id: Q92968
gene_symbol: PEX13
product_type: PROTEIN
status: IN_PROGRESS
taxon:
  id: NCBITaxon:9606
  label: Homo sapiens
description: >-
  PEX13 (Peroxin-13) is an integral peroxisomal membrane protein that functions as a core component
  of the PEX13-PEX14 docking/translocation module (DTM) required for import of peroxisomal matrix
  proteins. PEX13 contains an N-terminal YG-rich intrinsically disordered region (IDR) that forms
  a selective phase reminiscent of nucleoporin FG repeats, and a C-terminal SH3 domain that
  mediates interactions with PEX5 (PTS1 receptor) via WxxxF/Y motifs. A proximal FxxxF motif
  autoinhibits the SH3 domain; PEX14 NTD binding to FxxxF releases this autoinhibition, creating
  a dynamic interaction network that tunes matrix protein import. PEX13 is essential for both
  PTS1 and PTS2 protein import. Loss of PEX13 causes Zellweger spectrum disorders (complementation
  group 13). PEX13 also functions in peroxisome quality control by preventing inappropriate
  pexophagy through regulation of PEX5 ubiquitination state and peroxisomal ROS levels.
existing_annotations:
# --- IBA annotations (phylogenetic) ---
- term:
    id: GO:0005778
    label: peroxisomal membrane
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  review:
    summary: >-
      PEX13 is a well-established integral peroxisomal membrane protein. UniProt annotates it
      as "Peroxisome membrane; Multi-pass membrane protein" with three predicted transmembrane
      helices (PMID:8858165, PMID:11390669). IBA annotation is fully consistent with extensive
      experimental data.
    action: ACCEPT
    reason: >-
      Core localization supported by multiple IDA studies, UniProt annotation, and the deep
      research synthesis. PEX13 is an integral peroxisomal membrane protein by definition.
    supported_by:
      - reference_id: PMID:8858165
        supporting_text: "We have identified Pex13p, a novel integral peroxisomal membrane from both yeast and humans that binds the PTS1 receptor via a cytoplasmically oriented SH3 domain."
      - reference_id: PMID:9653144
        supporting_text: 'Recombinant Pex14p was specifically recognized by the "import inhibiting" ab-MF3 and bound Pex5p and the Src homology 3 (SH3) domain of Pex13p in ligand blots.'

- term:
    id: GO:0016560
    label: protein import into peroxisome matrix, docking
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  review:
    summary: >-
      PEX13 is a core component of the docking/translocation module (DTM) for peroxisomal matrix
      protein import. The docking function is the primary biological process role of PEX13 and
      is supported by extensive evidence from yeast to humans (PMID:8858165, PMID:28765278).
    action: ACCEPT
    reason: >-
      This is the core biological process annotation for PEX13. Loss of Pex13p eliminates import
      of PTS1 and PTS2 proteins and reduces peroxisome-associated Pex5p by ~40-fold (PMID:8858165).
      The DTM comprising PEX13 and PEX14 is the established docking complex.
    supported_by:
      - reference_id: PMID:8858165
        supporting_text: "loss of Pex13p further reduces the amount of peroxisome-associated Pex5p by approximately 40-fold. Furthermore, loss of Pex13p eliminates import of peroxisomal matrix proteins that contain either the type-1 or type-2 peroxisomal targeting signal"
      - reference_id: PMID:28765278
        supporting_text: "the peroxisomal membrane docking/translocation module (DTM) comprising PEX13, PEX14, and the three \u201CReally Interesting New Gene\u201D (RING) finger peroxins PEX2, PEX10, and PEX12"

- term:
    id: GO:1990429
    label: peroxisomal importomer complex
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  review:
    summary: >-
      PEX13 is part of the peroxisomal importomer complex (docking/translocation module),
      which includes PEX13, PEX14, PEX2, PEX10, and PEX12 (PMID:28765278). IBA annotation
      is well-supported by biochemical co-purification and functional studies.
    action: ACCEPT
    reason: >-
      PEX13 is a bona fide component of the importomer complex. Dias et al. (2017) describe the
      DTM as comprising PEX13, PEX14, and the RING peroxins. PEX14 complexes purified from human
      cells contain PEX13 (PMID:21525035).
    supported_by:
      - reference_id: PMID:28765278
        supporting_text: "the peroxisomal membrane docking/translocation module (DTM) comprising PEX13, PEX14, and the three \u201CReally Interesting New Gene\u201D (RING) finger peroxins PEX2, PEX10, and PEX12"

# --- IEA annotations (automated) ---
- term:
    id: GO:0005777
    label: peroxisome
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  review:
    summary: >-
      Automated annotation of PEX13 to peroxisome. This is correct but less specific than
      peroxisomal membrane (GO:0005778), which is more accurate for PEX13 as an integral
      membrane protein. Acceptable as a broader IEA annotation.
    action: ACCEPT
    reason: >-
      PEX13 is indeed a peroxisomal protein. While peroxisomal membrane is more specific,
      the broader peroxisome term is not incorrect for an IEA. Multiple IDA annotations
      also support peroxisome localization.

