. This is a broader term than peroxisomal
      membrane but acceptable as an electronic annotation consistent with experimental data.

- 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. PEX1 is recruited to the
      peroxisomal membrane by PEX26 in complex with PEX6.
    action: ACCEPT
    reason: >-
      Peroxisomal membrane localization is well-established for PEX1. This IEA annotation
      is consistent with IBA and multiple experimental annotations.

- term:
    id: GO:0005829
    label: cytosol
  evidence_type: IEA
  original_reference_id: GO_REF:0000044
  review:
    summary: >-
      PEX1 is found in the cytosol as a homo-oligomer. This IEA annotation from UniProt
      subcellular location mapping is consistent with IBA and experimental evidence.
    action: ACCEPT
    reason: >-
      Cytosol localization is well-established for PEX1. Consistent with the IBA annotation
      and direct experimental evidence.

- term:
    id: GO:0007031
    label: peroxisome organization
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  review:
    summary: >-
      PEX1 is essential for peroxisome biogenesis and organization. Loss of PEX1 leads
      to reduced peroxisome abundance and enlarged remnant peroxisomes (PMID:16449325).
      PEX1 mutations cause a spectrum of peroxisome biogenesis disorders.
    action: ACCEPT
    reason: >-
      Peroxisome organization is a consequence of PEX1 function in receptor recycling.
      This IEA annotation is consistent with the IMP annotation from PMID:11439091.

- term:
    id: GO:0015031
    label: protein transport
  evidence_type: IEA
  original_reference_id: GO_REF:0000043
  review:
    summary: >-
      PEX1 is involved in protein transport, specifically the recycling of the PEX5
      receptor. This term is very broad; more specific terms exist (protein import into
      peroxisome matrix, receptor recycling).
    action: ACCEPT
    reason: >-
      Protein transport is a valid parent term. While more specific annotations exist,
      this IEA annotation from keyword mapping is not incorrect and is acceptable.

- term:
    id: GO:0016787
    label: hydrolase activity
  evidence_type: IEA
  original_reference_id: GO_REF:0000043
  review:
    summary: >-
      PEX1 has ATPase (hydrolase) activity. This is a very broad term; more specific terms
      (ATP hydrolysis activity) are available.
    action: ACCEPT
    reason: >-
      Hydrolase activity is a parent term of ATP hydrolysis activity and is technically
      correct. While very general, this IEA annotation from keyword mapping is acceptable.

- term:
    id: GO:0016887
    label: ATP hydrolysis activity
  evidence_type: IEA
  original_reference_id: GO_REF:0000002
  review:
    summary: >-
      PEX1 has ATP hydrolysis activity via its two AAA cassettes. This IEA annotation from
      InterPro mapping is consistent with IBA and IMP evidence.
    action: ACCEPT
    reason: >-
      ATP hydrolysis activity is a core function of PEX1. This IEA annotation is consistent
      with the IBA and IMP annotations.

- term:
    id: GO:0044877
    label: protein-containing complex binding
  evidence_type: IEA
  original_reference_id: GO_REF:0000117
  review:
    summary: >-
      PEX1 binds protein-containing complexes, particularly the PEX5-PEX14 DTM complex
      and the PEX6-PEX26 complex. This term is somewhat vague but captures the interaction
      of PEX1 with the DTM complex on the peroxisomal membrane.
    action: ACCEPT
    reason: >-
      PEX1 does interact with protein-containing complexes (DTM, PEX1-PEX6-PEX26 complex).
      This IEA annotation from ARBA is consistent with the IDA annotation from PMID:16854980.

