id: O60683
gene_symbol: PEX10
product_type: PROTEIN
status: IN_PROGRESS
taxon:
  id: NCBITaxon:9606
  label: Homo sapiens
description: >-
  PEX10 (Peroxisome biogenesis factor 10) is an integral peroxisomal membrane protein
  containing a C-terminal C3HC4 RING finger domain. It is a component of the PEX2-PEX10-PEX12
  E3 ubiquitin ligase complex that forms a retrotranslocation channel in the peroxisomal
  membrane. PEX10 functions as an E3 ubiquitin-protein ligase (EC 2.3.2.27) that,
  together
  with PEX12, catalyzes monoubiquitination of the PTS1 receptor PEX5 at its conserved
  N-terminal cysteine (Cys11), an essential step for PEX5 recycling back to the cytosol
  during peroxisomal matrix protein import. When recycling is compromised, PEX10 participates
  in polyubiquitination of PEX5 leading to proteasomal degradation (RADAR pathway).
  The
  cryo-EM structure reveals that PEX10 contributes five transmembrane segments to
  the
  retrotranslocation channel, with its RING finger (RF10) forming part of the cytosolic
  tower
  positioned to facilitate ubiquitin transfer. Biallelic mutations in PEX10 cause
  Zellweger
  spectrum disorders (complementation group 7).
alternative_products:
- name: '1'
  id: O60683-1
- name: '2'
  id: O60683-2
  sequence_note: VSP_005771
existing_annotations:
# === Annotation 1: protein import into peroxisome matrix (IBA) ===
- term:
    id: GO:0016558
    label: protein import into peroxisome matrix
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  review:
    summary: >-
      PEX10 is required for peroxisomal matrix protein import. Loss of PEX10 abolishes
      import of PTS1 and PTS2 matrix proteins (PMID:9683594, PMID:9700193). PEX10
      functions
      within the PEX2-PEX10-PEX12 E3 ligase complex to ubiquitinate PEX5, which is
      essential
      for the import cycle (PMID:24662292). IBA annotation from phylogenetic analysis
      is
      well-supported and at the right level of specificity.
    action: ACCEPT
    reason: >-
      Core function of PEX10. Phylogenetic inference is consistent with extensive
      experimental
      evidence showing PEX10 is required for peroxisomal matrix protein import across
      eukaryotes. PEX10-deficient cells fail to import matrix proteins (PMID:9683594).
    supported_by:
    - reference_id: PMID:9683594
      supporting_text: >-
        PEX10-deficient PBD100 cells contain many peroxisomes and import peroxisomal
        membrane proteins but do not import peroxisomal matrix proteins, indicating
        that
        loss of PEX10 has its most pronounced effect on peroxisomal matrix-protein
        import.
    - reference_id: PMID:24662292
      supporting_text: >-
        RING peroxins are required for both modes of Pex5p ubiquitination, thus playing
        a pivotal role in Pex5p shuttling.

# === Annotation 2: peroxisomal membrane (IBA) ===
- term:
    id: GO:0005778
    label: peroxisomal membrane
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  review:
    summary: >-
      PEX10 is an integral peroxisomal membrane protein with five transmembrane segments
      (PMID:35768507). Localization confirmed by immunofluorescence and fractionation
      (PMID:9922452, PMID:9700193). IBA annotation is well-supported.
    action: ACCEPT
    reason: >-
      Core localization. PEX10 is an integral membrane protein of the peroxisome with
      multiple transmembrane domains. Confirmed experimentally and by structural analysis.
    supported_by:
    - reference_id: PMID:9922452
      supporting_text: >-
        The CG7 cell line, PBD100, is homozygous for a splice donor site mutation
        in
        PEX10 and expresses a PEX10 mRNA with a large internal deletion that lacks
        PEX10
        activity (Warren et al., 1998).
    - reference_id: PMID:35768507
      supporting_text: >-
        contributes five transmembrane segments that co-assemble into an open channel.

# === Annotation 3: peroxisomal membrane (IEA) ===
- term:
    id: GO:0005778
    label: peroxisomal membrane
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  review:
    summary: >-
      Automated annotation of peroxisomal membrane localization. Consistent with IBA
      and
      multiple IDA annotations for the same term.
    action: ACCEPT
    reason: >-
      Redundant with IBA and IDA annotations but correct. PEX10 is indeed a peroxisomal
      membrane protein.

# === Annotation 4: peroxisome organization (IEA) ===
- term:
    id: GO:0007031
    label: peroxisome organization
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  review:
    summary: >-
      PEX10 is involved in peroxisome biogenesis/organization. Loss of PEX10 function
      results in defective peroxisome biogenesis (Zellweger spectrum disorders). However,
      PEX10's primary role is specifically in matrix protein import via receptor recycling,
      not in peroxisome membrane formation or fission. Peroxisome ghosts (membrane
      structures)
      persist in PEX10-deficient cells (PMID:9683594).
    action: ACCEPT
    reason: >-
      While PEX10 does not directly organize peroxisome membranes (peroxisome ghosts
      persist
      in PEX10-null cells), it is required for functional peroxisome biogenesis. The
      term
      is broad enough to encompass PEX10's role in enabling functional peroxisomes
      through
      matrix protein import.
    supported_by:
    - reference_id: PMID:9700193
      supporting_text: >-
        HsPEX10 expression morphologically and biochemically restored peroxisome biogenesis
        in fibroblasts from Zellweger patients of complementation group B in Japan
        (complementation group VII in the USA).

