Peroxisome Biogenesis Project
Overview
Peroxisomes are single-membrane-bound organelles found in virtually all eukaryotic cells.
They perform essential metabolic functions including fatty acid beta-oxidation (especially
very long-chain fatty acids), ether lipid (plasmalogen) synthesis, bile acid synthesis,
and reactive oxygen species metabolism. The peroxisome biogenesis machinery is encoded by
PEX (peroxin) genes, mutations in which cause Zellweger spectrum disorders (ZSD) and
other peroxisomal biogenesis disorders (PBDs).
Model Species
Primary: Homo sapiens (human)
- Zellweger spectrum disorders provide clinical relevance
- Comprehensive proteomics data available
- Well-characterized import pathways
Functional Architecture of the PEX Machinery
1. Membrane Protein Insertion (Class I)
- PEX3 - Membrane anchor for PEX19-cargo complexes
- PEX19 - Cytosolic chaperone/receptor for peroxisomal membrane proteins (PMPs)
- PEX16 - Membrane receptor, recruits PEX3 to peroxisomes
2. Matrix Protein Import - Receptors (Class II)
- PEX5 - PTS1 (C-terminal -SKL) receptor, cycling receptor
- PEX7 - PTS2 (N-terminal nonapeptide) receptor
3. Docking Complex (Class III)
- PEX13 - Docking complex component, SH3 domain
- PEX14 - Central docking component, forms transient pore
4. RING Complex / Ubiquitination (Class IV)
- PEX2 - E3 ubiquitin ligase (RING domain)
- PEX10 - E3 ubiquitin ligase (RING domain)
- PEX12 - E3 ubiquitin ligase (RING domain)
5. Receptor Recycling / AAA ATPase Complex (Class V)
- PEX1 - AAA+ ATPase, receptor export
- PEX6 - AAA+ ATPase, receptor export
- PEX26 - Membrane anchor for PEX1-PEX6 complex
6. Peroxisome Proliferation / Division (Class VI)
- PEX11A - Peroxisome elongation/proliferation (inducible)
- PEX11B - Peroxisome elongation/proliferation (constitutive)
- PEX11G - Peroxisome elongation/proliferation (tissue-specific)
Evolutionary Conservation
The PEX machinery shows tiered conservation:
- Deeply conserved (yeast to human): PEX1, 2, 3, 5, 6, 7, 10, 12, 13, 14, 19
- Metazoan innovations: PEX11 family expansion (1 in yeast -> 3 in human)
- Vertebrate-specific: PEX26 (replaces yeast PEX15, convergent evolution)
- Recently characterized: PEX5L (PEX5-related), PEX39
Key reference: Jansen et al. (2021) "Comparative Genomics of Peroxisome Biogenesis Proteins:
Making Sense of the PEX Proteins" Front Cell Dev Biol 9:654163.
Disease Relevance
| Disease | OMIM | Key Genes |
|---|---|---|
| Zellweger syndrome (most severe) | 214100 | PEX1, PEX2, PEX3, PEX5, PEX6, PEX10, PEX12, PEX13, PEX14, PEX16, PEX19, PEX26 |
| Neonatal adrenoleukodystrophy | 202370 | PEX1, PEX5, PEX10, PEX13, PEX26 |
| Infantile Refsum disease | 266510 | PEX1, PEX2, PEX26 |
| Rhizomelic chondrodysplasia punctata type 1 | 215100 | PEX7 |
| Heimler syndrome | 234580 | PEX1, PEX6 |
PEX1 is the most commonly mutated gene (~65% of ZSD cases), followed by PEX6 (~16%) and PEX26 (~5%).
Candidate Genes - Priority Order
Priority is based on: (1) disease prevalence in ZSD, (2) functional centrality,
(3) evolutionary conservation depth.
Phase 1: Core Import/Recycling (highest priority)
| Gene | UniProt | Function | ZSD Frequency |
|---|---|---|---|
| PEX1 | O43933 | AAA+ ATPase, receptor recycling | ~65% |
| PEX5 | P50542 | PTS1 receptor | ~4% |
| PEX6 | Q13608 | AAA+ ATPase, receptor recycling | ~16% |
| PEX7 | O00628 | PTS2 receptor | RCDP1 |
| PEX14 | O75381 | Docking complex | Rare |
| PEX26 | Q7Z412 | PEX1/PEX6 anchor | ~5% |
Phase 2: RING Complex & Docking
| Gene | UniProt | Function | ZSD Frequency |
|---|---|---|---|
| PEX2 | P28328 | RING E3 ligase | ~3% |
| PEX10 | O60683 | RING E3 ligase | ~3% |
| PEX12 | O00623 | RING E3 ligase | ~4% |
| PEX13 | Q92968 | Docking complex, SH3 | Rare |
Phase 3: Membrane Biogenesis & Proliferation
| Gene | UniProt | Function |
|---|---|---|
| PEX3 | P56589 | PMP membrane anchor |
| PEX16 | Q9Y5Y5 | PMP membrane receptor |
| PEX19 | P40855 | PMP chaperone/receptor |
| PEX11A | O75192 | Proliferation (inducible) |
| PEX11B | O96011 | Proliferation (constitutive) |
| PEX11G | Q96HA9 | Proliferation (tissue-specific) |
STATUS
Phase 1 Genes
- [x] PEX1 (O43933)
- [x] PEX5 (P50542)
- [x] PEX6 (Q13608)
- [x] PEX7 (O00628)
- [x] PEX14 (O75381)
- [x] PEX26 (Q7Z412)
Phase 2 Genes