# ===== IPI ANNOTATIONS (protein binding) =====
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:32814053
  review:
    summary: >-
      PMID:32814053 is a large-scale interactome mapping study of neurodegenerative disease
      proteins. PEX1 was identified as an interactor in this high-throughput screen. The
      term protein binding is uninformative.
    action: REMOVE
    reason: >-
      Protein binding is uninformative per curation guidelines. This annotation from a
      large-scale interactome screen does not provide specific mechanistic insight into
      PEX1 function. PEX1 interactions are better captured by more specific terms.
    supported_by:
      - reference_id: PMID:32814053
        supporting_text: "an interactome map that focuses on neurodegenerative disease (ND), connects ∼5,000 human proteins via ∼30,000 candidate interactions and is generated by systematic yeast two-hybrid interaction screening of ∼500 ND-related proteins and integration of literature interactions"

- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:9588209
  review:
    summary: >-
      PMID:9588209 demonstrated PEX1-PEX6 interaction by co-immunoprecipitation. While
      the interaction is real and important, the term protein binding is uninformative.
      The PEX1-PEX6 interaction is better captured by the heterohexameric complex formation
      and the specific molecular functions that depend on it.
    action: REMOVE
    reason: >-
      Protein binding is uninformative per curation guidelines. The PEX1-PEX6 interaction
      demonstrated in PMID:9588209 is well-established but better represented by more
      specific functional annotations.
    supported_by:
      - reference_id: PMID:9588209
        supporting_text: "Immunoprecipitation of Pex1p using anti-Pex1p antibody resulted in concomitant recovery of 35S-Pex6p"

# ===== IDA/NAS ANNOTATIONS =====
- term:
    id: GO:0005777
    label: peroxisome
  evidence_type: IDA
  original_reference_id: GO_REF:0000052
  review:
    summary: >-
      Peroxisome localization based on curation of immunofluorescence data (HPA). PEX1
      is found at peroxisomes, specifically the peroxisomal membrane.
    action: ACCEPT
    reason: >-
      Peroxisome localization is well-established for PEX1. The IDA from immunofluorescence
      data is consistent with other evidence.

- term:
    id: GO:0005778
    label: peroxisomal membrane
  evidence_type: NAS
  original_reference_id: PMID:35805150
  review:
    summary: >-
      PMID:35805150 is a comprehensive review article on Pex1/Pex6 structure and function.
      It summarizes that PEX1/PEX6 is recruited to the peroxisomal membrane by PEX26.
    action: ACCEPT
    reason: >-
      Peroxisomal membrane localization is well-supported. While this specific annotation
      uses NAS from a review, the localization is confirmed by multiple IDA studies.
    supported_by:
      - reference_id: PMID:35805150
        supporting_text: "Pex15 in S. cerevisiae or PEX26 in other organisms—that recruits Pex1/Pex6 to the peroxisome membrane"

- term:
    id: GO:0016562
    label: protein import into peroxisome matrix, receptor recycling
  evidence_type: NAS
  original_reference_id: PMID:35805150
  review:
    summary: >-
      PMID:35805150 reviews the role of PEX1/PEX6 in receptor recycling, describing how
      the complex extracts monoubiquitinated PEX5 from the peroxisomal membrane. This is
      the canonical role of PEX1.
    action: ACCEPT
    reason: >-
      Receptor recycling is the primary biological process for PEX1. This NAS annotation
      from a comprehensive review is well-supported and consistent with multiple IDA
      annotations.
    supported_by:
      - reference_id: PMID:35805150
        supporting_text: "Receptor recycling remains the canonical role for Pex1/Pex6 across eukaryotes"

- term:
    id: GO:0005778
    label: peroxisomal membrane
  evidence_type: IDA
  original_reference_id: PMID:21362118
  review:
    summary: >-
      Nashiro et al. (PMID:21362118) studied the recruiting mechanism of PEX1 and PEX6
      to PEX26 on the peroxisomal membrane. They showed PEX1 targeting to peroxisomes
      is ATP hydrolysis-dependent and temperature-dependent.
    action: ACCEPT
    reason: >-
      Direct experimental evidence for peroxisomal membrane localization of PEX1, showing
      the mechanism of recruitment via PEX26.
    supported_by:
      - reference_id: PMID:21362118
        supporting_text: "Pex1p is targeted to peroxisomes in a manner dependent on ATP hydrolysis, while Pex6p targeting requires ATP but not its hydrolysis"

