ARBA00028584 peroxisomal membrane (GO:0005778)

id: ARBA00028584
description: >-
  Rule predicts GO:0005778 (peroxisomal membrane) localization for nine distinct
  protein families: fungal DysF-domain peroxins (PEX23-32), peroxisomal ABC
  transporters (ABCD1, ABCD3), peroxisomal import machinery (PEX13, PEX14),
  RING finger peroxins (PEX12), the peroxisomal solute carrier SLC25A17/PMP34,
  the autophagy cargo receptor NBR1, and peroxisomal 2,4-dienoyl-CoA reductase
  (DECR2). Each condition set uses different domain signatures with varying
  taxonomic restrictions.
status: COMPLETE
rule_type: ARBA
rule:
  rule_id: ARBA00028584
  condition_sets:
  - number: 1
    conditions:
    - condition_type: INTERPRO
      value: IPR010482
      curie: InterPro:IPR010482
      label: TECPR1-like, DysF domain
      negated: false
    - condition_type: TAXON
      value: '4751'
      curie: NCBITaxon:4751
      label: Fungi
      negated: false
    notes: >-
      Targets fungal DysF-domain peroxins PEX23, PEX24, PEX28, PEX29, PEX30,
      PEX31, and PEX32. UniProt search for IPR010482 + Fungi (reviewed) returns
      10 proteins, all established peroxisomal membrane proteins in S. cerevisiae,
      O. parapolymorpha, and S. pombe. The DysF domain in fungi is diagnostic
      for this peroxin subfamily. However, IPR010482 also covers non-fungal
      TECPR1 (an autophagy protein localized to lysosomes, not peroxisomes), so
      the Fungi taxonomic restriction is essential for accuracy. WELL-FOUNDED.
  - number: 2
    conditions:
    - condition_type: FUNFAM
      value: 3.40.50.300:FF:000800
      curie: CATH.FunFam:3.40.50.300:FF:000800
      label: ATP-binding cassette sub-family D member 1
      negated: false
    - condition_type: TAXON
      value: '314147'
      curie: NCBITaxon:314147
      label: Glires
      negated: false
    notes: >-
      Targets ABCD1 (adrenoleukodystrophy protein) in Glires (rodents +
      lagomorphs). ABCD1 is a well-established peroxisomal membrane ABC
      transporter that imports very long-chain fatty acyl-CoAs. Mutations cause
      X-linked adrenoleukodystrophy. The FunFam is specific to the ABCD1 NBD
      within the P-loop NTPase superfamily. The Glires restriction is overly
      narrow; ABCD1 is conserved across all vertebrates. WELL-FOUNDED but
      taxonomic scope should be broadened.
  - number: 3
    conditions:
    - condition_type: FUNFAM
      value: 2.30.30.40:FF:000109
      curie: CATH.FunFam:2.30.30.40:FF:000109
      label: Peroxisomal biogenesis factor 13
      negated: false
    - condition_type: TAXON
      value: '7711'
      curie: NCBITaxon:7711
      label: Chordata
      negated: false
    notes: >-
      Targets PEX13, a component of the peroxisomal docking/translocation
      machinery for matrix protein import. PEX13 contains an SH3 domain (CATH
      superfamily 2.30.30.40) and is an integral peroxisomal membrane protein.
      The FunFam label explicitly identifies it as PEX13. Chordata restriction
      is reasonable as the FunFam is trained on chordate sequences. WELL-FOUNDED.
  - number: 4
    conditions:
    - condition_type: FUNFAM
      value: 1.10.8.10:FF:000033
      curie: CATH.FunFam:1.10.8.10:FF:000033
      label: Next to BRCA1 gene 1 protein
      negated: false
    - condition_type: FUNFAM
      value: 2.60.40.10:FF:000199
      curie: CATH.FunFam:2.60.40.10:FF:000199
      label: next to BRCA1 gene 1 protein-like
      negated: false
    - condition_type: FUNFAM
      value: 3.30.60.90:FF:000007
      curie: CATH.FunFam:3.30.60.90:FF:000007
      label: Next to BRCA1 gene 1 protein
      negated: false
    notes: >-
      Targets NBR1 (Next to BRCA1 gene 1 protein) using three FunFam domains
      with no taxonomic restriction. NBR1 is primarily a cytoplasmic selective
      autophagy cargo receptor that is recruited to ubiquitinated peroxisomes
      during pexophagy. While NBR1 does associate with the peroxisomal surface
      during pexophagy (PMID:37493040, PMID:32388919), it is NOT an integral or
      peripheral peroxisomal membrane protein. Its primary localization is
      cytoplasm and autophagosomes. UniProt annotates human NBR1 (Q14596) with
      GO:0005778, but this annotation is debatable -- NBR1 transiently
      associates with peroxisomes as a signal for degradation, not as a
      resident membrane protein. PROBLEMATIC -- predicting peroxisomal membrane
      for an autophagy receptor risks false annotation of its primary function.