# === Annotation 5: zinc ion binding (IEA) ===
- term:
    id: GO:0008270
    label: zinc ion binding
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  review:
    summary: >-
      PEX10 contains a C3HC4 RING finger domain (aa 273-311) that coordinates two
      zinc
      ions. UniProt records eight zinc-binding residues. The cryo-EM structure of
      the
      homologous fungal complex confirms zinc coordination in the RING domains
      (PMID:35768507).
    action: ACCEPT
    reason: >-
      The RING finger domain of PEX10 requires zinc ions for structural integrity
      and
      E3 ligase activity. Zinc binding is intrinsic to the RING domain fold.
    supported_by:
    - reference_id: PMID:35768507
      supporting_text: >-
        Cys residues are shown in yellow and Zn2+ atoms in grey.
    - reference_id: PMID:9700193
      supporting_text: >-
        This cDNA encodes a peroxisomal protein (a peroxin Pex10p) comprising 326
        amino
        acids, with two putative transmembrane segments and a C3HC4zinc finger RING
        motif.

# === Annotation 6: protein transport (IEA) ===
- term:
    id: GO:0015031
    label: protein transport
  evidence_type: IEA
  original_reference_id: GO_REF:0000043
  review:
    summary: >-
      IEA from UniProt keyword mapping. PEX10 is involved in protein transport (specifically
      peroxisomal matrix protein import). The term is overly broad but not incorrect.
    action: ACCEPT
    reason: >-
      While protein transport is very general, it is a valid parent term for PEX10's
      role in peroxisomal matrix protein import. More specific annotations (GO:0016558)
      are also present. IEA annotations at broader levels are acceptable alongside
      more
      specific ones.

# === Annotation 7: protein import into peroxisome matrix (IEA) ===
- term:
    id: GO:0016558
    label: protein import into peroxisome matrix
  evidence_type: IEA
  original_reference_id: GO_REF:0000002
  review:
    summary: >-
      IEA from InterPro mapping. Consistent with IBA and IDA annotations for the same
      term. PEX10 is well-established as required for peroxisomal matrix protein import.
    action: ACCEPT
    reason: >-
      Correct automated annotation, redundant with IBA and experimental annotations.

# === Annotation 8: transferase activity (IEA) ===
- term:
    id: GO:0016740
    label: transferase activity
  evidence_type: IEA
  original_reference_id: GO_REF:0000043
  review:
    summary: >-
      IEA from UniProt keyword mapping. PEX10 is classified as EC 2.3.2.27
      (ubiquitin-protein transferase). Transferase activity is a very broad parent
      term
      but technically correct.
    action: ACCEPT
    reason: >-
      Correct but very broad. PEX10 has ubiquitin-protein transferase activity (EC
      2.3.2.27)
      which is a type of transferase. More specific MF annotations (GO:0061630 ubiquitin
      protein ligase activity) are present.

# === Annotation 9: metal ion binding (IEA) ===
- term:
    id: GO:0046872
    label: metal ion binding
  evidence_type: IEA
  original_reference_id: GO_REF:0000043
  review:
    summary: >-
      IEA from UniProt keyword mapping. PEX10 binds zinc ions through its RING finger
      domain. Metal ion binding is a broad parent of zinc ion binding (GO:0008270).
    action: ACCEPT
    reason: >-
      Correct but broad. Redundant with the more specific zinc ion binding annotation
      (GO:0008270) also present.

# === Annotation 10: ubiquitin protein ligase activity (IEA) ===
- term:
    id: GO:0061630
    label: ubiquitin protein ligase activity
  evidence_type: IEA
  original_reference_id: GO_REF:0000003
  review:
    summary: >-
      IEA from EC number mapping. PEX10 has E3 ubiquitin-protein ligase activity
      (EC 2.3.2.27) demonstrated in vitro with E2 UbcH5C (PMID:24662292). Consistent
      with IDA annotation for the same term.
    action: ACCEPT
    reason: >-
      Core molecular function. PEX10 RING finger has demonstrated E3 ligase activity.
      Consistent with IDA evidence.

# === Annotation 11: protein import into peroxisome matrix (NAS) ===
- term:
    id: GO:0016558
    label: protein import into peroxisome matrix
  evidence_type: NAS
  original_reference_id: PMID:24662292
  review:
    summary: >-
      NAS annotation based on PMID:24662292. This paper directly demonstrates PEX10
      E3
      ligase activity is required for PEX5 ubiquitination and recycling, which is
      essential
      for matrix protein import. The paper shows that RING finger mutants of PEX10
      cannot
      restore peroxisomal protein import.
    action: ACCEPT
    reason: >-
      Core function well-supported by this reference. PMID:24662292 provides direct
      evidence
      that PEX10 E3 activity is essential for peroxisomal matrix protein import.
    supported_by:
    - reference_id: PMID:24662292
      supporting_text: >-
        Several lines of evidence with lysine-to-arginine mutants of Pex5p demonstrate
        that Pex10p RING E3-mediated ubiquitination of Pex5p is required for its efficient
        export from peroxisomes to the cytosol and peroxisomal matrix protein import.