- 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 recruitment to peroxisomes
      via PEX26 is essential for receptor recycling. The study used in vitro transport
      assays and Walker-motif mutants to show that ATP hydrolysis by PEX1 is required
      for stable peroxisomal localization.
    action: ACCEPT
    reason: >-
      Receptor recycling is the core biological process for PEX1. Direct experimental
      evidence from in vitro transport assays.
    supported_by:
      - reference_id: PMID:21362118
        supporting_text: "peroxisomal localization of Pex1p and Pex6p is indispensable for the transport of matrix proteins"

- 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) provided direct evidence that monoubiquitinated PEX5
      (Ub-PEX5) is a bona fide substrate of the PEX1-PEX6 complex. Using cell-free in
      vitro assays, they showed Ub-PEX5 interacts directly with PEX1 and PEX6 and is
      extracted from the DTM in an ATP-dependent manner.
    action: ACCEPT
    reason: >-
      Key experimental evidence demonstrating that PEX1 directly participates in receptor
      recycling by extracting Ub-PEX5 from the DTM.
    supported_by:
      - reference_id: PMID:29884772
        supporting_text: "DTM-embedded Ub-PEX5 interacts directly with both PEX1 and PEX6 through its ubiquitin moiety"
      - reference_id: PMID:29884772
        supporting_text: "These findings strongly suggest that DTM-embedded Ub-PEX5 is a bona fide substrate of the PEX1-PEX6 complex"

- term:
    id: GO:0043335
    label: protein unfolding
  evidence_type: IDA
  original_reference_id: PMID:29884772
  review:
    summary: >-
      Pedrosa et al. (PMID:29884772) demonstrated that PEX5 is globally unfolded during
      ATP-dependent extraction from the peroxisomal membrane by the PEX1-PEX6 complex.
      PEX5 cysteine residues located far apart become exposed during dislocation, and
      fusing DHFR to PEX5 arrests export when DHFR is stabilized.
    action: ACCEPT
    reason: >-
      Protein unfolding is a core mechanistic activity of PEX1 as demonstrated by direct
      experimental evidence. The PEX1-PEX6 complex unfolds its substrate PEX5 during
      extraction.
    supported_by:
      - reference_id: PMID:29884772
        supporting_text: "the PEX5 polypeptide chain is globally unfolded during the ATP-dependent extraction event"
      - 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"

- 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) showed that the PEX1-PEX6 complex recognizes
      monoubiquitinated PEX5 (Ub-PEX5) through its ubiquitin moiety. Photocross-linking
      experiments demonstrated that DTM-embedded Ub-PEX5 interacts directly with both
      PEX1 and PEX6.
    action: ACCEPT
    reason: >-
      Ubiquitin-modified protein reader activity is a core molecular function of PEX1.
      The PEX1-PEX6 complex specifically recognizes Ub-PEX5 through its ubiquitin moiety,
      which is essential for substrate engagement and extraction.
    supported_by:
      - reference_id: PMID:29884772
        supporting_text: "DTM-embedded Ub-PEX5 interacts directly with both PEX1 and PEX6 through its ubiquitin moiety"

- term:
    id: GO:0140318
    label: protein transporter activity
  evidence_type: IDA
  original_reference_id: PMID:21362118
  review:
    summary: >-
      Nashiro et al. (PMID:21362118) demonstrated that PEX1 functions as part of the
      receptor export module (REM) that transports PEX5 from the peroxisomal membrane
      to the cytosol. This annotation captures the protein dislocase/transporter activity
      of the PEX1-PEX6 complex.
    action: ACCEPT
    reason: >-
      Protein transporter activity is an appropriate molecular function term for PEX1. The
      PEX1-PEX6 complex actively transports (dislocates) PEX5 from the peroxisomal membrane
      to the cytosol.
    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"

