Affinage

PEX2

Peroxisome biogenesis factor 2 · UniProt P28328

Length
305 aa
Mass
34.8 kDa
Annotated
2026-06-10
32 papers in source corpus 12 papers cited in narrative 12 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 5/5 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

PEX2 is a peroxisomal integral membrane protein essential for peroxisome biogenesis and matrix protein import, acting through a cytosol-exposed C3HC4 RING finger that confers E3 ubiquitin ligase activity (PMID:19687296, PMID:9382874). Together with the RING peroxins PEX10 and PEX12, PEX2 mediates Ubc4-dependent polyubiquitination of the PTS1 import receptor PEX5, targeting it for proteasomal degradation as part of receptor recycling downstream of cargo recognition (PMID:19687296). Structurally, the protein spans the membrane twice via two transmembrane domains that carry its membrane-targeting information and are critical for peroxisome assembly, while the RING domain modulates import efficiency (PMID:12751901, PMID:10652207); a point mutation in the RING motif (Cys258) selectively abolishes PTS1-dependent import and blocks the final maturation step of PTS2 cargo such as thiolase, showing that distinct PEX2 functions govern docking, translocation, and receptor handling (PMID:10772890, PMID:12031794). PEX2 also serves as the E3 ligase for pexophagy: under amino acid starvation it ubiquitinates PEX5 and PMP70 to drive NBR1-dependent autophagic degradation of peroxisomes, with its expression controlled by mTORC1 signaling (PMID:27597759). Loss of PEX2 in mice abolishes functional peroxisome assembly, leaving only membrane ghosts, and causes very long chain fatty acid accumulation, plasmalogen deficiency, disordered neuronal migration, and neonatal lethality, and PEX2-truncating mutations cause severe peroxisome biogenesis disease in humans (PMID:9382874, PMID:10652207).

Mechanistic history

Synthesis pass · year-by-year structured walk · 8 steps
  1. 1996 Medium

    Established that the PEX2 family is a conserved peroxisomal integral membrane protein with a RING motif required for peroxisome biogenesis, answering whether this peroxin is needed for organelle formation.

    Evidence Gene cloning, loss-of-function, fractionation, and cross-species targeting of the Pichia pastoris PER6/PEX2 homolog

    PMID:8628321

    Open questions at the time
    • Did not define the biochemical activity of the RING motif
    • Ortholog-based; mammalian mechanism not directly tested
  2. 1997 High

    Demonstrated in vivo that PEX2 is essential for functional peroxisome assembly and for peroxisomal lipid metabolism and brain development, establishing physiological consequences of its loss.

    Evidence PEX2 knockout mice with VLCFA/plasmalogen biochemistry and neuroanatomical analysis

    PMID:9382874

    Open questions at the time
    • Did not resolve the molecular step PEX2 performs in import
    • Mechanism linking assembly defect to neuronal migration unaddressed
  3. 2000 Medium

    Separated the functional contributions of the transmembrane region and the RING domain, showing transmembrane domains drive assembly while the RING finger tunes import efficiency.

    Evidence Patient mutation characterization and complementation in PEX2-deficient CHO cells

    PMID:10652207 PMID:10772890

    Open questions at the time
    • Molecular activity of the RING domain not yet defined
    • How the RING domain affects import efficiency mechanistically unclear
  4. 2002 Medium

    Resolved that PEX2 acts downstream of both PTS1 and PTS2 receptors and contributes to multiple separable import steps, including thiolase maturation and a temperature-sensitive, catalase-specific import function.

    Evidence Genetic epistasis in Podospora anserina and biochemical/protease-protection analysis of multiple CHO PEX2 mutant alleles

    PMID:12031794 PMID:12054689 PMID:16987176

    Open questions at the time
    • Did not identify the enzymatic mechanism distinguishing these steps
    • Single-organism/lab evidence for each separable function
  5. 2003 Medium

    Defined the peroxisomal membrane targeting signal of PEX2, answering how the protein reaches the peroxisome membrane.