- term:
    id: GO:0005778
    label: peroxisomal membrane
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  review:
    summary: >-
      Automated annotation to peroxisomal membrane. Correct and consistent with extensive
      experimental evidence showing PEX13 is an integral peroxisomal membrane protein.
    action: ACCEPT
    reason: >-
      Consistent with IBA and multiple IDA annotations for the same term.

- term:
    id: GO:0015031
    label: protein transport
  evidence_type: IEA
  original_reference_id: GO_REF:0000043
  review:
    summary: >-
      IEA annotation from UniProt keyword mapping. PEX13 is involved in protein transport,
      specifically peroxisomal matrix protein import. This term is very broad but not incorrect.
    action: ACCEPT
    reason: >-
      PEX13 is indeed involved in protein transport (specifically peroxisomal matrix protein
      import). This broad IEA is acceptable alongside the more specific docking term.

- term:
    id: GO:0016020
    label: membrane
  evidence_type: IEA
  original_reference_id: GO_REF:0000002
  review:
    summary: >-
      IEA annotation from InterPro mapping. PEX13 is a membrane protein. Very generic but
      not wrong for an automated annotation.
    action: ACCEPT
    reason: >-
      PEX13 is an integral membrane protein. This is a broad IEA that is subsumed by more
      specific peroxisomal membrane annotations but is not incorrect.

- term:
    id: GO:0016560
    label: protein import into peroxisome matrix, docking
  evidence_type: IEA
  original_reference_id: GO_REF:0000002
  review:
    summary: >-
      IEA from InterPro mapping for the docking function. Correct and consistent with IBA
      and experimental annotations for the same term.
    action: ACCEPT
    reason: >-
      Correctly maps the InterPro domain information to the core docking function.

# --- protein binding IPI annotations ---
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:10704444
  review:
    summary: >-
      This IPI annotation comes from Sacksteder et al. (2000), which demonstrates PEX19 binds
      PEX13 (among many other PMPs) using dihybrid and blot overlay assays. The interaction
      is with PEX19, the peroxisomal membrane protein import receptor/chaperone.
    action: MARK_AS_OVER_ANNOTATED
    reason: >-
      The generic "protein binding" term is uninformative. The actual interaction is PEX13
      binding PEX19, which is part of the PMP targeting pathway. PEX19 binds the mPTS region
      of PEX13 to facilitate its insertion into the peroxisomal membrane. This is better captured
      by other existing annotations (peroxisomal membrane localization) rather than a vague
      protein binding annotation.
    supported_by:
      - reference_id: PMID:10704444
        supporting_text: "PEX19 binds a broad spectrum of PMPs, displays saturable PMP binding, and interacts with regions of PMPs required for their targeting to peroxisomes."

- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:20531392
  review:
    summary: >-
      Schueller et al. (2010) characterized the Pex19p mPTS recognition domain structure.
      PEX13 is listed as a PEX19 binding partner. This is again generic "protein binding."
    action: MARK_AS_OVER_ANNOTATED
    reason: >-
      Generic protein binding is uninformative. The paper primarily characterizes PEX19 structure
      and its mPTS recognition; PEX13 is one of many PMPs that bind PEX19. The interaction is
      part of the PMP targeting pathway rather than a specific functional interaction of PEX13.
    supported_by:
      - reference_id: PMID:20531392
        supporting_text: "The protein Pex19p functions as a receptor and chaperone of peroxisomal membrane proteins (PMPs). The crystal structure of the folded C-terminal part of the receptor reveals a globular domain that displays a bundle of three long helices in an antiparallel arrangement."

- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:32296183
  review:
    summary: >-
      Luck et al. (2020) is a high-throughput binary protein interactome map. PEX13 was
      identified in a binary interaction. High-throughput Y2H data without specific functional
      context.
    action: MARK_AS_OVER_ANNOTATED
    reason: >-
      High-throughput interactome study; generic protein binding is uninformative for PEX13
      whose specific interaction partners (PEX5, PEX14, PEX19) are well characterized.
    supported_by:
      - reference_id: PMID:32296183
        supporting_text: "A reference map of the human binary protein interactome."

# --- IDA and NAS annotations ---
- term:
    id: GO:0005777
    label: peroxisome
  evidence_type: IDA
  original_reference_id: GO_REF:0000052
  review:
    summary: >-
      IDA from curation of immunofluorescence data showing PEX13 localizes to peroxisomes.
      Correct but less specific than peroxisomal membrane.
    action: ACCEPT
    reason: >-
      Immunofluorescence data correctly places PEX13 at peroxisomes. This is consistent
      with all other localization evidence. The broader term is acceptable alongside the
      more specific peroxisomal membrane annotations.