- term:
    id: GO:0140318
    label: protein transporter activity
  evidence_type: IDA
  original_reference_id: PMID:29884772
  review:
    summary: >-
      Pedrosa et al. (PMID:29884772) demonstrated that the PEX1-PEX6 complex extracts
      Ub-PEX5 from the peroxisomal DTM into the cytosol, consistent with protein
      transporter activity.
    action: ACCEPT
    reason: >-
      Consistent with the other protein transporter activity annotation. PEX1 functions
      as a protein dislocase that extracts PEX5 from the membrane.
    supported_by:
      - reference_id: PMID:29884772
        supporting_text: "Their role is to extract monoubiquitinated PEX5, the peroxisomal protein-shuttling receptor, from the peroxisomal membrane docking/translocation module (DTM)"

- 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
      complex and showed that both AAA cassettes are essential for peroxisome-restoring
      activity, which depends on receptor recycling.
    action: ACCEPT
    reason: >-
      Receptor recycling is the primary function of PEX1. This study provided key
      mechanistic insights into how PEX1 assembles with PEX6 and PEX26 to carry out
      this 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"

- 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) characterized the ubiquitin-PEX5 thiol ester conjugate
      and showed that monoubiquitination is required for ATP-dependent export of PEX5,
      which is the receptor recycling step mediated by PEX1-PEX6.
    action: ACCEPT
    reason: >-
      This study provides evidence that the PEX1-PEX6 mediated export step requires
      monoubiquitination of PEX5, consistent with PEX1 function in receptor recycling.
    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"

- 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 at Cys-11 is
      essential for ATP-dependent export, implicating the PEX1-PEX6 complex as a reader
      of ubiquitin-modified PEX5. The study demonstrated that the C11K mutant (producing
      isopeptide-linked ubiquitin) is functional.
    action: ACCEPT
    reason: >-
      This annotation is consistent with PEX1 recognizing monoubiquitinated PEX5. The
      requirement for ubiquitination before ATP-dependent export supports PEX1 as a
      ubiquitin reader.
    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"

- term:
    id: GO:0043335
    label: protein unfolding
  evidence_type: IDA
  original_reference_id: PMID:16854980
  review:
    summary: >-
      Tamura et al. (PMID:16854980) showed that PEX1-PEX6 interaction involves
      conformational changes and dissociation of PEX1 homo-oligomers. While this paper
      demonstrates conformational changes, the direct evidence for substrate unfolding
      by PEX1-PEX6 came from later work (PMID:29884772).
    action: ACCEPT
    reason: >-
      While the primary evidence for protein unfolding came from PMID:29884772, this
      annotation from PMID:16854980 is consistent with the protein unfolding function,
      as the conformational changes described are part of the PEX1 mechanistic cycle.
    supported_by:
      - reference_id: PMID:16854980
        supporting_text: "Interaction of Pex1p with Pex6p conferred a conformational change and dissociation of the Pex1p oligomer"

- term:
    id: GO:0140318
    label: protein transporter activity
  evidence_type: IDA
  original_reference_id: PMID:16854980
  review:
    summary: >-
      Tamura et al. (PMID:16854980) demonstrated the assembly and function of PEX1-PEX6
      complex with PEX26, showing that this complex is essential for peroxisome biogenesis,
      specifically the transport/extraction of PEX5 from the membrane.
    action: ACCEPT
    reason: >-
      Protein transporter activity is appropriate for PEX1 as it functions in extracting
      PEX5 from the peroxisomal membrane.
    supported_by:
      - reference_id: PMID:16854980
        supporting_text: "Pex26p, the recruiter of Pex1p.Pex6p complexes to peroxisomes"

- 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 a cell-free PEX5 translocation system
      and showed that PEX1, PEX6, and PEX26 are essential for ATP-dependent PEX5 export
      from peroxisomes. PEX5 was imported into peroxisome remnants of PEX1-defective cells
      but could not be exported.
    action: ACCEPT
    reason: >-
      This study directly demonstrated that PEX1 is required for PEX5 export/receptor
      recycling, a core function of PEX1.
    supported_by:
      - reference_id: PMID:16314507
        supporting_text: "(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"

# ===== TAS/Reactome annotations =====
- 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 activity in
      dissociating Ub:PEX5L from the DTM and translocating PEX5L to the cytosol. PEX1
      is present in the cytosol as part of this pathway.
    action: ACCEPT
    reason: >-
      Cytosol localization is well-established for PEX1. Reactome pathway is consistent
      with known biology.

- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-9033516
  review:
    summary: >-
      Reactome pathway annotation for PEX1:PEX6:PEX26 complex binding to the DTM complex.
      PEX1 participates in this reaction in the cytosol/at the peroxisomal membrane.
    action: ACCEPT
    reason: >-
      Duplicate cytosol annotation from Reactome. Consistent with known PEX1 biology.

- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-9033533
  review:
    summary: >-
      Another Reactome pathway annotation for PEX1:PEX6:PEX26 complex binding.
    action: ACCEPT
    reason: >-
      Duplicate cytosol annotation from Reactome. Consistent with known PEX1 biology.

# ===== HDA annotations =====
- term:
    id: GO:0070062
    label: extracellular exosome
  evidence_type: HDA
  original_reference_id: PMID:18570454
  review:
    summary: >-
      PMID:18570454 is a proteomic analysis of exosomes from human neural stem cells.
      PEX1 was identified in exosome fractions by mass spectrometry. PEX1 is not known
      to have any function related to exosomes; this is likely a contaminant or
      incidental finding from a high-throughput proteomics study.
    action: MARK_AS_OVER_ANNOTATED
    reason: >-
      PEX1 is a peroxisomal/cytosolic protein with no known function in exosomes. Detection
      in exosome fractions by mass spectrometry in a high-throughput study likely represents
      contamination or incidental incorporation rather than a biologically meaningful
      localization.
    supported_by:
      - reference_id: PMID:18570454
        supporting_text: "Exosomal lysates of each fraction were digested and analyzed using nanoflow LC-ESI-MS-MS for protein identification"

- term:
    id: GO:0005778
    label: peroxisomal membrane
  evidence_type: HDA
  original_reference_id: PMID:21525035
  review:
    summary: >-
      Bharti et al. (PMID:21525035) identified PEX1 as a constituent of PEX14 complexes
      at the peroxisomal membrane by mass spectrometry. This is consistent with PEX1
      localization to the peroxisomal membrane as part of the import/export machinery.
    action: ACCEPT
    reason: >-
      Peroxisomal membrane localization confirmed by mass spectrometric analysis of PEX14
      complexes. Consistent with known biology of PEX1 functioning at the peroxisomal
      membrane.
    supported_by:
      - reference_id: PMID:21525035
        supporting_text: "almost all known human peroxins involved in protein import were identified as constituents of the PEX14 complexes"

# ===== More IPI protein binding =====
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:16257970
  review:
    summary: >-
      Furuki et al. (PMID:16257970) studied PEX26 mutations and showed that PEX26 interacts
      with the PEX1-PEX6 complex. This study demonstrates PEX1-PEX26 interaction (indirect,
      via PEX6).
    action: REMOVE
    reason: >-
      Protein binding is uninformative per curation guidelines. The interaction between
      PEX1 and PEX26 (indirect, via PEX6) is better captured by the functional annotations
      describing the PEX1-PEX6-PEX26 receptor export module.
    supported_by:
      - reference_id: PMID:16257970
        supporting_text: "Pex26p functions in recruiting to peroxisomes the complexes of the AAA ATPase peroxins, Pex1p and Pex6p"