  - number: 5
    conditions:
    - condition_type: FUNFAM
      value: 1.20.1560.10:FF:000036
      curie: CATH.FunFam:1.20.1560.10:FF:000036
      label: ATP-binding cassette sub-family D member 3
      negated: false
    - condition_type: FUNFAM
      value: 3.40.50.300:FF:000636
      curie: CATH.FunFam:3.40.50.300:FF:000636
      label: ATP-binding cassette sub-family D member 3
      negated: false
    - condition_type: TAXON
      value: '9989'
      curie: NCBITaxon:9989
      label: Rodentia
      negated: false
    notes: >-
      Targets ABCD3 (PMP70) in Rodentia using both the transmembrane domain
      FunFam (ABC transporter type 1 TMD superfamily) and the NBD FunFam
      (P-loop NTPase superfamily). ABCD3 is a well-characterized peroxisomal
      membrane ABC transporter for branched-chain and long-chain fatty
      acyl-CoAs. The dual-FunFam requirement increases specificity. The
      Rodentia restriction is overly narrow; ABCD3 is conserved across
      vertebrates. Note partial overlap with CS2 (both target ABCD subfamily D
      but different members, ABCD1 vs ABCD3). WELL-FOUNDED but taxonomic scope
      should be broadened.
  - number: 6
    conditions:
    - condition_type: FUNFAM
      value: 1.50.40.10:FF:000023
      curie: CATH.FunFam:1.50.40.10:FF:000023
      label: peroxisomal membrane protein PMP34 isoform X1
      negated: false
    - condition_type: FUNFAM
      value: 1.50.40.10:FF:000045
      curie: CATH.FunFam:1.50.40.10:FF:000045
      label: peroxisomal membrane protein PMP34 isoform X1
      negated: false
    - condition_type: TAXON
      value: '2759'
      curie: NCBITaxon:2759
      label: Eukaryota
      negated: false
    notes: >-
      Targets SLC25A17/PMP34, the only member of the mitochondrial carrier
      family localized to peroxisomal membranes. Uses two FunFam domains from
      the mitochondrial carrier superfamily (1.50.40.10), both explicitly
      labeled as PMP34. The dual-FunFam requirement differentiates PMP34 from
      mitochondrial SLC25 family members. Eukaryota scope is appropriate as
      SLC25A17 is conserved across eukaryotes. PMID:22185573 demonstrates
      SLC25A17 is a peroxisomal transporter of CoA, FAD, and NAD+.
      WELL-FOUNDED.
  - number: 7
    conditions:
    - condition_type: FUNFAM
      value: 1.10.10.10:FF:000296
      curie: CATH.FunFam:1.10.10.10:FF:000296
      label: Peroxisomal membrane protein PEX14
      negated: false
    - condition_type: TAXON
      value: '10066'
      curie: NCBITaxon:10066
      label: Muridae
      negated: false
    notes: >-
      Targets PEX14, a core component of the peroxisomal docking complex for
      matrix protein import. The FunFam is from the winged helix-like
      superfamily, explicitly labeled as PEX14. PEX14 is an integral
      peroxisomal membrane protein conserved across all eukaryotes. The Muridae
      taxonomic restriction is excessively narrow -- PEX14 is found across all
      eukaryotes (PMID:37493040 describes PEX14 variants in human patients).
      WELL-FOUNDED but taxonomic scope far too narrow.