- term:
    id: GO:0005778
    label: peroxisomal membrane
  evidence_type: IDA
  original_reference_id: PMID:37165185
  review:
    summary: >-
      Ravindran et al. (2023, Nature) demonstrated that Pex13 localizes to the peroxisomal
      membrane where it forms phase-separated condensates with Pex5-cargo. Although primary
      experiments were in yeast, the annotation to human PEX13 peroxisomal membrane is supported
      by conserved function and multiple other human-specific studies.
    action: ACCEPT
    reason: >-
      PEX13 peroxisomal membrane localization is extremely well established. This study
      adds mechanistic insight about phase separation at the membrane.
    supported_by:
      - reference_id: PMID:37165185
        supporting_text: "the minimum transport machinery includes the membrane proteins Pex13 and Pex14 and the cargo-protein-binding transport receptor, Pex5"

- term:
    id: GO:0016560
    label: protein import into peroxisome matrix, docking
  evidence_type: NAS
  original_reference_id: PMID:37165185
  review:
    summary: >-
      NAS annotation based on Ravindran et al. (2023) which showed Pex13 forms LLPS-based
      transport channels with Pex5 and Pex14 for peroxisomal protein import. The docking
      function is well supported.
    action: ACCEPT
    reason: >-
      The paper provides strong evidence that Pex13 is central to the import process,
      forming transient protein transport channels. The docking step is well established.
    supported_by:
      - reference_id: PMID:37165185
        supporting_text: "Our findings lead us to suggest a model in which LLPS of Pex5-cargo with Pex13 and Pex14 results in transient protein transport channels"

- term:
    id: GO:0005778
    label: peroxisomal membrane
  evidence_type: IDA
  original_reference_id: PMID:28765278
  review:
    summary: >-
      Dias et al. (2017) characterized the DTM architecture and showed PEX13 is part of
      the peroxisomal membrane docking/translocation module in mammalian cells.
    action: ACCEPT
    reason: >-
      Direct biochemical evidence from cell-free import assays using mammalian peroxisomes.
    supported_by:
      - reference_id: PMID:28765278
        supporting_text: "the peroxisomal membrane docking/translocation module (DTM) comprising PEX13, PEX14, and the three \u201CReally Interesting New Gene\u201D (RING) finger peroxins PEX2, PEX10, and PEX12"

- term:
    id: GO:0008320
    label: protein transmembrane transporter activity
  evidence_type: IDA
  original_reference_id: PMID:28765278
  review:
    summary: >-
      Dias et al. (2017) showed PEX5 enters a large cavity formed by DTM components (including
      PEX13) to release cargo. This study supports that the DTM functions as a transporter.
      However, PEX13 alone is not the transporter; it is one component of a multi-protein
      translocon. The transport activity is a property of the DTM complex, not PEX13 individually.
    action: MARK_AS_OVER_ANNOTATED
    reason: >-
      While PEX13 contributes to the DTM that translocates proteins, ascribing "protein
      transmembrane transporter activity" to PEX13 individually is an over-annotation.
      PEX13 functions as a scaffold/docking component within the DTM. The transporter activity
      is an emergent property of the PEX13-PEX14-RING complex assembly. PEX13 is better
      described by its docking function and complex membership.
    supported_by:
      - reference_id: PMID:28765278
        supporting_text: "the DTM is best described as a large cavity-forming protein assembly into which cytosolic PEX5 can enter to release its cargo"

- term:
    id: GO:0016560
    label: protein import into peroxisome matrix, docking
  evidence_type: IDA
  original_reference_id: PMID:28765278
  review:
    summary: >-
      Dias et al. (2017) directly demonstrate PEX13 as part of the DTM docking machinery
      using cell-free import assays with truncated PEX5 molecules.
    action: ACCEPT
    reason: >-
      Core function of PEX13, supported by direct biochemical evidence.
    supported_by:
      - reference_id: PMID:28765278
        supporting_text: "This import involves binding of newly synthesized proteins by cytosolic peroxisomal biogenesis factor 5 (PEX5) followed by insertion of the PEX5-cargo complex into the peroxisomal membrane at the docking/translocation module (DTM)."

- term:
    id: GO:0016561
    label: protein import into peroxisome matrix, translocation
  evidence_type: IDA
  original_reference_id: PMID:28765278
  review:
    summary: >-
      Dias et al. (2017) present evidence that the DTM (including PEX13) forms a cavity into
      which PEX5 enters to release cargo, supporting both docking and translocation roles.
      The YG-rich IDR of PEX13 has been proposed to form the selective phase conduit through
      which cargo crosses the membrane (PMID:37165185).
    action: ACCEPT
    reason: >-
      Recent evidence supports PEX13 involvement in translocation, not just docking. The
      YG-rich IDR forms a phase-separated conduit analogous to nucleoporin FG repeats that
      enables cargo translocation. The DTM cavity model places PEX13 directly in the
      translocation process.
    supported_by:
      - reference_id: PMID:28765278
        supporting_text: "these results suggest that the DTM is best described as a large cavity-forming protein assembly into which cytosolic PEX5 can enter to release its cargo"
      - reference_id: PMID:37165185
        supporting_text: "Pex13 undergoes liquid-liquid phase separation (LLPS) with Pex5-cargo. Intrinsically disordered regions in Pex13 and Pex5 resemble those found in nuclear pore complex proteins."