# ===== IMP/IDA annotations =====
- term:
    id: GO:0016558
    label: protein import into peroxisome matrix
  evidence_type: IMP
  original_reference_id: PMID:9398847
  review:
    summary: >-
      Reuber et al. (PMID:9398847) identified PEX1 as the most commonly mutated gene in
      peroxisome biogenesis disorders and showed that PEX1 expression restored peroxisomal
      protein import in CG1 patient fibroblasts. PEX1-deficient cells had severe defects
      in peroxisomal matrix protein import.
    action: ACCEPT
    reason: >-
      This foundational study demonstrated that PEX1 is required for peroxisomal matrix
      protein import. The IMP evidence from complementation of patient cells is strong.
    supported_by:
      - reference_id: PMID:9398847
        supporting_text: "Expression of human PEX1 restored peroxisomal protein import in fibroblasts from 30 CG1 patients"
      - reference_id: PMID:9398847
        supporting_text: "PEX1-deficient cells revealed severe defects in peroxisomal matrix protein import"

- term:
    id: GO:0005737
    label: cytoplasm
  evidence_type: IDA
  original_reference_id: PMID:9588209
  review:
    summary: >-
      Tamura et al. (PMID:9588209) showed by immunofluorescent microscopy that
      flag-tagged PEX1 expressed in CHO-K1 cells was localized in the cytoplasm.
    action: ACCEPT
    reason: >-
      Cytoplasm localization is correct. PEX1 exists in the cytoplasm as a homo-oligomer
      and is recruited to peroxisomes. This is a broader term than cytosol but is consistent
      with the experimental observation by immunofluorescence.
    supported_by:
      - reference_id: PMID:9588209
        supporting_text: "Pex1p was localized in the cytoplasm, as assessed by immunofluorescent microscopy"

- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:16854980
  review:
    summary: >-
      Tamura et al. (PMID:16854980) demonstrated PEX1-PEX6 interaction and mapped the
      binding regions. While the interaction is important, the term protein binding is
      uninformative.
    action: REMOVE
    reason: >-
      Protein binding is uninformative per curation guidelines. The PEX1-PEX6 interaction
      is better represented by the specific functional annotations describing the PEX1-PEX6
      AAA ATPase complex activities.
    supported_by:
      - reference_id: PMID:16854980
        supporting_text: "We herein assigned the binding regions between human Pex1p and Pex6p"

- 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 (K605E, K887E)
      abolish ATP binding in the D1 and D2 cassettes respectively, demonstrating that
      PEX1 binds ATP and that this binding is essential for function.
    action: ACCEPT
    reason: >-
      ATP binding is a core molecular function of PEX1. IMP evidence from Walker A
      mutants is strong.
    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:0005777
    label: peroxisome
  evidence_type: IDA
  original_reference_id: PMID:16854980
  review:
    summary: >-
      Tamura et al. (PMID:16854980) showed that endogenous PEX1 localizes to peroxisomes
      (and cytoplasm) in HEK293 cells.
    action: ACCEPT
    reason: >-
      Peroxisome localization is well-established for PEX1. Direct 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"

- term:
    id: GO:0005778
    label: peroxisomal membrane
  evidence_type: IDA
  original_reference_id: PMID:11439091
  review:
    summary: >-
      Tamura et al. (PMID:11439091) studied PEX1-PEX6 interaction and showed that PEX1
      localizes to the peroxisomal membrane. The study demonstrated that PEX1 disease
      mutants have impaired PEX6 binding, which affects peroxisomal localization.
    action: ACCEPT
    reason: >-
      Peroxisomal membrane localization is a core localization for PEX1. The study provides
      evidence that PEX1-PEX6 interaction is required for proper localization.
    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"

- term:
    id: GO:0005829
    label: cytosol
  evidence_type: IDA
  original_reference_id: PMID:16854980
  review:
    summary: >-
      Tamura et al. (PMID:16854980) showed that endogenous PEX1 is partly localized as
      a homo-oligomer in the cytoplasm/cytosol.
    action: ACCEPT
    reason: >-
      Cytosol localization is well-established for PEX1. Direct experimental evidence from
      subcellular fractionation and immunofluorescence.
    supported_by:
      - reference_id: PMID:16854980
        supporting_text: "endogenous Pex1p was partly localized likely as a homo-oligomer in the cytoplasm"