# === Annotation 12: protein ubiquitination (IEA) ===
- term:
    id: GO:0016567
    label: protein ubiquitination
  evidence_type: IEA
  original_reference_id: GO_REF:0000041
  review:
    summary: >-
      IEA from UniPathway mapping. PEX10 is involved in protein ubiquitination, specifically
      ubiquitination of PEX5 receptor. Consistent with the demonstrated E3 ligase
      activity
      (PMID:24662292).
    action: ACCEPT
    reason: >-
      Correct. PEX10 catalyzes ubiquitination of PEX5 as its primary enzymatic function.
      More specific annotations for polyubiquitination and monoubiquitination aspects
      are
      also present.

# === Annotation 13: protein polyubiquitination (IDA) ===
- term:
    id: GO:0000209
    label: protein polyubiquitination
  evidence_type: IDA
  original_reference_id: PMID:24662292
  review:
    summary: >-
      PMID:24662292 demonstrates that PEX10 catalyzes polyubiquitination of PEX5 in
      vitro.
      The cryo-EM structure (PMID:35768507) further clarifies that when recycling
      is
      compromised, PEX5 is polyubiquitinated by the concerted action of RF10 and RF12
      and
      degraded via the RADAR pathway. Polyubiquitination is a secondary/quality-control
      function distinct from the primary monoubiquitination for recycling.
    action: ACCEPT
    reason: >-
      Experimentally demonstrated function of PEX10. While monoubiquitination for
      receptor
      recycling is the primary function, polyubiquitination for degradation is also
      a
      genuine activity of PEX10, particularly as part of the RADAR quality control
      pathway.
    supported_by:
    - reference_id: PMID:24662292
      supporting_text: >-
        The Pex10p·Pex12p complex catalyzes monoubiquitination of Pex5p at one of
        multiple lysine residues in vitro, following the dissociation of Pex5p from
        Pex14p and the PTS1 cargo.
    - reference_id: PMID:35768507
      supporting_text: >-
        If recycling is compromised, receptors are polyubiquitylated by the concerted
        action of RF10 and RF12 and degraded.

# === Annotation 14: peroxisomal membrane (IDA, PMID:12751901) ===
- term:
    id: GO:0005778
    label: peroxisomal membrane
  evidence_type: IDA
  original_reference_id: PMID:12751901
  review:
    summary: >-
      PMID:12751901 is primarily about PEX2 membrane targeting, not PEX10. The paper
      studies
      PEX2 targeting elements and uses PEX10/PEX12 for comparison in some experiments.
      PEX10
      localization to peroxisomal membrane is well-established from other references.
    action: ACCEPT
    reason: >-
      While this specific reference focuses on PEX2, PEX10 peroxisomal membrane localization
      is well-established from multiple other sources. The annotation itself is correct.
    supported_by:
    - reference_id: PMID:12751901
      supporting_text: >-
        Peroxin 2 (PEX2) is a 35-kDa integral peroxisomal membrane protein with two
        transmembrane regions and a zinc RING domain within its cytoplasmically exposed
        C-terminus.

# === Annotation 15: peroxisomal membrane (IDA, PMID:9090384) ===
- term:
    id: GO:0005778
    label: peroxisomal membrane
  evidence_type: IDA
  original_reference_id: PMID:9090384
  review:
    summary: >-
      PMID:9090384 is about PEX12 isolation and characterization, not directly about
      PEX10.
      The paper shows PEX12 localizes to peroxisome membrane and mentions PEX10 and
      PEX2 as
      related RING peroxins. Attribution of PEX10 localization to this reference may
      be
      indirect.
    action: ACCEPT
    reason: >-
      While the reference is primarily about PEX12, it establishes the RING peroxin
      family
      context. PEX10 peroxisomal membrane localization is unambiguously confirmed
      by other
      references. The annotation is correct.
    supported_by:
    - reference_id: PMID:9090384
      supporting_text: >-
        PEX12 shared the same subcellular distribution as yeast Pex12p and localized
        to
        the peroxisome membrane.

# === Annotation 16: protein quality control (ISS, PMID:35768507) ===
- term:
    id: GO:0006515
    label: protein quality control for misfolded or incompletely synthesized proteins
  evidence_type: ISS
  original_reference_id: PMID:35768507
  review:
    summary: >-
      PMID:35768507 demonstrates that the PEX2-PEX10-PEX12 complex mediates polyubiquitination
      and proteasomal degradation of import receptors when recycling fails (RADAR
      pathway).
      The paper also shows this pathway maintains homeostasis of other peroxisomal
      import
      factors. This is analogous to ERAD quality control. However, GO:0006515 specifically
      refers to misfolded/incompletely synthesized proteins, whereas PEX10 targets
      functional
      import receptors that are stuck in the membrane, not misfolded proteins per
      se.
    action: KEEP_AS_NON_CORE
    reason: >-
      The RADAR pathway is a quality control mechanism, but it targets import receptors
      that
      fail to recycle rather than classically misfolded proteins. The term is somewhat
      imprecise for this function but captures the quality control aspect. This is
      not a
      core function of PEX10.
    supported_by:
    - reference_id: PMID:35768507
      supporting_text: >-
        When the normal recycling of Pex5 or the other receptors is blocked, for example,
        by inactivating the Pex1–Pex6 ATPase, the receptors are instead polyubiquitylated
        on Lys residues and subsequently degraded by the proteasome.