- term:
    id: GO:0005778
    label: peroxisomal membrane
  evidence_type: IDA
  original_reference_id: PMID:19197237
  review:
    summary: >-
      Neufeld et al. (2009) studied the structural basis for PEX14 interactions with PEX5
      and PEX19. PEX13 peroxisomal membrane localization is established context in this study.
    action: ACCEPT
    reason: >-
      Consistent with all other evidence for PEX13 peroxisomal membrane localization.
    supported_by:
      - reference_id: PMID:19197237
        supporting_text: "Pex14 is a central component of the peroxisomal import machinery and binds the soluble receptors Pex5 and Pex19"

- term:
    id: GO:0034614
    label: cellular response to reactive oxygen species
  evidence_type: IDA
  original_reference_id: PMID:26344566
  review:
    summary: >-
      Zhang et al. (2015) demonstrated that ATM is localized to peroxisomes by PEX5 and
      activates pexophagy in response to ROS via PEX5 phosphorylation and ubiquitination.
      PEX13 is not a direct subject of this paper; the study focuses on ATM, PEX5, and p62.
      The annotation of PEX13 to "cellular response to reactive oxygen species" based on this
      paper is questionable since PEX13 is not shown to directly respond to or mediate the
      ROS response in this study.
    action: MARK_AS_OVER_ANNOTATED
    reason: >-
      PMID:26344566 focuses on ATM-PEX5-p62 signaling in ROS-induced pexophagy. PEX13 is
      not a direct participant in the ROS sensing or response pathway described. While
      Demers et al. (2023, PMID not in set) later showed PEX13 loss leads to increased
      peroxisomal ROS and pexophagy, the Zhang et al. paper does not provide direct evidence
      for PEX13 involvement in ROS response. PEX13 is a peroxisomal component that may be
      affected by pexophagy, but annotating it as involved in "cellular response to ROS"
      based on this paper over-annotates its role.
    supported_by:
      - reference_id: PMID:26344566
        supporting_text: "the PEX5 peroxisome import receptor binds ataxia-telangiectasia mutated (ATM) and localizes this kinase to the peroxisome. In response to ROS, ATM signalling activates ULK1 and inhibits mTORC1 to induce autophagy."

# --- Reactome TAS annotations: cytosol ---
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-9603775
  review:
    summary: >-
      Reactome annotation for PEX3:PEX19:class I PMP dissociation reaction. PEX13 as a class I
      PMP would transiently be in the cytosol as a PEX19-bound intermediate before membrane
      insertion. This represents a transient biosynthetic intermediate state, not a steady-state
      localization.
    action: KEEP_AS_NON_CORE
    reason: >-
      PEX13 is predominantly a peroxisomal membrane protein. The cytosol annotation reflects
      its transient state as a newly synthesized PMP bound to PEX19 before membrane insertion.
      This is a legitimate but non-core localization.

- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-9603784
  review:
    summary: >-
      Reactome annotation for PEX19:class I PMP binding PEX3. Same as above; PEX13 transiently
      passes through cytosol as PEX19-bound intermediate.
    action: KEEP_AS_NON_CORE
    reason: >-
      Transient biosynthetic intermediate state. PEX13 steady-state localization is peroxisomal
      membrane.

- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-9603804
  review:
    summary: >-
      Reactome annotation for PEX19 binding class I PMPs. PEX13 transiently in cytosol as
      newly synthesized protein before PEX19-mediated targeting to peroxisomes.
    action: KEEP_AS_NON_CORE
    reason: >-
      Same rationale as other cytosol annotations. Transient biosynthetic intermediate.

# --- Reactome TAS annotations: peroxisomal membrane ---
- term:
    id: GO:0005778
    label: peroxisomal membrane
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-8953917
  review:
    summary: >-
      Reactome reaction where PEX2:PEX10:PEX12 binds PEX5 in the PEX5:PEX13:PEX14 complex.
      PEX13 is correctly placed at the peroxisomal membrane in this reaction.
    action: ACCEPT
    reason: >-
      Consistent with PEX13 peroxisomal membrane localization during the import cycle.

- term:
    id: GO:0005778
    label: peroxisomal membrane
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-8953946
  review:
    summary: >-
      Reactome reaction for PEX5 monoubiquitination. PEX13 at peroxisomal membrane as part
      of the DTM during the ubiquitination step.
    action: ACCEPT
    reason: >-
      Consistent with core localization.

- term:
    id: GO:0005778
    label: peroxisomal membrane
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-9033235
  review:
    summary: >-
      Reactome reaction for cargo translocation from cytosol to peroxisomal matrix.
      PEX13 at peroxisomal membrane.
    action: ACCEPT
    reason: >-
      Consistent with core localization during the import cycle.

- term:
    id: GO:0005778
    label: peroxisomal membrane
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-9033236
  review:
    summary: >-
      Reactome reaction for PEX5:Cargo binding the DTM (PEX13:PEX14:PEX2:PEX10:PEX12).
      PEX13 at peroxisomal membrane.
    action: ACCEPT
    reason: >-
      Consistent with core localization.

