Affinage

PEX26

Peroxisome assembly protein 26 · UniProt Q7Z412

Length
305 aa
Mass
33.9 kDa
Annotated
2026-04-29
17 papers in source corpus 9 papers cited in narrative 9 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

PEX26 is a tail-anchored peroxisomal membrane protein essential for peroxisome biogenesis that functions as the docking factor for the PEX1/PEX6 AAA ATPase complex, facilitating retrotranslocation and recycling of ubiquitinated PEX5 cargo receptor from the peroxisomal membrane (PMID:15858711, PMID:28742939). PEX26 is targeted to peroxisomes via PEX19, which binds two sites in the C-terminal region (one overlapping the transmembrane domain and one in the luminal domain) and delivers PEX26 to the peroxisomal membrane through PEX3, with basic residues in the luminal domain essential for correct targeting and prevention of mitochondrial mislocalization (PMID:16763195, PMID:23460677). PEX26 associates with the peroxisomal translocation pore via PEX14, undergoes homooligomerization through heptad repeat domains flanking its transmembrane domain, and its N-terminal region (aa 29–174) constitutes the PEX6-binding domain required for PEX1/PEX6 recruitment and peroxisomal matrix protein import (PMID:15858711, PMID:30366024, PMID:30446579). Loss of PEX26 function causes peroxisome biogenesis disorder complementation group 8, and PEX26 deficiency triggers ATM-dependent pexophagy and proteasomal degradation of ubiquitinated PEX5 (PMID:12851857, PMID:34074205).

Mechanistic history

Synthesis pass · year-by-year structured walk · 8 steps
  1. 2003 High

    The gene responsible for peroxisome biogenesis disorder complementation group 8 was unknown; identification of PEX26 and rescue of peroxisome assembly in patient fibroblasts established it as essential for peroxisome biogenesis.

    Evidence Complementation cloning in CG8 patient fibroblasts and pex26 CHO cells with catalase import rescue

    PMID:12851857

    Open questions at the time
    • Molecular mechanism by which PEX26 supports peroxisome assembly was not defined
    • No binding partners identified
  2. 2005 High

    The mechanism by which PEX26 supports peroxisome biogenesis was unclear; mapping of the PEX6-binding domain to the N-terminal region (aa 29–174) and demonstration that PEX26 serves as the peroxisomal docking factor for the PEX1/PEX6 AAA ATPase complex established its core molecular function.

    Evidence Co-immunoprecipitation, deletion mapping, chimeric PEX26-Mito redirection to mitochondria with functional rescue in PEX26-deficient cells

    PMID:15858711

    Open questions at the time
    • How PEX26 itself is targeted to peroxisomes was not resolved
    • Whether peroxisomal membrane localization is strictly required remained paradoxical given the soluble splice variant rescue
  3. 2006 High

    The targeting mechanism of PEX26 as a tail-anchored protein was undefined; identification of two PEX19-binding sites in the C-terminal region and demonstration that the luminal PEX19-binding site prevents mitochondrial mislocalization revealed the dual-signal targeting logic.

    Evidence Deletion/chimeric constructs, heterologous TMD insertion, PEX19 knockdown and binding assays, fluorescence microscopy

    PMID:16763195

    Open questions at the time
    • Whether PEX19 delivers PEX26 directly to peroxisomes or via the ER was not resolved
    • Role of TRC40/GET pathway in PEX26 targeting was not tested
  4. 2013 High

    The delivery pathway for PEX26 to peroxisomes was unresolved; demonstration that PEX19 forms a cytosolic complex with PEX26 and delivers it to peroxisomes via PEX3, independent of TRC40, defined a direct PEX19/PEX3-dependent insertion route.