# === Annotation 17: transmembrane protein transporter activity (ISS, PMID:35768507) ===
- term:
    id: GO:0008320
    label: protein transmembrane transporter activity
  evidence_type: ISS
  original_reference_id: PMID:35768507
  review:
    summary: >-
      PMID:35768507 demonstrates through cryo-EM that the PEX2-PEX10-PEX12 complex
      forms
      a retrotranslocation channel with a ~10 Angstrom pore. PEX10 contributes five
      transmembrane segments to this channel. The channel facilitates passage of PEX5
      through
      the peroxisomal membrane. This is based on the fungal complex structure but
      is inferred
      by sequence similarity for the human complex.
    action: ACCEPT
    reason: >-
      The structural evidence from PMID:35768507 strongly supports that PEX10 is part
      of a
      transmembrane protein transporter (retrotranslocation channel for PEX5). ISS
      from
      the fungal structure is well-justified given high conservation.
    supported_by:
    - reference_id: PMID:35768507
      supporting_text: >-
        Each subunit of the complex
        contributes five transmembrane segments that co-assemble into an open channel.

# === Annotation 18: cellular response to reactive oxygen species (IDA, PMID:26344566) ===
- term:
    id: GO:0034614
    label: cellular response to reactive oxygen species
  evidence_type: IDA
  original_reference_id: PMID:26344566
  review:
    summary: >-
      PMID:26344566 shows that the PEX2/PEX10/PEX12 E3 ligase is involved in pexophagy
      in response to ROS. However, PEX10 is not directly sensing or responding to
      ROS; rather
      ATM kinase senses ROS and phosphorylates PEX5, which then gets ubiquitinated
      by the
      PEX2/10/12 complex. The E3 ligase activity of PEX10 exists independently of
      ROS
      signaling. PEX10's role here is as a downstream effector (E3 ligase) rather
      than a
      direct participant in ROS response signaling.
    action: MARK_AS_OVER_ANNOTATED
    reason: >-
      PEX10 is not directly involved in sensing or responding to ROS. The paper demonstrates
      that ATM is the ROS sensor that phosphorylates PEX5, which then becomes a better
      substrate for ubiquitination by the PEX2/10/12 complex. PEX10 performs its constitutive
      E3 ligase activity on PEX5 regardless of ROS status. Annotating PEX10 to cellular
      response to ROS conflates the constitutive E3 ligase function with the ATM-mediated
      ROS signaling pathway.
    supported_by:
    - reference_id: PMID:26344566
      supporting_text: >-
        The RING peroxins PEX2, PEX10 and PEX12 are part of a peroxisome-localized
        E3
        ligase responsible for polyubiquitination of PEX534, and as expected, siRNA
        knockdown of these peroxins reduced polyubiquitination of PEX5 (Supplementary
        Fig. S5d).

# === Annotation 19: proteasome-mediated ubiquitin-dependent protein catabolic process (ISS) ===
- term:
    id: GO:0043161
    label: proteasome-mediated ubiquitin-dependent protein catabolic process
  evidence_type: ISS
  original_reference_id: PMID:35768507
  review:
    summary: >-
      PMID:35768507 demonstrates that when receptor recycling is blocked, the PEX2-PEX10-PEX12
      complex polyubiquitinates PEX5 and other import factors, targeting them for
      proteasomal
      degradation (RADAR pathway). ISS inference from the fungal system is well-justified.
    action: KEEP_AS_NON_CORE
    reason: >-
      This is a secondary quality control function (RADAR pathway) rather than the
      primary
      function of PEX10, which is monoubiquitination for receptor recycling. The proteasomal
      degradation pathway activates when normal recycling fails.
    supported_by:
    - reference_id: PMID:35768507
      supporting_text: >-
        If recycling is compromised, receptors are polyubiquitylated by the concerted
        action of RF10 and RF12 and degraded. This polyubiquitylation pathway also
        maintains the homeostasis of other peroxisomal import factors.

# === Annotation 20: peroxisomal membrane (IDA, PMID:9922452) ===
- term:
    id: GO:0005778
    label: peroxisomal membrane
  evidence_type: IDA
  original_reference_id: PMID:9922452
  review:
    summary: >-
      PMID:9922452 (South and Gould 1999) used PEX10-deficient PBD100 cells as a control
      and characterized PEX16. The paper describes PBD100 as CG7 with a PEX10 splice
      mutation. PEX10 localization to peroxisomal membrane is established by the epitope
      tagging and immunofluorescence work referenced in this paper and prior publications.
    action: ACCEPT
    reason: >-
      PEX10 peroxisomal membrane localization is well-established. UniProt records
      peroxisome membrane localization with evidence from PMID:9922452.
    supported_by:
    - reference_id: PMID:9922452
      supporting_text: >-
        The CG7 cell line, PBD100, is homozygous for a splice donor site mutation
        in
        PEX10 and expresses a PEX10 mRNA with a large internal deletion that lacks
        PEX10
        activity (Warren et al., 1998).

