Affinage

PEX5

Peroxisomal targeting signal 1 receptor · UniProt P50542

Length
639 aa
Mass
70.9 kDa
Annotated
2026-04-29
100 papers in source corpus 39 papers cited in narrative 39 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

PEX5 is the cytosolic cycling receptor for peroxisomal matrix protein import, recognizing PTS1 cargo through its C-terminal TPR domain and, in its longer isoform (PEX5L), bridging PTS2 cargo via a conserved N-terminal motif that binds PEX7 (PMID:7719337, PMID:11101887, PMID:9418886, PMID:11546814). Cargo-loaded PEX5 docks at the peroxisomal membrane through multiple WxxxF/Y pentapeptide motifs that bind PEX14 with nanomolar affinity, then inserts fully into the lumenal cavity of the docking/translocation machinery (DTM) where it releases cargo; PEX5 is subsequently monoubiquitinated at a conserved cysteine (Cys11) via a thioester bond whose reversibility prevents polyubiquitination, and the ubiquitin–PEX5 conjugate is extracted back to the cytosol by the PEX1–PEX6 AAA-ATPase complex through global unfolding of both ubiquitin and PEX5 (PMID:10026185, PMID:11438541, PMID:35931083, PMID:29884772, PMID:36442669, PMID:38470934). Cys11 additionally serves as a redox sensor that inactivates PEX5 under oxidative stress, preferentially retaining catalase in the cytosol as a protective response, while monoubiquitinated PEX5 that fails to be exported acts as a pexophagy signal linking import failure to organelle quality control (PMID:24118911, PMID:28760655, PMID:26086376, PMID:36541703). Mutations in PEX5 cause peroxisome biogenesis disorders: complete loss underlies Zellweger-spectrum disease (complementation group 2), whereas isoform-specific PEX5L mutations cause rhizomelic chondrodysplasia punctata type 5 (RCDP5), and a PEX7-interaction-domain missense variant causes congenital cataracts (PMID:7719337, PMID:26220973, PMID:33389129).

Mechanistic history

Synthesis pass · year-by-year structured walk · 20 steps
  1. 1995 High

    Identification of PEX5 as the cytosolic PTS1 receptor resolved how peroxisomal matrix proteins are recognized in the cytosol and established that PEX5 mutations define complementation group 2 of peroxisome biogenesis disorders.

    Evidence Complementation cloning and rescue of PTS1 import in patient fibroblasts

    PMID:7719337

    Open questions at the time
    • Mechanism of membrane engagement unknown
    • Structural basis for PTS1 recognition undetermined
    • Role in PTS2 import unclear
  2. 1998 High

    Discovery of two PEX5 isoforms (PEX5S and PEX5L) established that the longer isoform is uniquely required for PTS2 protein import, separating PTS1 and PTS2 import pathways at the receptor level.

    Evidence CHO cell mutant complementation with isoform-specific constructs and TPR mutagenesis

    PMID:9418886

    Open questions at the time
    • Molecular basis of PEX5L–PEX7 interaction not mapped
    • Whether PEX5L acts as a co-receptor or independent receptor for PTS2 unclear
  3. 1999 High

    Mapping of multiple PEX14-binding sites in PEX5's N-terminal half and demonstration of nanomolar affinity defined the docking mechanism at the peroxisomal membrane, while interaction with PEX12 was placed downstream of docking.

    Evidence Surface plasmon resonance, two-hybrid, co-IP, and genetic suppressor experiments

    PMID:10026185 PMID:10562279

    Open questions at the time
    • Nature of the translocation pore unknown
    • Order of PEX5 steps at the membrane unresolved
  4. 2000 High

    The crystal structure of PEX5's TPR domain bound to a PTS1 peptide revealed a novel two-cluster TPR architecture that nearly encircles the cargo signal, providing the molecular basis for PTS1 recognition specificity.

    Evidence X-ray crystallography of human PEX5 TPR–PTS1 complex

    PMID:11101887

    Open questions at the time
    • How TPR domain conformational changes regulate binding/release not established
    • Full-length PEX5 structure unavailable
  5. 2001 High

    Identification of the conserved WxxxF/Y pentapeptide motifs as independent PEX14-binding elements and the 21-amino-acid PEX7-binding motif in PEX5L resolved the modular architecture underlying receptor docking and PTS2 co-receptor function.

    Evidence Mutagenesis, SPR quantification, in vitro binding, and complementation assays

    PMID:10767287 PMID:11438541 PMID:11546814

    Open questions at the time
    • Functional non-equivalence among the seven WxxxF/Y motifs not understood
    • Stoichiometry of PEX5–PEX14 complex at the membrane unresolved
  6. 2005 High

    Establishment that PEX5 insertion into peroxisomes is ATP-independent whereas its export requires ATP and the PEX1–PEX6–PEX26 complex defined the energy-dependent recycling step and ordered the import cycle.