    Evidence GFP-fusion deletion and motif mutagenesis in COS-7 cells

    PMID:12751901

    Open questions at the time
    • Targeting machinery recognizing the motif not identified
    • Single lab, cell-based assay only
  6. 2009 High

    Identified PEX2 as a RING E3 ligase that polyubiquitinates PEX5 for proteasomal degradation via Ubc4, defining its molecular activity within the import/recycling cycle.

    Evidence In vitro ubiquitin ligase assays with defined E2 partners across the RING peroxins

    PMID:19687296

    Open questions at the time
    • Did not define how E3 activity is regulated in vivo
    • Relationship to membrane assembly function not integrated
  7. 2016 High

    Showed PEX2 is the E3 ligase driving pexophagy, ubiquitinating PEX5 and PMP70 under starvation to trigger NBR1-dependent autophagy under mTORC1 control, extending its role from import recycling to organelle turnover.

    Evidence PEX2 overexpression ubiquitination assays, NBR1 knockdown rescue, substrate identification, mTOR inhibitor treatment, and in vivo validation

    PMID:27597759

    Open questions at the time
    • How a single ligase switches between recycling and pexophagy substrates unresolved
    • Precise mTORC1-to-PEX2 transcriptional link not defined
  8. 2025 Medium

    Placed the Pex2/Pex10/Pex12 RING complex into the structural sequence of receptor recycling, showing it assembles with the Pex5/Pex8 complex after cargo release.

    Evidence Cryo-EM/structural analysis and translocation/mutagenesis assays in yeast (preprint)

    PMID:bio_10.1101_2025.08.30.673231

    Open questions at the time
    • Preprint, not peer-reviewed
    • Yeast ortholog system; mammalian complex architecture not directly shown

Open questions

Synthesis pass · forward-looking unresolved questions
  • How PEX2 substrate choice and activity are switched between routine receptor recycling and starvation-induced pexophagy at the molecular level remains unresolved.
  • No mechanism defining recycling vs. pexophagy substrate selection
  • Structural basis of mammalian RING complex assembly not established

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0016874 ligase activity 2 GO:0140096 catalytic activity, acting on a protein 2
Pathway
R-HSA-9609507 Protein localization 3 R-HSA-1852241 Organelle biogenesis and maintenance 2 R-HSA-9612973 Autophagy 1
Partners
NBR1PEX10PEX12PEX5PEX7PEX8PMP70
Complex memberships
Pex2/Pex10/Pex12 RING E3 ligase complex