# === Annotation 21: protein import into peroxisome matrix, substrate release (ISS) ===
- term:
    id: GO:0044721
    label: protein import into peroxisome matrix, substrate release
  evidence_type: ISS
  original_reference_id: PMID:35768507
  review:
    summary: >-
      PMID:35768507 shows the PEX2-PEX10-PEX12 complex forms a retrotranslocation
      channel.
      The paper discusses that cargo release occurs after PEX5 docking and before
      receptor
      recycling. PEX10 is part of the translocation complex involved in cargo delivery.
      However, the specific role of PEX10 in substrate release (as opposed to receptor
      recycling) is less directly demonstrated.
    action: KEEP_AS_NON_CORE
    reason: >-
      While PEX10 is part of the translocation machinery, its primary demonstrated
      function
      is in receptor ubiquitination/recycling rather than substrate release specifically.
      The substrate release step involves the broader DTM complex. This annotation
      is not
      wrong but represents a secondary or indirect function.
    supported_by:
    - reference_id: PMID:35768507
      supporting_text: >-
        We propose that the N terminus of a recycling receptor is inserted from the
        peroxisomal lumen into the pore and monoubiquitylated by RF2 to enable extraction
        into the cytosol.

# === Annotation 22: protein import into peroxisome matrix, receptor recycling (IDA) ===
- term:
    id: GO:0016562
    label: protein import into peroxisome matrix, receptor recycling
  evidence_type: IDA
  original_reference_id: PMID:24662292
  review:
    summary: >-
      PMID:24662292 directly demonstrates that PEX10 E3 ligase activity is essential
      for
      PEX5 receptor recycling. The paper shows PEX10 ubiquitinates PEX5, which is
      required
      for PEX5 export from peroxisomes back to the cytosol. RING finger mutations
      abolish
      both E3 activity and peroxisome-restoring function.
    action: ACCEPT
    reason: >-
      Core function. PEX10-mediated ubiquitination of PEX5 is the key step enabling
      receptor
      recycling. This is the most specific and accurate annotation for PEX10's primary
      biological process function.
    supported_by:
    - reference_id: PMID:24662292
      supporting_text: >-
        Here, we establish an in vitro ubiquitination assay system and demonstrate
        that
        RING finger Pex10p functions as an E3 with an E2, UbcH5C. The E3 activity
        of
        Pex10p is essential for its peroxisome-restoring activity, being enhanced
        by
        another RING peroxin, Pex12p.
    - reference_id: PMID:24662292
      supporting_text: >-
        Several lines of evidence with lysine-to-arginine mutants of Pex5p demonstrate
        that Pex10p RING E3-mediated ubiquitination of Pex5p is required for its efficient
        export from peroxisomes to the cytosol and peroxisomal matrix protein import.

# === Annotation 23: ubiquitin protein ligase activity (IDA) ===
- term:
    id: GO:0061630
    label: ubiquitin protein ligase activity
  evidence_type: IDA
  original_reference_id: PMID:24662292
  review:
    summary: >-
      PMID:24662292 provides direct experimental evidence that PEX10 RING finger has
      E3
      ubiquitin ligase activity with UbcH5C as E2, and that this activity is enhanced
      by
      PEX12. Mutations C273A and C310G abolish ligase activity, as does the disease
      mutation H290Q.
    action: ACCEPT
    reason: >-
      Core molecular function directly demonstrated by in vitro ubiquitination assays.
      This is PEX10's primary enzymatic activity.
    supported_by:
    - reference_id: PMID:24662292
      supporting_text: >-
        Here, we establish an in vitro ubiquitination assay system and demonstrate
        that
        RING finger Pex10p functions as an E3 with an E2, UbcH5C.

# === Annotation 24: peroxisomal membrane (TAS, Reactome:R-HSA-8953917) ===
- term:
    id: GO:0005778
    label: peroxisomal membrane
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-8953917
  review:
    summary: >-
      Reactome pathway step describing PEX2:PEX10:PEX12 binding PEX5 and ubiquitin-conjugating
      enzymes at the peroxisomal membrane. Consistent with established localization.
    action: ACCEPT
    reason: >-
      Correct localization annotation from Reactome. Redundant with other peroxisomal
      membrane annotations but valid.

# === Annotation 25: peroxisomal membrane (TAS, Reactome:R-HSA-8953946) ===
- term:
    id: GO:0005778
    label: peroxisomal membrane
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-8953946
  review:
    summary: >-
      Reactome step for PEX2:PEX10:PEX12 monoubiquitinating PEX5 at Cys11. Peroxisomal
      membrane localization is correct.
    action: ACCEPT
    reason: Correct. Redundant with other peroxisomal membrane annotations.

# === Annotation 26: peroxisomal membrane (TAS, Reactome:R-HSA-9033235) ===
- term:
    id: GO:0005778
    label: peroxisomal membrane
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-9033235
  review:
    summary: >-
      Reactome step for cargo translocation. PEX10 is at the peroxisomal membrane
      during
      this process as part of the DTM.
    action: ACCEPT
    reason: Correct. Redundant with other peroxisomal membrane annotations.