    Evidence Cell-free translocation assay with isolated peroxisomes and blue-native PAGE

    PMID:16314507

    Open questions at the time
    • Whether PEX5 fully enters the lumen or remains membrane-embedded debated
    • Ubiquitination requirement for export not yet shown
  7. 2009 High

    NMR structures of the PEX14-N domain bound to PEX5 and PEX19 helices, and SAXS analysis showing a 1:6 PEX5:PEX14 stoichiometry, provided atomic-level understanding of docking and revealed that PEX5 remains extended in solution.

    Evidence NMR structure, SAXS, competitive binding, mutagenesis, and in vivo localization

    PMID:19197237 PMID:19584060

    Open questions at the time
    • PEX5–PEX14 complex structure in a membrane context not determined
    • Function of the intrinsically disordered N-terminus beyond PEX14 binding unclear
  8. 2009 High

    Ordering cargo translocation as concurrent with PEX5 membrane insertion and upstream of ubiquitination clarified that cargo release precedes the ATP-dependent extraction step.

    Evidence In vitro peroxisomal import with protease protection and ATP depletion

    PMID:19632994 PMID:23963456

    Open questions at the time
    • Mechanism of cargo release inside the organelle not established
    • Whether PEX14 directly triggers cargo release in vivo unconfirmed
  9. 2011 High

    Discovery that PEX5 binds monomeric but not tetrameric catalase, and that PEX14 disrupts the PEX5–catalase complex, suggested a cargo-release mechanism at the docking site; identification of AWP1/ZFAND6 as a PEX6 cofactor that preferentially binds Cys-ubiquitinated PEX5 added a new component to the export machinery.

    Evidence In vitro reconstitution, size-exclusion chromatography, siRNA knockdown, and export assays

    PMID:21976670 PMID:21980954

    Open questions at the time
    • AWP1's exact role in the extraction mechanism unclear
    • How catalase monomeric state is maintained during transport unresolved
  10. 2012 High

    Identification of USP9X as the primary deubiquitinase for the Ub–PEX5 thioester conjugate established the recycling pathway's final step returning PEX5 to its import-competent state.

    Evidence Biochemical fractionation of rat liver and HeLa cytosol, in vitro DUB assay, mass spectrometry

    PMID:22371489

    Open questions at the time
    • Whether USP9X acts before or after PEX5 extraction not determined
    • Redundancy with other DUBs not excluded
  11. 2013 High

    Demonstration that PEX5 Cys11 monoubiquitination is mandatory for export, and that this cysteine functions as a redox switch inactivated by oxidized glutathione, unified the ubiquitination and redox-sensing functions into a single regulatory residue; a novel LVAEF motif with distinct kinetics was added to the PEX14-binding repertoire.

    Evidence Cell-free import, Cys11 mutagenesis, PEGylation assays, NMR of LVAEF–PEX14 complex, SPR kinetics

    PMID:24118911 PMID:24235149

    Open questions at the time
    • How redox state transitions are reversed in vivo unknown
    • Functional hierarchy among WxxxF/Y and LVAEF motifs in the import cycle not fully mapped
  12. 2014 High

    Crystal structures showing that PEX5's TPR cavity compacts upon PTS1 binding (volume reduced to one-third) established a receptor-adapts-to-cargo model and linked cavity plasticity to import efficiency.

    Evidence High-resolution crystal structures, mutagenesis, in vivo import quantification

    PMID:25369882

    Open questions at the time
    • Whether compaction triggers downstream signaling events unknown
    • Structural basis for non-canonical cargo binding not defined
  13. 2015 High

    Demonstration that export-deficient monoubiquitinated PEX5 retained at the membrane triggers autophagy-dependent pexophagy established PEX5 as a quality-control signal; a frameshift mutation selectively ablating PEX5L confirmed isoform-specific causation of RCDP5.

    Evidence Export-block assays in MEFs with autophagy readouts; patient fibroblast complementation with PEX5L rescue

    PMID:26086376 PMID:26220973

    Open questions at the time
    • Receptor for ubiquitinated PEX5 in pexophagy not identified
    • Whether RCDP5 phenotype involves additional PEX5L-specific functions beyond PEX7 binding unknown
  14. 2017 High

    TRIM37 was identified as a peroxisomal E3 ligase that stabilizes PEX5 through non-degradative K464 ubiquitination, maintaining receptor levels for efficient import; concurrent studies confirmed PEX5 Cys11 as a redox sensor in live cells and characterized the DTM as a large cavity that accommodates multiple PEX5 molecules.