    Evidence Co-immunoprecipitation, cytosol fractionation, dominant-negative TRC40 expression, site-directed mutagenesis of basic residues

    PMID:23460677

    Open questions at the time
    • Structural basis of PEX19–PEX26 recognition not determined
    • Whether additional chaperones participate in cytosolic PEX26 stabilization is unknown
  5. 2017 Medium

    Conservation and the direct substrate of the PEX26-dependent export machinery were uncertain; Arabidopsis pex26 mutants showed accumulation of ubiquitinated PEX5 on peroxisomal membranes and its proteasomal degradation, confirming that PEX26 functions in retrotranslocation of ubiquitinated PEX5 across kingdoms.

    Evidence Arabidopsis pex26 mutant analysis, proteasome inhibitor treatment, double-mutant epistasis with ubiquitination machinery

    PMID:28742939

    Open questions at the time
    • Plant ortholog evidence; direct demonstration of PEX5 retrotranslocation dependence on PEX26 in mammalian cells not shown in this study
    • Role of PEX26 in oil body utilization is correlative
  6. 2018 Medium

    How PEX26 integrates with the peroxisomal translocation machinery was unclear; identification of PEX26 homooligomerization via heptad repeat domains and its association with the translocation pore through PEX14 revealed its architectural role in connecting the exportomer to the importomer.

    Evidence Co-immunoprecipitation, domain mapping, functional rescue via peroxisomal β-oxidation assay

    PMID:30366024

    Open questions at the time
    • Stoichiometry and structure of the PEX26 oligomer not determined
    • Functional significance of differential splice variant interactions with PEX2-PEX10 versus PEX13-PEX14 is unclear
  7. 2019 Medium

    The functional significance of specific PEX26 residues for PEX1/PEX6 docking was unresolved; the F51L missense mutation demonstrated that a single N-terminal residue is critical for PEX1/PEX6 binding, protein stability, and peroxisomal matrix protein import.

    Evidence Co-immunoprecipitation and matrix protein import assays in patient fibroblasts carrying the PEX26-F51L mutation

    PMID:30446579

    Open questions at the time
    • Whether instability is the primary defect or loss of binding is causative was not disentangled
    • Structural basis of F51-dependent PEX6 interaction unknown
  8. 2021 Medium

    The broader interaction network of PEX26 and consequences of its loss for peroxisome homeostasis were incompletely defined; systematic interactomics revealed PEX26 as a hub connecting import, division, and membrane assembly pathways, while CRISPRi silencing showed that PEX26 loss triggers ATM-dependent pexophagy.

    Evidence Co-immunoprecipitation interaction screen with network analysis; CRISPRi knockdown with mass spectrometry, ATM inhibitor rescue, and in vivo xenograft model

    PMID:34074205 PMID:34804114

    Open questions at the time
    • Many novel interactions lack reciprocal validation
    • Mechanism by which ATM senses PEX26 deficiency is unknown
    • Whether pexophagy is a direct consequence of PEX5 recycling failure or a secondary quality-control response is unresolved

Open questions

Synthesis pass · forward-looking unresolved questions
  • No high-resolution structural model of PEX26 or the PEX1–PEX6–PEX26 ternary complex exists, and the mechanism by which PEX26 couples PEX1/PEX6 ATPase activity to PEX5 retrotranslocation across the peroxisomal membrane remains undefined.
  • No cryo-EM or crystal structure of PEX26 or the exportomer complex
  • Mechanochemical coupling between ATPase activity and receptor recycling not reconstituted
  • Functional role of the PEX26Δex5 splice variant in vivo is unclear

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0060090 molecular adaptor activity 3
Localization
GO:0005777 peroxisome 4
Pathway
R-HSA-1852241 Organelle biogenesis and maintenance 3 R-HSA-9609507 Protein localization 2 R-HSA-9612973 Autophagy 1
Partners
PEX1PEX14PEX19PEX3PEX5PEX6
Complex memberships
PEX1-PEX6-PEX26 exportomer