# === Annotation 27: peroxisomal membrane (TAS, Reactome:R-HSA-9033236) ===
- term:
    id: GO:0005778
    label: peroxisomal membrane
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-9033236
  review:
    summary: >-
      Reactome step for PEX5 cargo binding to the docking and translocation module
      at
      the peroxisomal membrane.
    action: ACCEPT
    reason: Correct. Redundant with other peroxisomal membrane annotations.

# === Annotation 28: peroxisomal membrane (TAS, Reactome:R-HSA-9033485) ===
- term:
    id: GO:0005778
    label: peroxisomal membrane
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-9033485
  review:
    summary: >-
      Reactome step for PEX5L monoubiquitination at Cys11 at the peroxisomal membrane.
    action: ACCEPT
    reason: Correct. Redundant with other peroxisomal membrane annotations.

# === Annotation 29: peroxisomal membrane (TAS, Reactome:R-HSA-9033499) ===
- term:
    id: GO:0005778
    label: peroxisomal membrane
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-9033499
  review:
    summary: >-
      Reactome step for PEX1/PEX6-mediated receptor extraction from the peroxisomal
      membrane.
    action: ACCEPT
    reason: Correct. Redundant with other peroxisomal membrane annotations.

# === Annotation 30: peroxisomal membrane (TAS, Reactome:R-HSA-9033514) ===
- term:
    id: GO:0005778
    label: peroxisomal membrane
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-9033514
  review:
    summary: >-
      Reactome step for PEX5L:PEX7 cargo translocation at the peroxisomal membrane.
    action: ACCEPT
    reason: Correct. Redundant with other peroxisomal membrane annotations.

# === Annotation 31: peroxisomal membrane (TAS, Reactome:R-HSA-9033516) ===
- term:
    id: GO:0005778
    label: peroxisomal membrane
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-9033516
  review:
    summary: >-
      Reactome step for receptor export complex assembly at the peroxisomal membrane.
    action: ACCEPT
    reason: Correct. Redundant with other peroxisomal membrane annotations.

# === Annotation 32: peroxisomal membrane (TAS, Reactome:R-HSA-9033527) ===
- term:
    id: GO:0005778
    label: peroxisomal membrane
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-9033527
  review:
    summary: >-
      Reactome step for PEX5L binding and ubiquitin-conjugating enzyme recruitment
      at
      the peroxisomal membrane.
    action: ACCEPT
    reason: Correct. Redundant with other peroxisomal membrane annotations.

# === Annotation 33: peroxisomal membrane (TAS, Reactome:R-HSA-9033533) ===
- term:
    id: GO:0005778
    label: peroxisomal membrane
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-9033533
  review:
    summary: >-
      Reactome step for receptor export complex assembly at the peroxisomal membrane.
    action: ACCEPT
    reason: Correct. Redundant with other peroxisomal membrane annotations.

# === Annotation 34: zinc ion binding (NAS, PMID:10862081, isoform 2) ===
- term:
    id: GO:0008270
    label: zinc ion binding
  evidence_type: NAS
  original_reference_id: PMID:10862081
  isoform: O60683-2
  review:
    summary: >-
      PMID:10862081 discusses PEX10 genotype-phenotype relationships and emphasizes
      the
      importance of the C-terminal zinc-binding domain (RING finger) for PEX10 function.
      The paper notes that the zinc-binding domain is critical for PEX10 function.
      Zinc
      binding is a property of the RING domain present in both isoforms (isoform 2
      has
      an insertion at position 200, before the RING domain at 273-311).
    action: ACCEPT
    reason: >-
      Correct. The RING finger domain coordinates zinc ions, and this is essential
      for
      PEX10 function. Both isoforms retain the RING domain.
    supported_by:
    - reference_id: PMID:10862081
      supporting_text: >-
        These results demonstrate serious flaws in the PEX10 functional complementation
        assay, they do suggest that the C-terminal zinc-binding domain is critical
        for
        PEX10 function.

# === Annotation 35: protein import into peroxisome matrix (IMP, PMID:10862081, isoform 2) ===
- term:
    id: GO:0016558
    label: protein import into peroxisome matrix
  evidence_type: IMP
  original_reference_id: PMID:10862081
  isoform: O60683-2
  review:
    summary: >-
      PMID:10862081 reports phenotype-genotype relationships in PEX10-deficient patients.
      Mutations in PEX10 cause defective peroxisomal protein import (IMP evidence
      from
      mutant phenotype analysis). The functional complementation assay showed that
      PEX10
      expression restores matrix protein import in PEX10-deficient cells.
    action: ACCEPT
    reason: >-
      Core function confirmed by mutant phenotype analysis. PEX10 mutations cause
      loss of
      peroxisomal matrix protein import, demonstrating PEX10 is required for this
      process.
    supported_by:
    - reference_id: PMID:10862081
      supporting_text: >-
        All four PEX10-deficient Zellweger Syndrome (ZS) patients were found to have
        nonsense, frameshift, or splice site mutations that remove large portions
        of the
        PEX10 coding region.