    Evidence Co-IP, ubiquitination site mapping, siRNA, FRET-based import assays, proteinase K accessibility on DTM

    PMID:28724525 PMID:28760655 PMID:28765278

    Open questions at the time
    • TRIM37 regulation and its coordination with Cys11 ubiquitination unexplored
    • DTM architecture at atomic resolution unknown
  15. 2018 High

    Direct interaction of ubiquitinated PEX5 with both PEX1 and PEX6, and demonstration that the PEX5 polypeptide is globally unfolded during extraction, established Ub-PEX5 as a bona fide substrate of the AAA-ATPase complex and linked unfolding to cargo release.

    Evidence Cell-free system, photoaffinity cross-linking, PEGylation-based unfolding assay, chemically synthesized Ub-PEX5

    PMID:29884772 PMID:30375424

    Open questions at the time
    • Structure of PEX1–PEX6 engaged with Ub-PEX5 not determined
    • How unfolded PEX5 refolds in the cytosol unknown
  16. 2020 High

    Discovery that PEX5 escorts ATGL to peroxisome–lipid droplet contact sites during fasting expanded PEX5's role beyond matrix protein import to inter-organelle lipid metabolism.

    Evidence Adipocyte-specific PEX5 conditional knockout mice, live imaging, co-IP

    PMID:31996685

    Open questions at the time
    • Whether PEX5's ATGL-escort function uses the same WxxxF/PEX14 docking or a distinct mechanism unknown
    • Generality to other non-peroxisomal cargoes not tested
  17. 2022 High

    Reconstitution in Xenopus egg extract proved PEX5 enters the peroxisomal lumen entirely, using WxxxF/Y motifs for lumenal docking-complex interaction and an amphipathic helix for ubiquitin-ligase engagement to initiate N-terminal extrusion; concurrent electrophysiology showed PEX5L forms ion-conducting channels in lipid bilayers.

    Evidence Xenopus egg extract import system with mutagenesis; horizontal lipid bilayer electrophysiology

    PMID:35931083 PMID:36260915

    Open questions at the time
    • Physiological relevance of PEX5 channel activity not established
    • Identity of the lumenal PEX5 receptor unknown
  18. 2022 High

    Demonstration that the ubiquitin moiety conjugated to Cys11 must itself be unfolded before PEX1–PEX6-mediated extraction, using cross-linked ubiquitin to block threading, defined ubiquitin unfolding as the extraction-initiating event.

    Evidence Cell-free system with engineered intramolecularly cross-linked ubiquitin–PEX5 conjugates

    PMID:36442669

    Open questions at the time
    • Step-by-step threading directionality not visualized
    • Whether ubiquitin refolding after extraction is spontaneous or chaperone-assisted unknown
  19. 2024 High

    Elucidation of why PEX5 uses a thioester (Cys11) rather than an isopeptide bond for monoubiquitination showed that rapid E2-mediated deubiquitination outcompetes polyubiquitin chain elongation, preventing premature degradation and maintaining the cycling receptor pool.

    Evidence Cell-free reconstitution with Cys11Lys mutant, ubiquitination kinetics quantification

    PMID:38470934

    Open questions at the time
    • In vivo kinetics of thioester turnover not measured
    • Potential regulatory inputs controlling E2 deubiquitination rate unknown
  20. 2025 High

    Cryo-EM structure of yeast Pex5 with cargo Eci1 revealed non-canonical binding interfaces beyond PTS1, demonstrating that PEX5 can import proteins lacking a canonical PTS1 signal.

    Evidence Cryo-EM structure determination with PTS1-deletion mutant analysis

    PMID:40376748

    Open questions at the time
    • Prevalence of non-canonical PEX5 cargoes in the human proteome unknown
    • Whether non-canonical binding uses the same translocation mechanism not tested

Open questions

Synthesis pass · forward-looking unresolved questions
  • Key unresolved questions include: the atomic structure of the full DTM translocon with PEX5 engaged, the identity and regulation of the pexophagy receptor that recognizes membrane-retained Ub-PEX5, and how PEX5 refolds in the cytosol after extraction-coupled global unfolding.
  • No high-resolution structure of the assembled DTM–PEX5 complex
  • Pexophagy receptor for Ub-PEX5 not identified
  • PEX5 refolding mechanism after extraction unknown

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0038024 cargo receptor activity 5 GO:0060090 molecular adaptor activity 3 GO:0005215 transporter activity 2
Localization
GO:0005829 cytosol 3 GO:0005886 plasma membrane 3 GO:0005777 peroxisome 2
Pathway
R-HSA-9609507 Protein localization 3 R-HSA-1852241 Organelle biogenesis and maintenance 2 R-HSA-9612973 Autophagy 2 R-HSA-1430728 Metabolism 1
Partners
PEX1PEX12PEX13PEX14PEX6PEX7TRIM37USP9X
Complex memberships
DTM (docking/translocation machinery)PEX5–PEX7 co-receptor complex