  - number: 8
    conditions:
    - condition_type: FUNFAM
      value: 3.30.40.10:FF:000266
      curie: CATH.FunFam:3.30.40.10:FF:000266
      label: Peroxisome assembly protein 12
      negated: false
    - condition_type: TAXON
      value: '89593'
      curie: NCBITaxon:89593
      label: Craniata
      negated: false
    notes: >-
      Targets PEX12, a RING finger E3 ubiquitin ligase that is an integral
      peroxisomal membrane protein. PEX12 forms a complex with PEX2 and PEX10
      in the peroxisomal membrane and is essential for matrix protein import.
      The FunFam is from the RING/zinc finger superfamily, explicitly labeled
      as PEX12. Craniata restriction is narrow but defensible for this specific
      FunFam. WELL-FOUNDED.
  - number: 9
    conditions:
    - condition_type: FUNFAM
      value: 3.40.50.720:FF:000477
      curie: CATH.FunFam:3.40.50.720:FF:000477
      label: Peroxisomal 2,4-dienoyl-CoA reductase
      negated: false
    - condition_type: TAXON
      value: '33208'
      curie: NCBITaxon:33208
      label: Metazoa
      negated: false
    notes: >-
      Targets DECR2 (peroxisomal 2,4-dienoyl-CoA reductase), a Rossmann-fold
      enzyme in the peroxisomal beta-oxidation pathway. DECR2 is a soluble
      peroxisomal enzyme. While UniProt Q9NUI1 carries GO:0005778 (peroxisomal
      membrane) via Reactome, DECR2 lacks transmembrane domains and is likely a
      peroxisomal matrix enzyme. The GO:0005778 annotation may be incorrect;
      GO:0005782 (peroxisomal matrix) may be more appropriate. DEBATABLE --
      the protein is peroxisomal but may not be membrane-associated.
  go_annotations:
  - go_id: GO:0005778
    go_label: peroxisomal membrane
    aspect: CC
  reviewed_protein_count: 0
  unreviewed_protein_count: 0
  created_date: '2021-10-20'
  modified_date: '2025-05-15'
  entries: []
review_summary: >-
  This rule predicts GO:0005778 (peroxisomal membrane) for nine protein
  families using diverse domain signatures. Contrary to the initial review
  that recommended deprecation based on "biological incoherence," enriched
  analysis of the actual condition sets reveals that 7 of 9 condition sets
  target well-established peroxisomal membrane proteins: fungal DysF-domain
  peroxins (CS1: PEX23-32), peroxisomal ABC transporters (CS2: ABCD1; CS5:
  ABCD3), peroxisomal import machinery (CS3: PEX13; CS7: PEX14), RING finger
  peroxins (CS8: PEX12), and the peroxisomal solute carrier (CS6: PMP34/
  SLC25A17). Two condition sets are problematic: CS4 targets NBR1, a
  cytoplasmic autophagy receptor that transiently associates with peroxisomes
  during pexophagy but is not a resident peroxisomal membrane protein; and
  CS9 targets DECR2, a peroxisomal matrix enzyme that likely lacks membrane
  association. The taxonomic restrictions are inconsistent, with some being
  far too narrow (PEX14 restricted to Muridae, ABCD3 to Rodentia) for
  proteins conserved across all eukaryotes. The rule should be MODIFIED to
  remove CS4 (NBR1) and potentially CS9 (DECR2), and to broaden taxonomic
  restrictions where justified. The initial deprecation recommendation was
  based on a review that lacked actual condition set data and made factually
  incorrect claims about the proteins targeted.
action: MODIFY
action_rationale: >-
  The rule is fundamentally biologically sound for 7 of 9 condition sets. The
  FunFam labels and InterPro domains unambiguously identify well-characterized
  peroxisomal membrane proteins: PEX23-32 (CS1), ABCD1 (CS2), PEX13 (CS3),
  ABCD3 (CS5), PMP34 (CS6), PEX14 (CS7), and PEX12 (CS8). Two modifications
  are needed: (1) Remove CS4 (NBR1) because NBR1 is a cytoplasmic pexophagy
  receptor that transiently associates with peroxisomes for degradation
  signaling, not a resident peroxisomal membrane protein. While some GO
  databases include GO:0005778 for NBR1, this represents over-annotation of
  a transient association. (2) Review CS9 (DECR2), which is a soluble
  peroxisomal enzyme without transmembrane domains -- GO:0005782 (peroxisomal
  matrix) may be more accurate. (3) Broaden overly narrow taxonomic
  restrictions: PEX14 (Muridae to at least Mammalia or Eukaryota), ABCD1
  (Glires to Vertebrata), ABCD3 (Rodentia to Vertebrata).