Evidence

Reading pass · 9 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2006 PEX26 is a tail-anchored peroxisomal membrane protein whose C-terminal targeting signal contains two PEX19-binding sites: one overlapping with the transmembrane domain (TMD) and one within the luminal domain. The luminal PEX19-binding site is essential for correct peroxisomal targeting, preventing mislocalization to mitochondria, and PEX19 is required for PEX26 import into peroxisomes. Targeting signal analysis by deletion/chimeric constructs, heterologous TMD insertion assay, PEX19 knockdown/binding assays, fluorescence microscopy Journal of cell science High 16763195
2003 PEX26 encodes an integral peroxisomal membrane protein (305 aa) that is deficient in peroxisome biogenesis disorder complementation group 8 (CG8); re-expression of PEX26 restores peroxisome assembly in CG8 patient fibroblasts, confirming its essential role in peroxisome biogenesis. Complementation assay in patient fibroblasts and pex26 CHO cells, catalase import assay, temperature-sensitivity rescue American journal of human genetics High 12851857
2005 PEX26 functions as the peroxisomal docking factor for the PEX1/PEX6 AAA ATPase heterodimer; the PEX6-binding domain maps to the N-terminal region (aa 29–174) of PEX26. A splice variant PEX26-Δex5 lacking the TMD retains full ability to rescue peroxisome biogenesis in PEX26-deficient cells, demonstrating that peroxisomal localization of PEX26 is not strictly required for its function. Co-immunoprecipitation, deletion mapping, chimeric protein (PEX26-Mito) redirected to mitochondria, rescue assay in PEX26-deficient cells, immunofluorescence American journal of human genetics High 15858711
2013 PEX19 forms a cytosolic complex with PEX26 and translocates it directly to peroxisomes by interacting with the peroxisomal membrane protein PEX3. Basic amino acids within the luminal domain of PEX26 are essential for PEX19 binding and peroxisomal targeting. Unlike yeast, the TRC40 ATPase (which delivers TA proteins to the ER) is dispensable for peroxisomal PEX26 targeting. Co-immunoprecipitation, cytosol fractionation, dominant-negative TRC40 expression, site-directed mutagenesis of basic residues, fluorescence microscopy The Journal of cell biology High 23460677
2018 PEX26 undergoes homooligomerization mediated by two heptad repeat domains adjacent to its transmembrane domain. PEX26 associates with the peroxisomal translocation pore via PEX14. The full-length PEX26 and the splice variant PEX26Δex5 show different interaction patterns with PEX2-PEX10 or PEX13-PEX14 complexes, and the splice variant uses a PEX14-dependent mechanism for peroxisomal membrane association. Co-immunoprecipitation, domain mapping, protein interaction assays, functional rescue (peroxisomal β-oxidation assay), fluorescence microscopy Biochimica et biophysica acta. Molecular cell research Medium 30366024
2019 The PEX26-F51L missense mutation severely impairs binding to PEX1 and PEX6 AAA ATPases and reduces peroxisomal matrix protein import rate; Pex26-F51L protein is unstable in cells (~30% of control levels), establishing that the N-terminal region of PEX26 is required for PEX1/PEX6 docking and peroxisome assembly. Co-immunoprecipitation in patient fibroblasts, immunostaining for matrix proteins (PTS1, PTS2, catalase), biochemical quantitation of protein levels, temperature-sensitivity assay Cold Spring Harbor molecular case studies Medium 30446579
2021 Systematic protein interaction screen identified 14 novel PEX26 protein-protein interactions, revealing PEX26 as a hub in the peroxisomal interactome. Variant-specific disruption of individual interactions (edgetic perturbations) correlates with severity of matrix protein import defects, and PEX26 participates in peroxisomal matrix protein import, division/proliferation, and membrane assembly. Organelle protein interaction screen (co-immunoprecipitation panel), network medicine analysis, correlation with matrix protein import phenotype Frontiers in genetics Medium 34804114
2021 Genetic silencing of PEX26 (component of the peroxisome exportomer complex with PEX1 and PEX6) via CRISPRi increases pexophagy and causes peroxisomal matrix protein import defects, linking the PEX1-PEX6-PEX26 complex to peroxisome homeostasis. ATM kinase mediates the pexophagy induced by PEX26 loss. CRISPRi knockdown, autophagosome enrichment by mass spectrometry, immunofluorescence for peroxisomal matrix proteins, ATM inhibitor rescue, in vivo xenograft model Autophagy Medium 34074205
2017 In Arabidopsis (plant ortholog context), PEX26 functions together with PEX1 and PEX6 to remove ubiquitinated PEX5 from the peroxisomal membrane (retrotranslocation); loss of PEX26 leads to proteasomal degradation of ubiquitinated PEX5 and defective peroxisomal matrix protein import. Peroxisomes cluster around persisting oil bodies in pex26 seedlings, suggesting a role in oil body utilization. Arabidopsis pex26 mutant genetic analysis, proteasome inhibitor treatment, double-mutant epistasis with ubiquitination machinery mutants, 35S:PEX5 transgene, fluorescence microscopy The Plant journal Medium 28742939