- term:
    id: GO:0006625
    label: protein targeting to peroxisome
  evidence_type: IMP
  original_reference_id: PMID:11439091
  review:
    summary: >-
      Tamura et al. (PMID:11439091) demonstrated that PEX1 mutations cause defective
      peroxisome biogenesis, including impaired protein targeting to peroxisomes.
      Temperature-sensitive PEX1 mutants showed reduced protein targeting at 37C but
      improved targeting at permissive temperatures.
    action: ACCEPT
    reason: >-
      Protein targeting to peroxisome is a consequence of PEX1 function in receptor
      recycling. Loss of PEX1 impairs PEX5 recycling which prevents ongoing matrix
      protein targeting. This is a core process for PEX1.
    supported_by:
      - reference_id: PMID:11439091
        supporting_text: "temperature-sensitive peroxisome assembly is responsible for the mildness of the clinical features of IRD"

- 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 Walker motif mutations in PEX1 impair
      peroxisome-restoring activity, demonstrating that PEX1 ATPase activity is required
      for protein targeting to peroxisomes.
    action: ACCEPT
    reason: >-
      Consistent with other annotations. PEX1 ATPase activity is essential for sustained
      protein targeting to peroxisomes via receptor 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"

- term:
    id: GO:0007031
    label: peroxisome organization
  evidence_type: IMP
  original_reference_id: PMID:11439091
  review:
    summary: >-
      Tamura et al. (PMID:11439091) showed that PEX1 mutations lead to impaired peroxisome
      biogenesis/organization, with the severity correlating with the degree of PEX1-PEX6
      interaction impairment.
    action: ACCEPT
    reason: >-
      Peroxisome organization is a downstream consequence of PEX1 function. Loss of PEX1
      leads to peroxisome biogenesis disorders with reduced peroxisome abundance and function.
    supported_by:
      - reference_id: PMID:11439091
        supporting_text: "Failure in Pex1p-Pex6p interaction gives rise to more severe abnormalities, such as those manifested by patients with ZS"

- term:
    id: GO:0016887
    label: ATP hydrolysis activity
  evidence_type: IMP
  original_reference_id: PMID:16854980
  review:
    summary: >-
      Tamura et al. (PMID:16854980) demonstrated PEX1 ATPase activity through Walker B
      mutations (D662N, D940N) that abolish ATP hydrolysis. UniProt assigns EC 3.6.4.-
      based on this reference.
    action: ACCEPT
    reason: >-
      ATP hydrolysis is a core molecular function of PEX1. IMP evidence from Walker B
      mutants directly demonstrates 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"

- term:
    id: GO:0044877
    label: protein-containing complex binding
  evidence_type: IDA
  original_reference_id: PMID:16854980
  review:
    summary: >-
      Tamura et al. (PMID:16854980) showed that PEX1 interacts with PEX6 to form a
      heterohexameric complex, and this complex interacts with PEX26 on the peroxisomal
      membrane. The term captures PEX1 binding to the PEX6-PEX26 complex.
    action: ACCEPT
    reason: >-
      PEX1 does bind protein-containing complexes, particularly the PEX6-PEX26 complex
      and the DTM. While somewhat vague, this annotation captures a real and important
      aspect of PEX1 function.
    supported_by:
      - reference_id: PMID:16854980
        supporting_text: "Pex26p, the recruiter of Pex1p.Pex6p complexes to peroxisomes"