suggested_modifications:
- Remove condition set 4 (NBR1) -- NBR1 is a cytoplasmic autophagy receptor,
  not a peroxisomal membrane protein. Its transient recruitment to peroxisomes
  during pexophagy does not justify GO:0005778 annotation.
- Review condition set 9 (DECR2) -- DECR2 lacks transmembrane domains and is
  a soluble peroxisomal enzyme. Consider changing the GO annotation to
  GO:0005782 (peroxisomal matrix) or GO:0005777 (peroxisome).
- Broaden CS7 taxonomic scope from Muridae to at least Mammalia or Eukaryota,
  as PEX14 is conserved across all eukaryotes.
- Broaden CS2 taxonomic scope from Glires to Vertebrata or broader, as ABCD1
  is conserved across vertebrates.
- Broaden CS5 taxonomic scope from Rodentia to Vertebrata, as ABCD3 is
  conserved across vertebrates.
parsimony:
  assessment: ACCEPTABLE
  notes: >-
    The 9 condition sets target 7 distinct peroxisomal protein families using
    different domain architectures. Each condition set captures a structurally
    distinct protein family: DysF-domain peroxins, ABC transporter subfamily D
    members 1 and 3 (using different FunFam combinations), SH3-domain PEX13,
    PMP34 (mitochondrial carrier fold), winged-helix PEX14, RING-finger PEX12,
    and Rossmann-fold DECR2. The diversity of condition sets reflects the
    genuine structural diversity of peroxisomal membrane proteins, which span
    multiple unrelated protein folds. CS2 (ABCD1) and CS5 (ABCD3) both target
    ABCD family members but capture different paralogs using different FunFam
    signatures, which is appropriate. The only unnecessary complexity is CS4
    (NBR1), which targets a non-membrane protein.
  supported_by:
  - reference_id: file:rules/arba/ARBA00028584/ARBA00028584.enriched.json
    supporting_text: >-
      Condition sets use distinct domain signatures from different CATH
      superfamilies: 2.30.30.40 (SH3 domains for PEX13), 1.50.40.10
      (mitochondrial carrier for PMP34), 1.10.10.10 (winged helix for PEX14),
      3.30.40.10 (RING finger for PEX12), 3.40.50.720 (Rossmann-like for
      DECR2), 1.20.1560.10 and 3.40.50.300 (ABC transporter domains).
literature_support:
  assessment: STRONG
  notes: >-
    The peroxisomal membrane localization of the proteins targeted by 7 of 9
    condition sets is supported by extensive literature spanning decades of
    research. PEX23-32 are established yeast peroxisomal membrane peroxins.
    ABCD1 and ABCD3 are well-characterized peroxisomal ABC transporters with
    cryo-EM structures confirming their membrane integration. PEX13 and PEX14
    are core components of the peroxisomal import docking complex.
    SLC25A17/PMP34 was functionally characterized as the sole peroxisomal
    member of the mitochondrial carrier family. PEX12 is a RING finger E3
    ligase integral to the peroxisomal membrane. The only weakly supported
    condition sets are CS4 (NBR1 is an autophagy receptor, not a membrane
    protein) and CS9 (DECR2 may be a matrix rather than membrane enzyme).
  supported_by:
  - reference_id: PMID:22185573
    supporting_text: >-
      Recombinant and purified SLC25A17 was reconstituted into liposomes
  - reference_id: PMID:35908918
    supporting_text: >-
      ABCD1-3 are localized to peroxisomal membranes and involved in the
      transport of various acyl-CoAs from the cytosol to the peroxisomal lumen.
  - reference_id: PMID:37493040
    supporting_text: >-
      Inhibition of pexophagy by different autophagy inhibitors or genetic
      knockdown of the peroxisomal autophagy receptor NBR1 resulted in
      restoration of peroxisomal functions in the patients' fibroblasts.