Evidence

Reading pass · 12 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2009 PEX2 (along with PEX10 and PEX12) functions as a RING-domain E3 ubiquitin-protein isopeptide ligase in peroxisomal matrix protein import. Specifically, PEX2 mediates Ubc4-dependent polyubiquitination of the import receptor Pex5, targeting it for proteasomal degradation, while PEX12 mediates Pex4-dependent monoubiquitination of Pex5 for receptor recycling. In vitro ubiquitin ligase activity assays, RING domain functional analysis, identification of cognate E2 enzymes (Ubc4 vs Pex4) for each RING peroxin Molecular and cellular biology High 19687296
2016 Mammalian PEX2 is the E3 ubiquitin ligase responsible for pexophagy: its expression causes gross ubiquitination of peroxisomes and their degradation via an NBR1-dependent autophagic process. PEX5 and PMP70 are identified as direct substrates ubiquitinated by PEX2 during amino acid starvation. PEX2 expression is upregulated during amino acid starvation and rapamycin treatment, indicating that mTORC1 pathway controls pexophagy by regulating PEX2 levels. PEX2 overexpression with ubiquitination assays, NBR1 knockdown rescue experiments, substrate identification (PEX5 and PMP70), mTOR pathway inhibitor treatment, in vivo animal model validation The Journal of cell biology High 27597759
1997 Targeted deletion of PEX2 in mice abolishes functional peroxisome assembly (leaving only empty membrane ghosts), causes accumulation of very long chain fatty acids, deficient plasmalogens, disordered neuronal migration in cerebral cortex, and neonatal lethality, establishing PEX2 as essential for peroxisomal biogenesis and function in vivo. Gene targeting/knockout in mice, biochemical analysis (VLCFA, plasmalogens), immunohistochemistry, neuroanatomical analysis The Journal of cell biology High 9382874
2000 A missense mutation changing cysteine-258 to tyrosine in the RING finger motif of PEX2 selectively abolishes PTS1-dependent peroxisomal protein import while leaving PTS2-dependent import (e.g., 3-ketoacyl-CoA thiolase) intact, demonstrating that the RING finger domain is specifically required for the PTS1 import pathway. Site-directed mutagenesis of RING finger domain, immunocytochemical localization of PTS1 and PTS2 cargo proteins in CHO mutant cells and stable transformants with wild-type or mutant PEX2 cDNA Biochemical and biophysical research communications Medium 10772890
2003 The minimum peroxisomal membrane targeting signal of human PEX2 consists of an internal 30 amino acid region (AA130–159) plus the first transmembrane domain; the targeting motif 'KX6(I/L)X(L/F/I)LK(L/F/I)' within this region is essential, and mutations in it mislocalize PEX2 to the cytosol. The second transmembrane domain increases targeting efficiency but does not contain specific targeting information. GFP-fusion deletion constructs expressed in COS-7 cells with intracellular localization determination; motif mutagenesis; chimeric construct with heterologous transmembrane domain European journal of cell biology Medium 12751901
1998 Overexpression of PMP70 (a 70 kDa peroxisomal membrane protein) suppresses the peroxisome biogenesis defect caused by PEX2 mutations in CHO cells, restoring catalase latency, catalase localization, and VLCFA beta-oxidation, suggesting a functional interaction between PEX2 and PMP70 in the peroxisome membrane. A disease-causing mutant allele of PMP70 did not rescue, confirming specificity. Expression of PMP70 in PEX2-deficient CHO cell clones, subcellular catalase latency assay, immunohistochemical localization of catalase, VLCFA beta-oxidation assay European journal of cell biology Medium 9765053