- term:
    id: GO:0005778
    label: peroxisomal membrane
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-9033485
  review:
    summary: >-
      Reactome reaction for PEX5L monoubiquitination. PEX13 at peroxisomal membrane.
    action: ACCEPT
    reason: >-
      Consistent with core localization.

- term:
    id: GO:0005778
    label: peroxisomal membrane
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-9033499
  review:
    summary: >-
      Reactome reaction for PEX1:PEX6 extracting PEX5L from the DTM. PEX13 at peroxisomal
      membrane as part of the complex from which PEX5 is extracted.
    action: ACCEPT
    reason: >-
      Consistent with core localization.

- term:
    id: GO:0005778
    label: peroxisomal membrane
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-9033514
  review:
    summary: >-
      Reactome reaction for PTS2 cargo translocation. PEX13 at peroxisomal membrane.
    action: ACCEPT
    reason: >-
      Consistent with core localization.

- term:
    id: GO:0005778
    label: peroxisomal membrane
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-9033516
  review:
    summary: >-
      Reactome reaction for DTM-REM complex assembly. PEX13 at peroxisomal membrane.
    action: ACCEPT
    reason: >-
      Consistent with core localization.

- term:
    id: GO:0005778
    label: peroxisomal membrane
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-9033527
  review:
    summary: >-
      Reactome reaction for E3 ligase binding PEX5L in the PTS2 pathway complex.
      PEX13 at peroxisomal membrane.
    action: ACCEPT
    reason: >-
      Consistent with core localization.

- term:
    id: GO:0005778
    label: peroxisomal membrane
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-9033533
  review:
    summary: >-
      Reactome reaction for Ub-PEX5:PEX13:PEX14 binding PEX1:PEX6:PEX26. PEX13 at
      peroxisomal membrane.
    action: ACCEPT
    reason: >-
      Consistent with core localization.

- term:
    id: GO:0005778
    label: peroxisomal membrane
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-9603775
  review:
    summary: >-
      Reactome reaction for PEX3:PEX19:PMP dissociation. PEX13 as a class I PMP is inserted
      into the peroxisomal membrane in this step.
    action: ACCEPT
    reason: >-
      Consistent with core localization. This reaction represents PEX13 arriving at its
      functional destination.

# --- HDA annotations ---
- term:
    id: GO:0016020
    label: membrane
  evidence_type: HDA
  original_reference_id: PMID:19946888
  review:
    summary: >-
      Ghosh et al. (2010) identified PEX13 in a membrane proteomics study of NK cells.
      The generic "membrane" term is very broad but correct.
    action: ACCEPT
    reason: >-
      PEX13 is an integral membrane protein. Identification in a membrane proteome is
      consistent. This broad HDA annotation is acceptable.
    supported_by:
      - reference_id: PMID:19946888
        supporting_text: "The present study was initiated to define the composition of the membrane proteome of the Natural Killer (NK) like cell line YTS."

- term:
    id: GO:0005778
    label: peroxisomal membrane
  evidence_type: HDA
  original_reference_id: PMID:21525035
  review:
    summary: >-
      Bharti et al. (2011) identified PEX13 as a constituent of PEX14 complexes purified
      from human cells using mass spectrometry, confirming its presence in the peroxisomal
      membrane import machinery.
    action: ACCEPT
    reason: >-
      Direct identification of PEX13 in PEX14 complexes from human peroxisomal membranes
      supports peroxisomal membrane localization.
    supported_by:
      - reference_id: PMID:21525035
        supporting_text: "Using mass spectrometric analysis, almost all known human peroxins involved in protein import were identified as constituents of the PEX14 complexes."

# --- IDA annotations from specific publications ---
- term:
    id: GO:0005777
    label: peroxisome
  evidence_type: IDA
  original_reference_id: PMID:17881773
  review:
    summary: >-
      Nenicu et al. (2007) characterized peroxisomal proteins in testis cell types, including
      PEX13 as a peroxisomal marker protein. PEX13 was detected in peroxisomes of various
      testicular cell types.
    action: ACCEPT
    reason: >-
      Direct detection of PEX13 in peroxisomes by immunolocalization in testis tissue.
    supported_by:
      - reference_id: PMID:17881773
        supporting_text: "our results obtained by detection of different peroxisomal marker proteins show the presence of these organelles in most cell types in the testis"

- term:
    id: GO:0005778
    label: peroxisomal membrane
  evidence_type: IDA
  original_reference_id: PMID:11402059
  review:
    summary: >-
      Jones et al. (2001) showed PEX13 contains two independent peroxisomal targeting signals,
      confirming it as an integral peroxisomal membrane protein. PEX13-GFP constructs targeted
      to peroxisomes.
    action: ACCEPT
    reason: >-
      Direct experimental evidence from GFP-fusion targeting experiments demonstrating PEX13
      localizes to the peroxisomal membrane.
    supported_by:
      - reference_id: PMID:11402059
        supporting_text: "another integral PMP, the peroxin PEX13, also contains two independent sets of peroxisomal targeting information"

- term:
    id: GO:0005777
    label: peroxisome
  evidence_type: IDA
  original_reference_id: PMID:11829486
  review:
    summary: >-
      Bjorkman et al. (2002) localized mouse Pex13 protein to peroxisomes in mouse liver and
      showed the human PEX13 protein sorts to peroxisomes in human fibroblasts.
    action: ACCEPT
    reason: >-
      Direct experimental localization of PEX13 to peroxisomes.
    supported_by:
      - reference_id: PMID:11829486
        supporting_text: "We have localized PEX13 protein to peroxisomes in mouse liver and show that this protein also sorts to peroxisomes in human skin fibroblasts."