# === Annotation 36: peroxisome (IDA, PMID:9922452) ===
- term:
    id: GO:0005777
    label: peroxisome
  evidence_type: IDA
  original_reference_id: PMID:9922452
  review:
    summary: >-
      PMID:9922452 uses PEX10-deficient cells as a control line. PEX10 localizes to
      peroxisomes. The more specific term peroxisomal membrane (GO:0005778) is also
      annotated
      with multiple evidence lines. GO:0005777 (peroxisome) is the parent term.
    action: ACCEPT
    reason: >-
      Correct localization. While GO:0005778 (peroxisomal membrane) is more specific
      and
      also annotated, GO:0005777 (peroxisome) is a valid broader annotation.

# === Annotation 37: protein binding (IPI, PMID:10837480) ===
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:10837480
  review:
    summary: >-
      PMID:10837480 demonstrates that PEX10 interacts with PEX12, PEX2, and PEX5 using
      yeast two-hybrid and in vitro binding assays. PEX12 RING finger binds PEX10,
      and
      PEX10 also interacts with PEX2 and PEX5. PEX12 was co-immunoprecipitated with
      PEX10
      from CHO-K1 cells. However, protein binding is an uninformative annotation.
    action: MODIFY
    reason: >-
      Protein binding is too vague to be informative. PEX10 has specific interactions
      with
      PEX12 (within the E3 ligase complex), PEX2 (within the retrotranslocation channel),
      and transiently with PEX5 (the ubiquitination substrate). These are functional
      interactions within the peroxisomal import machinery, not generic protein binding.
      A more informative term would be ubiquitin protein ligase activity (already
      annotated)
      or a term reflecting its role in the E3 ligase complex.
    proposed_replacement_terms:
    - id: GO:0061630
      label: ubiquitin protein ligase activity
    supported_by:
    - reference_id: PMID:10837480
      supporting_text: >-
        The RING finger of Pex12p bound to Pex10p and the PTS1-receptor Pex5p

# === Annotation 38: peroxisome organization (IDA, PMID:9700193) ===
- term:
    id: GO:0007031
    label: peroxisome organization
  evidence_type: IDA
  original_reference_id: PMID:9700193
  review:
    summary: >-
      PMID:9700193 shows that PEX10 expression restores peroxisome biogenesis in
      complementation group B fibroblasts. The paper demonstrates that PEX10 is required
      for functional peroxisome assembly, though its specific role is in matrix protein
      import rather than membrane assembly.
    action: ACCEPT
    reason: >-
      PEX10 is essential for peroxisome organization as demonstrated by restoration
      of
      peroxisome biogenesis upon PEX10 expression in patient cells. While the primary
      mechanism is through matrix protein import/receptor recycling, this directly
      impacts
      peroxisome organization.
    supported_by:
    - reference_id: PMID:9700193
      supporting_text: >-
        HsPEX10 expression morphologically and biochemically restored peroxisome biogenesis
        in fibroblasts from Zellweger patients of complementation group B in Japan
        (complementation group VII in the USA).

# === Annotation 39: protein import into peroxisome matrix (IDA, PMID:9683594) ===
- term:
    id: GO:0016558
    label: protein import into peroxisome matrix
  evidence_type: IDA
  original_reference_id: PMID:9683594
  review:
    summary: >-
      PMID:9683594 is the original identification of PEX10 as the gene defective in
      complementation group 7. The paper shows PEX10 expression rescues peroxisomal
      matrix-protein import in CG7 patient fibroblasts, and PEX10-deficient cells
      fail
      to import matrix proteins while membrane protein import is normal.
    action: ACCEPT
    reason: >-
      Core function with direct experimental evidence. This is the founding paper
      demonstrating PEX10 is required for peroxisomal matrix protein import.
    supported_by:
    - reference_id: PMID:9683594
      supporting_text: >-
        We identified the human orthologue of yeast PEX10 and observed that its expression
        rescues peroxisomal matrix-protein import in PBD patients' fibroblasts from
        complementation group 7 (CG7).
    - reference_id: PMID:9683594
      supporting_text: >-
        PEX10-deficient PBD100 cells contain many peroxisomes and import peroxisomal
        membrane proteins but do not import peroxisomal matrix proteins, indicating
        that
        loss of PEX10 has its most pronounced effect on peroxisomal matrix-protein
        import.