- term:
    id: GO:0060152
    label: microtubule-based peroxisome localization
  evidence_type: IMP
  original_reference_id: PMID:16449325
  review:
    summary: >-
      Nguyen et al. (PMID:16449325) showed that PEX1-null cells have peroxisomal remnants
      that exhibit clustering and loss of alignment along peripheral microtubules. However,
      this is an indirect consequence of peroxisome dysfunction rather than a direct role
      of PEX1 in microtubule-based peroxisome localization. The defect is shared with
      other peroxisome biogenesis disorders and D-BP deficiency.
    action: KEEP_AS_NON_CORE
    reason: >-
      The defect in microtubule-based peroxisome localization in PEX1-null cells is a
      secondary consequence of impaired peroxisome biogenesis rather than a direct function
      of PEX1. Nguyen et al. showed similar defects in D-BP deficiency (a single-enzyme
      defect), suggesting this is a general consequence of peroxisome dysfunction rather
      than specific to PEX1. PEX14, not PEX1, was later shown to be the actual mediator
      of peroxisome-microtubule interaction (PMID:21525035).
    supported_by:
      - reference_id: PMID:16449325
        supporting_text: "remnant peroxisomes in fibroblasts from patients with PEX1-null Zellweger syndrome or D-BP deficiency exhibited clustering and loss of alignment along peripheral microtubules"
      - reference_id: PMID:21525035
        supporting_text: "human PEX14 is a multi-tasking protein that not only facilitates peroxisomal protein import but is also required for peroxisome motility by serving as membrane anchor for microtubules"

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: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: []
- 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: []
- id: PMID:16314507
  title: 'Shuttling mechanism of peroxisome targeting signal type 1 receptor Pex5:
    ATP-independent import and ATP-dependent export.'
  findings: []
- id: PMID:16449325
  title: Failure of microtubule-mediated peroxisome division and trafficking in disorders
    with reduced peroxisome abundance.
  findings: []
- id: PMID:16854980
  title: Dynamic and functional assembly of the AAA peroxins, Pex1p and Pex6p, and
    their membrane receptor Pex26p.
  findings: []
- id: PMID:18570454
  title: Proteomic analysis of exosomes from human neural stem cells by flow field-flow
    fractionation and nanoflow liquid chromatography-tandem mass spectrometry.
  findings: []
- id: PMID:19208625
  title: Properties of the ubiquitin-pex5p thiol ester conjugate.
  findings: []
- id: PMID:21362118
  title: Recruiting mechanism of the AAA peroxins, Pex1p and Pex6p, to Pex26p on the
    peroxisomal membrane.
  findings: []
- id: PMID:21525035
  title: PEX14 is required for microtubule-based peroxisome motility in human cells.
  findings: []
- 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: []
- id: PMID:32814053
  title: Interactome Mapping Provides a Network of Neurodegenerative Disease Proteins
    and Uncovers Widespread Protein Aggregation in Affected Brains.
  findings: []
- id: PMID:35805150
  title: Insights into the Structure and Function of the Pex1/Pex6 AAA-ATPase in Peroxisome
    Homeostasis.
  findings: []
- id: PMID:9398847
  title: Mutations in PEX1 are the most common cause of peroxisome biogenesis disorders.
  findings: []
- id: PMID:9588209
  title: A cytoplasmic AAA family peroxin, Pex1p, interacts with Pex6p.
  findings: []
- 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: []

core_functions:
- description: >-
    PEX1 is an AAA+ ATPase that functions as part of the receptor export module (REM).
    It forms a heterohexameric complex with PEX6, anchored to the peroxisomal membrane
    by PEX26. The PEX1-PEX6 complex recognizes monoubiquitinated PEX5 (Ub-PEX5) through
    its ubiquitin moiety and extracts it from the peroxisomal docking/translocation module
    (DTM) in an ATP-dependent manner. During extraction, PEX5 is globally unfolded by
    processive threading through the central pore. This enables PEX5 recycling for
    additional rounds of peroxisomal matrix protein import.
  molecular_function:
    id: GO:0140318
    label: protein transporter activity
  directly_involved_in:
    - id: GO:0016562
      label: protein import into peroxisome matrix, receptor recycling
  locations:
    - id: GO:0005778
      label: peroxisomal membrane
    - id: GO:0005829
      label: cytosol
  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"
    - reference_id: PMID:16314507
      supporting_text: "Pex1 and Pex6 of the AAA ATPase family and their recruiter, Pex26, were essential for Pex5 export"