# --- ISS annotations (from mouse/orthologs) ---
- term:
    id: GO:0001561
    label: fatty acid alpha-oxidation
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  review:
    summary: >-
      ISS annotation transferred from mouse ortholog. PEX13 knockout mice likely show
      deficiency in fatty acid alpha-oxidation as a downstream consequence of failed
      peroxisomal matrix protein import, since alpha-oxidation enzymes are peroxisomal
      matrix proteins. This is a secondary consequence of loss of peroxisomal import,
      not a direct function of PEX13.
    action: KEEP_AS_NON_CORE
    reason: >-
      Fatty acid alpha-oxidation is a peroxisomal metabolic process that would be disrupted
      when PEX13 is lost due to failure of matrix protein import. This is an indirect
      phenotypic consequence, not a direct molecular function. PEX13 does not catalyze
      alpha-oxidation; it enables import of the enzymes that do. Keep as non-core to
      indicate the indirect relationship.

- term:
    id: GO:0001764
    label: neuron migration
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  review:
    summary: >-
      ISS annotation from mouse Pex13 knockout phenotype. PEX13-null mice show
      neurological defects consistent with Zellweger syndrome. Neuron migration defects
      are a pleiotropic downstream consequence of peroxisome dysfunction, not a direct
      function of PEX13.
    action: KEEP_AS_NON_CORE
    reason: >-
      Neuron migration defects in Pex13 knockout mice reflect the broad developmental
      consequences of peroxisome biogenesis failure (Zellweger spectrum). PEX13 does not
      directly regulate neuron migration; this is several steps removed from its
      molecular function as a docking complex component.

- term:
    id: GO:0001967
    label: suckling behavior
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  review:
    summary: >-
      ISS annotation from mouse Pex13 knockout phenotype. Suckling behavior defects in
      PEX13-null mice are a pleiotropic downstream consequence of peroxisome dysfunction
      affecting brain/neurological development.
    action: KEEP_AS_NON_CORE
    reason: >-
      Highly pleiotropic phenotype far removed from PEX13 molecular function. Suckling
      behavior impairment is a clinical feature of Zellweger syndrome mouse models due
      to neurological dysfunction, not a direct role of PEX13.

- term:
    id: GO:0007626
    label: locomotory behavior
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  review:
    summary: >-
      ISS annotation from mouse Pex13 knockout phenotype. Locomotory behavior defects
      in PEX13-null mice are a pleiotropic downstream consequence of Zellweger-like
      neurological dysfunction.
    action: KEEP_AS_NON_CORE
    reason: >-
      Pleiotropic phenotype far removed from PEX13 molecular function. Locomotory
      defects arise from broad neurological and developmental impacts of peroxisome
      dysfunction.

- term:
    id: GO:0021795
    label: cerebral cortex cell migration
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  review:
    summary: >-
      ISS annotation from mouse Pex13 knockout phenotype. Cerebral cortex cell migration
      defects are observed in Zellweger syndrome models due to peroxisome dysfunction
      affecting brain development.
    action: KEEP_AS_NON_CORE
    reason: >-
      Pleiotropic developmental phenotype. PEX13 does not directly regulate cortical
      cell migration; defects arise from broad peroxisomal metabolic dysfunction
      affecting brain development in Zellweger spectrum disorders.

- term:
    id: GO:0060152
    label: microtubule-based peroxisome localization
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  review:
    summary: >-
      ISS annotation transferred from mouse. Nguyen et al. (2006, PMID:16449325) showed
      that PEX13-null mouse cells exhibit loss of microtubule-based peroxisome distribution.
      However, this effect is secondary to reduced peroxisome abundance and size due to
      import failure, not a direct role of PEX13 in microtubule-peroxisome interactions.
      The direct mediator of microtubule-peroxisome interaction is PEX14 (PMID:21525035).
    action: MARK_AS_OVER_ANNOTATED
    reason: >-
      The microtubule-peroxisome localization defect in PEX13-null cells is an indirect
      consequence of peroxisome dysfunction. Bharti et al. (2011) showed PEX14, not PEX13,
      directly binds tubulin and mediates peroxisome motility along microtubules. The PEX13
      knockout phenotype reflects general peroxisome biogenesis failure rather than a
      specific role in microtubule-based localization.
    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. Similar effects were observed for both cultured embryonic fibroblasts and brain neurons from a PEX13-null mouse"
      - 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"