Source papers

Stage 0 corpus · 17 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2006 Targeting of the tail-anchored peroxisomal membrane proteins PEX26 and PEX15 occurs through C-terminal PEX19-binding sites. Journal of cell science 104 16763195
2013 Tail-anchored PEX26 targets peroxisomes via a PEX19-dependent and TRC40-independent class I pathway. The Journal of cell biology 80 23460677
2003 Mutations in novel peroxin gene PEX26 that cause peroxisome-biogenesis disorders of complementation group 8 provide a genotype-phenotype correlation. American journal of human genetics 66 12851857
2017 Next-generation sequencing reveals the mutational landscape of clinically diagnosed Usher syndrome: copy number variations, phenocopies, a predominant target for translational read-through, and PEX26 mutated in Heimler syndrome. Molecular genetics & genomic medicine 51 28944237
2005 Alternative splicing suggests extended function of PEX26 in peroxisome biogenesis. American journal of human genetics 41 15858711
2021 Silencing PEX26 as an unconventional mode to kill drug-resistant cancer cells and forestall drug resistance. Autophagy 17 34074205
2017 Disparate peroxisome-related defects in Arabidopsis pex6 and pex26 mutants link peroxisomal retrotranslocation and oil body utilization. The Plant journal : for cell and molecular biology 16 28742939
2019 A newly identified mutation in the PEX26 gene is associated with a milder form of Zellweger spectrum disorder. Cold Spring Harbor molecular case studies 14 30446579
2018 Isoform-specific domain organization determines conformation and function of the peroxisomal biogenesis factor PEX26. Biochimica et biophysica acta. Molecular cell research 12 30366024
2021 Identification of a Homozygous PEX26 Mutation in a Heimler Syndrome Patient. Genes 7 33926089
2021 PEX26 gene genotype-phenotype correlation in neonates with Zellweger syndrome. Translational pediatrics 4 34430430
2023 PEX26 Functions as a Metastasis Suppressor in Colorectal Cancer. Digestive diseases and sciences 3 37957408
2021 A novel mutation in the PEX26 gene in a family from Dagestan with members affected by Zellweger spectrum disorder. Molecular genetics and metabolism reports 3 33912394
2025 Zellweger syndrome; identification of mutations in PEX19 and PEX26 gene in Saudi families. Annals of medicine 2 39757991
2021 Edgetic Perturbations Contribute to Phenotypic Variability in PEX26 Deficiency. Frontiers in genetics 2 34804114
2024 Identification of a novel heterozygous variant in the PEX26 gene in an infant: a case report. Translational pediatrics 1 38323187
2024 Biallelic Deletion of PEX26 Exon 4 in a Boy with Phenotypic Features of both Zellweger Syndrome and Infantile Refsum Disease. Molecular syndromology 0 39359950