  - reference_id: PMID:36541703
    supporting_text: >-
      PEX13, a component of the peroxisomal matrix import system, is required
      to prevent the degradation of otherwise healthy peroxisomes.
  - reference_id: PMID:36462131
    supporting_text: >-
      Pex30 is a peroxisomal protein whose role in peroxisome biogenesis via
      the endoplasmic reticulum has been established
  - reference_id: PMID:22342342
    supporting_text: >-
      Strikingly, TECPR1 localizes to and recruits Atg5 to autolysosome
      membrane
condition_overlap:
  assessment: MINOR
  notes: >-
    The 9 condition sets show minimal overlap because they target structurally
    distinct protein families using different CATH superfamily signatures. CS2
    (ABCD1, Glires) and CS5 (ABCD3, Rodentia) both target peroxisomal ABC
    transporters but capture different paralogs: ABCD1 (adrenoleukodystrophy
    protein) and ABCD3 (PMP70). Their FunFam identifiers are from different
    CATH superfamilies or different FunFams within the same superfamily,
    indicating they target genuinely different protein sets. The taxonomic
    overlap (Rodentia is a subset of Glires) means some rodent ABCD1 proteins
    could be captured by both CS2 and CS5 in principle, but since they use
    different FunFam signatures, the same protein will not match both condition
    sets. No other condition set pairs show meaningful overlap.
  supported_by:
  - reference_id: file:rules/arba/ARBA00028584/ARBA00028584.enriched.json
    supporting_text: >-
      CS2 uses FunFam 3.40.50.300:FF:000800 (labeled ABCD1) while CS5 uses
      FunFams 1.20.1560.10:FF:000036 and 3.40.50.300:FF:000636 (both labeled
      ABCD3). These are different FunFam families targeting different ABC
      transporter paralogs.
go_specificity:
  assessment: APPROPRIATE
  notes: >-
    GO:0005778 (peroxisomal membrane) is the correct cellular component term
    for 7 of 9 condition sets. The peroxisomal membrane is defined as "the
    lipid bilayer surrounding a peroxisome." Integral membrane proteins (ABCD1,
    ABCD3, PEX13, PEX14, PEX12, PMP34) and peripheral membrane proteins
    (PEX23-32 family) are all appropriately annotated with this term. Two
    condition sets may be better served by different GO terms: CS4 (NBR1)
    should use GO:0005776 (autophagosome) or a pexophagy-specific term; CS9
    (DECR2) should potentially use GO:0005782 (peroxisomal matrix) if it
    lacks genuine membrane association.
  supported_by:
  - reference_id: PMID:35908918
    supporting_text: >-
      ABCD1-3 are localized to peroxisomal membranes and involved in the
      transport of various acyl-CoAs from the cytosol to the peroxisomal lumen.
  - reference_id: PMID:22185573
    supporting_text: >-
      In the present study we have functionally identified and characterized
      SLC25A17 (solute carrier family 25 member 17), which is the only member
      of the mitochondrial carrier family that has previously been shown to be
      localized in the peroxisomal membrane
taxonomic_scope:
  assessment: TOO_NARROW
  notes: >-
    Several condition sets have taxonomic restrictions that are far too narrow
    relative to the biological conservation of their target proteins. PEX14
    (CS7, Muridae) is conserved across all eukaryotes -- restricting to Muridae
    misses the vast majority of organisms with PEX14. ABCD1 (CS2, Glires) and
    ABCD3 (CS5, Rodentia) are conserved across vertebrates. In contrast, CS1
    (IPR010482 + Fungi) is appropriately restricted because the DysF domain
    outside of fungi captures TECPR1, which is NOT a peroxisomal membrane
    protein. CS6 (PMP34, Eukaryota) has an appropriately broad scope. The
    inconsistency likely reflects the ARBA algorithm training on available
    annotation data rather than biological reality.
  supported_by:
  - reference_id: PMID:37493040
    supporting_text: >-
      We identified 2 different single heterozygous de novo variants in the
      PEX14 genes of 2 patients diagnosed with ZSD.