Phase 3 Genes
- [x] PEX3 (P56589)
- [x] PEX16 (Q9Y5Y5)
- [x] PEX19 (P40855)
- [x] PEX11A (O75192)
- [x] PEX11B (O96011)
- [x] PEX11G (Q96HA9)
NOTES
2026-03-05
- Phase 3 annotation reviews complete (all 6 genes: PEX3, PEX16, PEX19, PEX11A, PEX11B, PEX11G)
- Key findings across Phase 3:
- PEX19: 37 REMOVE actions (45% of annotations!) — likely many protein binding annotations from HTP interactome studies
- PEX3: 17 over-annotations flagged — highest proportion of any gene; many downstream metabolic processes
- PEX11B: 12 over-annotations — many guilt-by-phenotype annotations from KO studies
- PEX11G: smallest gene (11 annotations) reviewed cleanly; tissue-specific role confirmed
- PEX16: 3 annotations removed; well-characterized ER-to-peroxisome pathway annotations retained
- Several NEW annotations proposed across Phase 3 genes (PEX16, PEX19, PEX11A, PEX11G)
- Review statistics:
- PEX3: 47 annotations (20 ACCEPT, 17 OVER, 6 MODIFY, 3 NON_CORE, 1 UNDECIDED)
- PEX16: 34 annotations (26 ACCEPT, 3 REMOVE, 3 MODIFY, 1 OVER, 1 NEW)
- PEX19: 82 annotations (38 ACCEPT, 37 REMOVE, 4 NEW, 1 MODIFY, 1 OVER, 1 NON_CORE)
- PEX11A: 21 annotations (17 ACCEPT, 2 REMOVE, 1 OVER, 1 NEW)
- PEX11B: 40 annotations (23 ACCEPT, 12 OVER, 3 NON_CORE, 2 REMOVE)
-
PEX11G: 12 annotations (8 ACCEPT, 1 REMOVE, 1 MODIFY, 1 OVER, 1 NEW)
-
Phase 2 annotation reviews complete (all 4 genes: PEX2, PEX10, PEX12, PEX13)
- Key findings across Phase 2:
- RING complex (PEX2/PEX10/PEX12) shows cleaner annotations than Phase 1 receptors — fewer over-annotations
- PEX2: 5 annotations removed, including generic protein binding; 9 non-core (downstream metabolic processes)
- PEX10: cleanest review — only 1 over-annotation, 1 modify; strong ISS evidence from cryo-EM channel paper (PMID:35768507)
- PEX12: 4 modify actions, mostly refining E3 ligase specificity; bridges RING complex to docking via PEX5/PEX10 interactions
- PEX13: 8 over-annotations flagged (mostly downstream metabolic); 1 NEW annotation proposed; SH3 domain scaffold function confirmed
- Review statistics:
- PEX2: 59 annotations (40 ACCEPT, 9 NON_CORE, 5 REMOVE, 4 OVER, 1 UNDECIDED)
- PEX10: 39 annotations (34 ACCEPT, 3 NON_CORE, 1 MODIFY, 1 OVER)
- PEX12: 55 annotations (44 ACCEPT, 6 NON_CORE, 4 MODIFY, 1 OVER)
-
PEX13: 52 annotations (35 ACCEPT, 8 OVER, 8 NON_CORE, 1 NEW)
-
Phase 1 annotation reviews complete (all 6 genes)
- Key findings across Phase 1:
- Pervasive over-annotation of generic "protein binding" (GO:0005515) across all genes (25+ instances)
- PEX7: homodimerization annotation (GO:0042803) contradicted by cited paper PMID:10978175 which shows WD40 repeat mediates PTS2 binding, not dimerization
- PEX14: phase separation behavior emerging as new paradigm for import pore (PMID:34551879)
- PEX14: beta-tubulin binding (GO:0048487) is a validated core function, connecting peroxisomes to cytoskeleton
- PEX5: 118 annotations reviewed, highest annotation count; 19 over-annotations flagged
- PEX26: convergent evolution with yeast PEX15 visible in annotation evidence patterns
- Guilt-by-cargo pattern: several genes annotated with cargo metabolic processes (e.g. ether lipid biosynthesis for PEX7)
- Review statistics:
- PEX1: 52 annotations (46 ACCEPT, 4 REMOVE, 1 OVER, 1 NON_CORE)
- PEX5: 118 annotations (89 ACCEPT, 19 OVER, 4 NON_CORE, 3 MODIFY, 2 REMOVE, 1 UNDECIDED)
- PEX6: 50 annotations (43 ACCEPT, 4 MODIFY, 3 NON_CORE)
- PEX7: 47 annotations (35 ACCEPT, 6 REMOVE, 2 MODIFY, 2 OVER, 2 NON_CORE)
- PEX14: 81 annotations (56 ACCEPT, 17 OVER, 4 NON_CORE, 3 MODIFY, 1 REMOVE)
- PEX26: 36 annotations (24 ACCEPT, 8 OVER, 3 NON_CORE, 1 REMOVE)
2026-05-01
- Tracking upstream obsoletion of GO:0005052/GO:0005053/GO:0033328 (peroxisome
matrix/membrane targeting signal binding) → merged into renamed parent
"peroxisome signal sequence receptor activity". Affects PEX5, PEX7, PEX19
reviews. See PEROXISOME_TARGETING_SIGNAL_OBSOLETION.md.
2026-03-05 (initial)
- Project created, focusing on human peroxisome biogenesis (PEX) genes
- Prioritized Phase 1 as core import/recycling machinery (PEX1, PEX5, PEX6, PEX7, PEX14, PEX26)
- PEX1 is highest priority: most commonly mutated in Zellweger spectrum disorders
- Will start with Phase 1 genes, fetching data and performing annotation review