2000 PEX2 encodes a 35-kDa peroxisomal membrane protein with two membrane-spanning domains and a C-terminal RING finger motif exposed to the cytosol. Mutations truncating the protein and removing both transmembrane domains and the RING domain cause severe disease, while a mutation disrupting only the C-terminal RING finger domain (del642G) causes milder phenotype with residual peroxisome assembly, demonstrating that the transmembrane domains are critical for peroxisome assembly and the C-terminal RING finger domain modulates import efficiency. Patient mutation characterization, expression of mutated PEX2 in PEX2-deficient CHO cells, immunocytochemistry for catalase-containing peroxisomes Biochemical and biophysical research communications Medium 10652207
2002 PEX2 functions in the peroxisomal RING-finger complex downstream of both PEX5 (PTS1 receptor) and PEX7 (PTS2 receptor), making it required for import of both PTS1 and PTS2 proteins. Genetic epistasis in Podospora anserina shows that pex2 deletion causes both metabolic (oleic acid growth) and developmental (meiotic commitment) defects, and that PEX2 has functions beyond those of the PTS1/PTS2 receptors. Genetic epistasis analysis in Podospora anserina (single and double knockouts of pex2, pex5, pex7), immunofluorescence and GFP staining for peroxisome biogenesis, growth assays Molecular microbiology Medium 16987176
2002 PEX2 protein functions differentially in two steps of thiolase (PTS2 cargo) maturation: its RING finger domain (Cys258) is required for the final maturation/processing step of thiolase precursor, while a distinct domain supports initial peroxisomal docking/association of the precursor. CHO cells with Pex2pC258Y mutation accumulate thiolase precursor in peroxisomes rather than excluding it to cytosol, in contrast to complete truncation mutants. SDS-PAGE analysis of thiolase precursor form, salt wash, sodium carbonate extraction, proteinase K protection assay, differential digitonin permeabilization with immunofluorescence in five PEX2 CHO mutant cell lines Biochimica et biophysica acta Medium 12031794
2002 A novel PEX2 point mutation (Arg50 nonsense) in CHO cells produces a unique phenotype: defective catalase import but temperature-sensitive PTS1 and PTS2 import (normal at 37°C, abrogated at 39°C), demonstrating that catalase import and general PTS1/PTS2 import are mechanistically separable functions of PEX2. Mutagenesis screen in CHO cells, temperature-shift experiments, immunolocalization of catalase and PTS1/PTS2 cargo proteins, sequencing of PEX2 mutation Biochemical and biophysical research communications Medium 12054689
1996 The Pichia pastoris PER6 gene product (Per6p), a homolog of human PAF-1/PEX2, is a peroxisomal integral membrane protein with a C3HC4 RING motif; loss of PER6 causes absence of morphologically recognizable peroxisomes and cytosolic mislocalization of peroxisomal matrix proteins, establishing the conserved role of this peroxin family in peroxisome biogenesis. Per6p is correctly targeted to mammalian peroxisomes, demonstrating evolutionary conservation of targeting. Gene cloning and functional complementation, immunolocalization, fractionation, cross-species targeting experiment (Per6p expressed in mammalian cells) Molecular and cellular biology Medium 8628321
2025 In yeast, the Pex2/Pex10/Pex12 E3-ubiquitin ligase complex assembles with the Pex5/Pex8 complex to initiate receptor recycling after cargo release into peroxisomes, as supported by structural and functional evidence showing that Pex8 interaction with Pex5 N-terminal domain is required for peroxisomal protein translocation and enables downstream assembly with the RING E3 complex. Cryo-EM/structural analysis of Pex8-Pex5 complex, functional translocation assays, mutagenesis of interaction interface bioRxivpreprint Medium bio_10.1101_2025.08.30.673231