# --- Remaining IPI/IDA/IMP/TAS annotations ---
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:8858165
  review:
    summary: >-
      Gould et al. (1996) showed PEX13 binds PEX5 (PTS1 receptor) via its SH3 domain.
      The interaction is specific and functionally important for peroxisomal protein import.
      However, "protein binding" is uninformative and does not capture the specific SH3-mediated
      interaction with PEX5.
    action: MARK_AS_OVER_ANNOTATED
    reason: >-
      The specific interaction is PEX13 SH3 domain binding PEX5 WxxxF/Y motifs, which is
      better captured by the docking process annotations. Generic "protein binding" fails
      to convey the specific and functionally critical nature of this interaction.
    supported_by:
      - reference_id: PMID:8858165
        supporting_text: "We have identified Pex13p, a novel integral peroxisomal membrane from both yeast and humans that binds the PTS1 receptor via a cytoplasmically oriented SH3 domain."

- term:
    id: GO:0005778
    label: peroxisomal membrane
  evidence_type: IDA
  original_reference_id: PMID:8858165
  review:
    summary: >-
      Foundational paper by Gould et al. (1996) identifying PEX13 as an integral peroxisomal
      membrane protein with a cytoplasmically oriented SH3 domain.
    action: ACCEPT
    reason: >-
      Primary discovery paper establishing PEX13 peroxisomal membrane localization.
    supported_by:
      - reference_id: PMID:8858165
        supporting_text: "We have identified Pex13p, a novel integral peroxisomal membrane from both yeast and humans that binds the PTS1 receptor via a cytoplasmically oriented SH3 domain."

- term:
    id: GO:0016560
    label: protein import into peroxisome matrix, docking
  evidence_type: IMP
  original_reference_id: PMID:8858165
  review:
    summary: >-
      Gould et al. (1996) showed loss of Pex13p eliminates PTS1 and PTS2 protein import and
      reduces peroxisome-associated Pex5p ~40-fold, establishing PEX13 as a docking factor.
    action: ACCEPT
    reason: >-
      Foundational IMP evidence for PEX13 docking function. Loss-of-function phenotype
      directly demonstrates requirement for matrix protein import docking.
    supported_by:
      - reference_id: PMID:8858165
        supporting_text: "loss of Pex13p further reduces the amount of peroxisome-associated Pex5p by approximately 40-fold. Furthermore, loss of Pex13p eliminates import of peroxisomal matrix proteins that contain either the type-1 or type-2 peroxisomal targeting signal but does not affect targeting and insertion of integral peroxisomal membrane proteins. We conclude that Pex13p functions as a docking factor for the predominantly cytoplasmic PTS1 receptor."

- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:9653144
  review:
    summary: >-
      Fransen et al. (1998) showed human PEX14 binds PEX13 SH3 domain in ligand blots,
      and PEX13 SH3 interacts with PEX14. This demonstrates a specific interaction between
      PEX13 and PEX14. Generic "protein binding" is uninformative.
    action: MARK_AS_OVER_ANNOTATED
    reason: >-
      The specific interaction is PEX13 SH3 domain binding PEX14, which is central to
      DTM assembly. This is better captured by the complex membership (GO:1990429) and
      docking process annotations. Generic "protein binding" is uninformative.
    supported_by:
      - reference_id: PMID:9653144
        supporting_text: "Recombinant Pex14p was specifically recognized by the \u201Cimport inhibiting\u201D ab-MF3 and bound Pex5p and the Src homology 3 (SH3) domain of Pex13p in ligand blots."

- term:
    id: GO:0005778
    label: peroxisomal membrane
  evidence_type: IDA
  original_reference_id: PMID:16449325
  review:
    summary: >-
      Nguyen et al. (2006) studied peroxisome distribution defects in PEX13-null mouse
      cells, with PEX13 detected at the peroxisomal membrane in control cells.
    action: ACCEPT
    reason: >-
      Consistent with all other localization evidence. PEX13 at peroxisomal membrane in
      cell biological studies.
    supported_by:
      - reference_id: PMID:16449325
        supporting_text: "Similar effects were observed for both cultured embryonic fibroblasts and brain neurons from a PEX13-null mouse with a Zellweger-syndrome-like phenotype"

- term:
    id: GO:0016560
    label: protein import into peroxisome matrix, docking
  evidence_type: TAS
  original_reference_id: PMID:10704444
  review:
    summary: >-
      Sacksteder et al. (2000) reference PEX13 as a known component of the peroxisomal
      protein import docking machinery in the context of studying PEX19 function.
    action: ACCEPT
    reason: >-
      TAS annotation consistent with the established role of PEX13 in docking, referenced
      in the study context.