references:
- id: GO_REF:0000002
  title: Gene Ontology annotation through association of InterPro records with GO
    terms
  findings: []
- id: GO_REF:0000003
  title: Gene Ontology annotation based on Enzyme Commission mapping
  findings: []
- id: GO_REF:0000033
  title: Annotation inferences using phylogenetic trees
  findings: []
- id: GO_REF:0000041
  title: Gene Ontology annotation based on UniPathway vocabulary mapping
  findings: []
- id: GO_REF:0000043
  title: Gene Ontology annotation based on UniProtKB/Swiss-Prot keyword mapping
  findings: []
- id: GO_REF:0000120
  title: Combined Automated Annotation using Multiple IEA Methods
  findings: []
- id: PMID:10837480
  title: 'Molecular anatomy of the peroxin Pex12p: ring finger domain is essential
    for Pex12p function and interacts with the peroxisome-targeting signal type 1-receptor
    Pex5p and a ring peroxin, Pex10p.'
  findings:
  - statement: PEX10 interacts with PEX12 RING finger, PEX2, and PEX5 in yeast two-hybrid
      and in vitro binding assays
  - statement: PEX12 co-immunoprecipitates with PEX10 from CHO-K1 cells
- id: PMID:10862081
  title: Phenotype-genotype relationships in PEX10-deficient peroxisome biogenesis
    disorder patients.
  findings:
  - statement: C-terminal zinc-binding domain (RING finger) is critical for PEX10
      function
  - statement: PEX10-deficient patients show genotype-phenotype correlation with severe
      mutations causing ZS
- id: PMID:12751901
  title: The peroxisomal membrane targeting elements of human peroxin 2 (PEX2).
  findings:
  - statement: Primarily about PEX2 membrane targeting; establishes RING peroxin family
      context
- id: PMID:24662292
  title: Distinct modes of ubiquitination of peroxisome-targeting signal type 1 (PTS1)
    receptor Pex5p regulate PTS1 protein import.
  findings:
  - statement: PEX10 RING finger has E3 ubiquitin ligase activity with E2 UbcH5C
  - statement: E3 activity enhanced by PEX12
  - statement: PEX10-PEX12 complex monoubiquitinates PEX5 at multiple lysine residues
  - statement: PEX10 E3 activity required for PEX5 export and peroxisomal protein
      import
  - statement: RING finger mutations C273A and C310G abolish E3 activity
- id: PMID:26344566
  title: ATM functions at the peroxisome to induce pexophagy in response to ROS.
  findings:
  - statement: PEX2/10/12 E3 ligase participates in PEX5 ubiquitination during pexophagy
  - statement: Knockdown of RING peroxins reduces both mono- and polyubiquitination
      of PEX5
  - statement: ATM phosphorylates PEX5 at S141 to promote ubiquitination
- id: PMID:35768507
  title: A peroxisomal ubiquitin ligase complex forms a retrotranslocation channel.
  findings:
  - statement: Cryo-EM structure of PEX2-PEX10-PEX12 complex at 3.1 Angstrom resolution
  - statement: Each subunit contributes 5 TM segments forming an open channel with
      10 Angstrom pore
  - statement: RF10 and RF12 have extensive interface mediating RING-RING interaction
  - statement: RF2 positioned above pore for monoubiquitination; RF10 and RF12 cooperate
      for polyubiquitination
  - statement: Channel facilitates retrotranslocation of PEX5 through peroxisomal
      membrane
- id: PMID:9090384
  title: Isolation of the human PEX12 gene, mutated in group 3 of the peroxisome biogenesis
    disorders.
  findings:
  - statement: PEX12 localizes to peroxisome membrane; establishes PEX10/PEX2 as related
      RING peroxins
- id: PMID:9683594
  title: Identification of PEX10, the gene defective in complementation group 7 of
    the peroxisome-biogenesis disorders.
  findings:
  - statement: PEX10 identified as gene defective in CG7 of PBDs
  - statement: PEX10 expression rescues matrix protein import in CG7 cells
  - statement: PEX10-deficient cells import membrane but not matrix proteins
  - statement: H290Q missense mutation in zinc-binding domain identified in NALD patient
- id: PMID:9700193
  title: Mutations in PEX10 is the cause of Zellweger peroxisome deficiency syndrome
    of complementation group B.
  findings:
  - statement: PEX10 encodes 326 aa protein with two TM segments and C3HC4 RING motif
  - statement: Both N- and C-terminal regions exposed to cytosol
  - statement: PEX10 expression restores peroxisome biogenesis in CG-B patients
  - statement: RING finger required for biological function
- id: PMID:9922452
  title: Peroxisome synthesis in the absence of preexisting peroxisomes.
  findings:
  - statement: PEX10-deficient PBD100 cells used as control; PEX10 localizes to peroxisomes
- 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: []

core_functions:
- description: >-
    PEX10 functions as an E3 ubiquitin-protein ligase via its C-terminal C3HC4 RING
    finger
    domain. Together with PEX12, PEX10 monoubiquitinates the PTS1 receptor PEX5 at
    Cys11,
    which is essential for PEX5 recycling and continued peroxisomal matrix protein
    import.
    PEX10 also contributes to the retrotranslocation channel through which PEX5 is
    exported
    from the peroxisomal membrane back to the cytosol.
  molecular_function:
    id: GO:0061630
    label: ubiquitin protein ligase activity
  directly_involved_in:
  - id: GO:0016558
    label: protein import into peroxisome matrix
  locations:
  - id: GO:0005778
    label: peroxisomal membrane
  in_complex:
    id: GO:0000151
    label: ubiquitin ligase complex
  supported_by:
  - reference_id: PMID:24662292
    supporting_text: >-
      Here, we report that RING finger of human Pex10p possesses ubiquitin ligase
      activity with E2 UbcH5C and that the E3 activity is dramatically augmented by
      formation of a Pex10p complex with Pex12p
  - reference_id: PMID:35768507
    supporting_text: >-
      A peroxisomal ubiquitin ligase complex forms a retrotranslocation channel
  - reference_id: PMID:9683594
    supporting_text: >-
      PEX10-deficient PBD100 cells contain many peroxisomes and import peroxisomal
      membrane proteins but do not import peroxisomal matrix proteins