Source papers

Stage 0 corpus · 32 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2009 Pex2 and pex12 function as protein-ubiquitin ligases in peroxisomal protein import. Molecular and cellular biology 164 19687296
2016 PEX2 is the E3 ubiquitin ligase required for pexophagy during starvation. The Journal of cell biology 152 27597759
1997 Targeted deletion of the PEX2 peroxisome assembly gene in mice provides a model for Zellweger syndrome, a human neuronal migration disorder. The Journal of cell biology 130 9382874
2003 Abnormal cerebellar histogenesis in PEX2 Zellweger mice reflects multiple neuronal defects induced by peroxisome deficiency. The Journal of comparative neurology 59 12746876
2007 Bile acid treatment alters hepatic disease and bile acid transport in peroxisome-deficient PEX2 Zellweger mice. Hepatology (Baltimore, Md.) 57 17393522
1996 The Pichia pastoris PER6 gene product is a peroxisomal integral membrane protein essential for peroxisome biogenesis and has sequence similarity to the Zellweger syndrome protein PAF-1. Molecular and cellular biology 55 8628321
2006 The peroxisomal import proteins PEX2, PEX5 and PEX7 are differently involved in Podospora anserina sexual cycle. Molecular microbiology 51 16987176
2001 The peroxisome deficient PEX2 Zellweger mouse: pathologic and biochemical correlates of lipid dysfunction. Journal of molecular neuroscience : MN 49 11478384
2010 Different functions of the C3HC4 zinc RING finger peroxins PEX10, PEX2, and PEX12 in peroxisome formation and matrix protein import. Proceedings of the National Academy of Sciences of the United States of America 48 20679226
2004 Disturbed cholesterol homeostasis in a peroxisome-deficient PEX2 knockout mouse model. Molecular and cellular biology 48 14673138
2011 Autosomal recessive cerebellar ataxia caused by mutations in the PEX2 gene. Orphanet journal of rare diseases 47 21392394
2006 Identification of novel mutations in PEX2, PEX6, PEX10, PEX12, and PEX13 in Zellweger spectrum patients. Human mutation 39 17041890
1996 The Yarrowia lipolytica gene PAY5 encodes a peroxisomal integral membrane protein homologous to the mammalian peroxisome assembly factor PAF-1. The Journal of biological chemistry 39 8702763
2012 Peroxisome deficiency-induced ER stress and SREBP-2 pathway activation in the liver of newborn PEX2 knock-out mice. Biochimica et biophysica acta 33 22441164
2012 Zellweger Spectrum Disorder with Mild Phenotype Caused by PEX2 Gene Mutations. JIMD reports 29 23430938
2002 Identification of six loci in which mutations partially restore peroxisome biogenesis and/or alleviate the metabolic defect of pex2 mutants in podospora. Genetics 20 12136013
2000 A missense mutation in the RING finger motif of PEX2 protein disturbs the import of peroxisome targeting signal 1 (PTS1)-containing protein but not the PTS2-containing protein. Biochemical and biophysical research communications 20 10772890
2003 Novel mutations in the PEX2 gene of four unrelated patients with a peroxisome biogenesis disorder. Pediatric research 18 14630978
2000 Molecular mechanism of detectable catalase-containing particles, peroxisomes, in fibroblasts from a PEX2-defective patient. Biochemical and biophysical research communications 18 10652207
1998 Analysis of isoprenoid biosynthesis in peroxisomal-deficient Pex2 CHO cell lines. Journal of lipid research 17 9741690
2003 The peroxisomal membrane targeting elements of human peroxin 2 (PEX2). European journal of cell biology 12 12751901
1998 Restoration of PEX2 peroxisome assembly defects by overexpression of PMP70. European journal of cell biology 12 9765053
2025 Jiangtang Tiaozhi formula ameliorates MASLD by regulating liver ABCD2/PEX2/ATGL axis-mediated fatty acid metabolic reprogramming. Phytomedicine : international journal of phytotherapy and phytopharmacology 7 40674914
2002 A novel pex2 mutant: catalase-deficient but temperature-sensitive PTS1 and PTS2 import. Biochemical and biophysical research communications 7 12054689
1994 Structure and expression of mammalian peroxisome assembly factor-1 (PMP35) genes. Biochemical medicine and metabolic biology 7 8043297
2013 A deleterious mutation in the PEX2 gene causes Zellweger syndrome in individuals of Ashkenazi Jewish descent. Clinical genetics 5 23590336
2002 Different accumulations of 3-ketoacyl-CoA thiolase precursor in peroxisomes of Chinese hamster ovary cells harboring a dysfunction in the PEX2 protein. Biochimica et biophysica acta 5 12031794
2000 Genomic organization and characterization of human PEX2 encoding a 35-kDa peroxisomal membrane protein. Biochemical and biophysical research communications 5 10891359
1994 Genetic evidence supporting the role of peroxisome assembly factor (PAF)-1 in peroxisome biogenesis. Polymerase chain reaction detection of a missense mutation in PAF-1 of Chinese hamster ovary cells. The Journal of biological chemistry 3 7512952
1998 Metabolic fate of platelet-activating factor (PAF, 1-O-alkyl-2-acetyl-sn-glycero-3-phosphocholine) and lyso-PAF (1-O-alkyl-2-lyso-sn-glycero-3-phosphocholine) in FRTL5 cells. Journal of lipid research 2 9643362
2025 Distinguishing PEX2 and PEX16 gene variant severity for mild, severe and atypical peroxisome biogenesis disorders. Disease models & mechanisms 1 40621817
2026 Dysregulated lipid metabolism and hypomyelination in postnatal peroxisome-deficient Pex2 knockout Zellweger mice. Frontiers in molecular neuroscience 0 41815956

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