  - reference_id: PMID:31187491
    supporting_text: >-
      We found that the zebrafish genome contains two slc25a17 genes that
      function redundantly, but additively
confidence: 0.8
references:
- id: PMID:22185573
  title: >-
    The human gene SLC25A17 encodes a peroxisomal transporter of coenzyme A,
    FAD and NAD+
  findings:
  - statement: >-
      SLC25A17 is the only member of the mitochondrial carrier family
      localized to the peroxisomal membrane. It transports CoA, FAD, FMN,
      AMP, and to a lesser extent NAD+, PAP, and ADP into peroxisomes.
- id: PMID:35908918
  title: >-
    Substrate Specificity and the Direction of Transport in the ABC
    Transporters ABCD1-3 and ABCD4
  findings:
  - statement: >-
      ABCD1-3 are localized to peroxisomal membranes and transport various
      acyl-CoAs from the cytosol to the peroxisomal lumen. ABCD4 is
      lysosomal. Mutations in ABCD1, ABCD3, and ABCD4 cause genetic diseases.
- id: PMID:37493040
  title: >-
    Autosomal dominant Zellweger spectrum disorder caused by de novo variants
    in PEX14 gene
  findings:
  - statement: >-
      PEX14 is a core peroxisomal membrane protein required for matrix protein
      import. Truncated PEX14 exerts dominant-negative effects on peroxisome
      function. Knockdown of NBR1 restored peroxisomal functions, confirming
      NBR1's role as a pexophagy signal rather than a structural membrane
      component.
- id: PMID:36541703
  title: >-
    PEX13 prevents pexophagy by regulating ubiquitinated PEX5 and peroxisomal
    ROS
  findings:
  - statement: >-
      PEX13 is a component of the peroxisomal matrix import system and is
      required to prevent degradation of healthy peroxisomes. Loss of PEX13
      causes accumulation of ubiquitinated PEX5 on peroxisomes and induces
      pexophagy.
- id: PMID:36462131
  title: >-
    Characterization of the Multiple Domains of Pex30 Involved in Subcellular
    Localization of the Protein and Regulation of Peroxisome Number
  findings:
  - statement: >-
      Pex30 is a peroxisomal membrane protein with DysF domain that regulates
      peroxisome number. Lack of the DysF domain increases peroxisome number
      similar to PEX30 deletion. Pex30 facilitates contact site formation
      between peroxisomes and ER.
- id: PMID:22342342
  title: >-
    A mammalian autophagosome maturation mechanism mediated by TECPR1 and the
    Atg12-Atg5 conjugate
  findings:
  - statement: >-
      TECPR1 localizes to autolysosomes, NOT peroxisomes. This confirms that
      the DysF domain (IPR010482) in non-fungal organisms captures TECPR1
      which has a different localization, justifying the Fungi restriction
      in CS1.
- id: PMID:31187491
  title: >-
    Slc25a17 acts as a peroxisomal coenzyme A transporter and regulates
    multiorgan development in zebrafish
  findings:
  - statement: >-
      SLC25A17/PMP34 is a peroxisomal CoA transporter conserved from zebrafish
      to mammals, demonstrating the broad phylogenetic distribution of this
      peroxisomal membrane protein.
- id: PMID:32388919
  title: 'Mycobacterium tuberculosis Rv3034c regulates mTORC1 and PPAR-γ dependant pexophagy mechanism to control redox levels in macrophages.'
  findings:
  - statement: >-
      NBR1 and p62/SQSTM1 are described as pexophagy-associated adaptor
      molecules. M. tuberculosis Rv3034c down-regulates expression of NBR1
      and other pexophagy proteins to inhibit peroxisome degradation.
- id: file:rules/arba/ARBA00028584/ARBA00028584.enriched.json
  title: Enriched rule data with CATH FunFam and InterPro labels
  findings:
  - statement: >-
      FunFam labels explicitly identify the target proteins for each condition
      set: ABCD1, PEX13, NBR1, ABCD3, PMP34, PEX14, PEX12, and DECR2.
supported_by:
- reference_id: file:rules/arba/ARBA00028584/ARBA00028584.enriched.json
  supporting_text: >-
    All 9 condition sets have been identified via enriched FunFam labels. Seven
    of nine target well-established peroxisomal membrane proteins. CS4 targets
    NBR1 (autophagy receptor) and CS9 targets DECR2 (likely matrix enzyme).