# --- NEW annotations to suggest ---
- term:
    id: GO:0016558
    label: protein import into peroxisome matrix
  evidence_type: IMP
  original_reference_id: PMID:8858165
  review:
    summary: >-
      PEX13 is required for import of both PTS1 and PTS2 matrix proteins into peroxisomes.
      Loss of PEX13 eliminates import of both types of cargo. This broader process term
      captures the full import role beyond just the docking step.
    action: NEW
    reason: >-
      While the docking step is well annotated, the broader peroxisomal matrix protein import
      process (GO:0140888) captures PEX13's role in the entire import cycle including both
      docking and translocation. Supported by loss-of-function evidence.
    supported_by:
      - reference_id: PMID:8858165
        supporting_text: "loss of Pex13p eliminates import of peroxisomal matrix proteins that contain either the type-1 or type-2 peroxisomal targeting signal"

references:
- id: GO_REF:0000002
  title: Gene Ontology annotation through association of InterPro records with GO
    terms
  findings: []
- id: GO_REF:0000024
  title: Manual transfer of experimentally-verified manual GO annotation data to orthologs
    by curator judgment of sequence similarity
  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:0000052
  title: Gene Ontology annotation based on curation of immunofluorescence data
  findings: []
- id: GO_REF:0000120
  title: Combined Automated Annotation using Multiple IEA Methods
  findings: []
- id: PMID:10704444
  title: PEX19 binds multiple peroxisomal membrane proteins, is predominantly cytoplasmic,
    and is required for peroxisome membrane synthesis.
  findings: []
- id: PMID:11402059
  title: Multiple distinct targeting signals in integral peroxisomal membrane proteins.
  findings: []
- id: PMID:11829486
  title: 'Pex13, the mouse ortholog of the human peroxisome biogenesis disorder PEX13
    gene: gene structure, tissue expression, and localization of the protein to peroxisomes.'
  findings: []
- id: PMID:16449325
  title: Failure of microtubule-mediated peroxisome division and trafficking in disorders
    with reduced peroxisome abundance.
  findings: []
- id: PMID:17881773
  title: 'Peroxisomes in human and mouse testis: differential expression of peroxisomal
    proteins in germ cells and distinct somatic cell types of the testis.'
  findings: []
- id: PMID:19197237
  title: Structural basis for competitive interactions of Pex14 with the import receptors
    Pex5 and Pex19.
  findings: []
- id: PMID:19946888
  title: Defining the membrane proteome of NK cells.
  findings: []
- id: PMID:20531392
  title: The peroxisomal receptor Pex19p forms a helical mPTS recognition domain.
  findings: []
- id: PMID:21525035
  title: PEX14 is required for microtubule-based peroxisome motility in human cells.
  findings: []
- id: PMID:26344566
  title: ATM functions at the peroxisome to induce pexophagy in response to ROS.
  findings: []
- id: PMID:28765278
  title: The peroxisomal matrix protein translocon is a large cavity-forming protein
    assembly into which PEX5 protein enters to release its cargo.
  findings: []
- id: PMID:32296183
  title: A reference map of the human binary protein interactome.
  findings: []
- id: PMID:37165185
  title: Peroxisome biogenesis initiated by protein phase separation.
  findings: []
- id: PMID:8858165
  title: Pex13p is an SH3 protein of the peroxisome membrane and a docking factor
    for the predominantly cytoplasmic PTs1 receptor.
  findings: []
- id: PMID:9653144
  title: Identification of a human PTS1 receptor docking protein directly required
    for peroxisomal protein import.
  findings: []
- id: Reactome:R-HSA-8953917
  title: PEX2:PEX10:PEX12 binds PEX5S,L (in PEX5S:PEX13:PEX14) and Ub:UBE2D1,2,3
  findings: []
- id: Reactome:R-HSA-8953946
  title: PEX2:PEX10:PEX12 monoubiquitinates PEX5S,L at cysteine-11
  findings: []
- id: Reactome:R-HSA-9033235
  title: Cargo of PEX5S,L translocates from the cytosol to the peroxisomal matrix
  findings: []
- id: Reactome:R-HSA-9033236
  title: PEX5S,L:Cargo binds PEX13:PEX14:PEX2:PEX10:PEX12 (Docking and Translocation
    Module)
  findings: []
- id: Reactome:R-HSA-9033485
  title: PEX2:PEX10:PEX12 monoubiquitinates PEX5L at cysteine-11
  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-9033514
  title: Cargo of PEX5L:PEX7 translocates from the cytosol to the peroxisomal matrix
  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-9033527
  title: PEX2:PEX10:PEX12 binds PEX5L (in PEX5L:PEX7:PEX13:PEX14:PEX2:PEX10:PEX12)
    and Ub:UBE2D1,2,3
  findings: []
- id: Reactome:R-HSA-9033533
  title: PEX2:PEX10:PEX12:Ub:PEX5S,L:PEX13:PEX14 binds PEX1:PEX6:PEX26 and ZFAND6
  findings: []
- id: Reactome:R-HSA-9603775
  title: PEX3:PEX19:class I PMP dissociates
  findings: []
- id: Reactome:R-HSA-9603784
  title: PEX19:class I PMP binds PEX3
  findings: []
- id: Reactome:R-HSA-9603804
  title: PEX19 binds class I peroxisomal membrane proteins
  findings: []