Evidence

Reading pass · 39 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1995 PEX5 (PXR1) functions as the cytosolic receptor for peroxisomal targeting signal type-1 (PTS1), recognizing PTS1-containing proteins in the cytosol and directing them to the peroxisome. Mutations in PEX5 define complementation group 2 of peroxisome biogenesis disorders, and PEX5 expression rescues the PTS1 import defect in patient fibroblasts. Complementation assay in patient fibroblasts, homology cloning, subcellular fractionation showing cytosolic and peroxisome-associated pools Nature genetics High 7719337
2000 Crystal structure of the C-terminal TPR domain of human PEX5 in complex with a PTS1 pentapeptide revealed that two clusters of three TPRs almost completely surround the peptide, while a hinge region (TPR4) enables the two sets to form a single binding site, establishing the molecular basis for PTS1 recognition via a novel TPR-peptide interaction mode. X-ray crystallography of PEX5 TPR domain in complex with PTS1 peptide Nature structural biology High 11101887
1998 The longer isoform of PEX5 (PEX5L/PTS1RL) is required for PTS2 protein import in addition to PTS1 import, whereas the shorter isoform (PEX5S) supports only PTS1 import. Mutations in the TPR domains (TPR1 and TPR6) abolish protein translocation, demonstrating the functional importance of these domains. CHO cell mutant complementation assays, reverse transcription-PCR mutation analysis, isoform-specific rescue experiments Molecular and cellular biology High 9418886
1999 PEX5 possesses multiple binding sites for PEX14 distributed throughout its N-terminal half, with nanomolar affinity interaction. The N-terminal half of PEX5 also mediates oligomerization, while the C-terminal TPR domain binds PTS1 cargo. Surface plasmon resonance demonstrated that PEX5 binds PEX14-(1-78) with very high affinity in the low nanomolar range. Surface plasmon resonance, in vitro binding assays, sizing chromatography, electron microscopy The Journal of biological chemistry High 10026185
1999 PEX12 (zinc RING domain) binds both PEX5 and PEX10 downstream of receptor docking; a patient missense mutation S320F in the PEX12 zinc-binding domain reduces binding to both PEX5 and PEX10. Overexpression of PEX5 or PEX10 suppresses this PEX12 mutation, providing genetic evidence for biologically relevant interactions. Loss of PEX12 or PEX10 does not reduce PEX5 association with peroxisomes, placing them downstream of docking. Two-hybrid studies, blot overlay assays, coimmunoprecipitation, genetic suppressor overexpression The Journal of cell biology High 10562279
2001 Human PEX5L amino acids 191-222 are sufficient for PEX7 interaction, and amino acids 1-214 are sufficient for peroxisome targeting. A 21-amino acid motif (aa 209-229) shared with yeast Pex18p/Pex21p mediates PTS2 import and PEX7 binding; a conserved serine mutation in this motif abolishes PTS2 import and reduces PEX5L-PEX7 interaction in vitro. Domain mapping, in vitro binding assays, mutagenesis, complementation assays The Journal of biological chemistry High 11546814
2000 Disruption of the Pex5pL-Pex7p interaction by a point mutation (S214F in the PEX5L-specific region) completely abolishes PTS2 import in mammalian cells without affecting PTS1 import or Pex14p binding, establishing that the Pex5pL-Pex7p interaction is essential and sufficient for PTS2 pathway function. CHO cell mutant isolation, point mutation analysis, co-immunoprecipitation, complementation rescue The Journal of biological chemistry High 10767287
2001 The seven conserved di-aromatic pentapeptide repeats (WX(E/D/Q/A/S)(E/D/Q)(F/Y) motifs) in the N-terminus of PEX5 each bind independently to the same site in the N-terminus of PEX14 with nanomolar affinity. The conserved aromatic residues at positions 1 and 5 of the motif are essential for high-affinity binding. Two-hybrid analysis, in vitro binding assays, surface plasmon resonance, mutational analysis The Journal of biological chemistry High 11438541
2005 PEX5 shuttles into peroxisomes in an ATP-independent manner and is exported in an ATP-dependent manner. PEX1 and PEX6 (AAA ATPases) and their recruiter PEX26 are essential for PEX5 export. PEX14 is required as a docking site for PEX5 import. DTM-embedded PEX5 exists in two distinct membrane complexes (~500 kDa and ~800 kDa) comprising different sets of peroxins. Cell-free translocation assay with isolated peroxisomes, blue-native PAGE, multiple cell mutant lines Molecular and cellular biology High 16314507
2009 The N-terminal domain of PEX14 adopts a three-helical fold, and PEX5 and PEX19 ligand helices bind competitively to the same surface in PEX14(N) with opposite directionality. The conserved aromatic side chains in the PEX5 WxxxF/Y motif mediate this interaction. Mutations in the PEX14 binding surface disrupt PEX5 and/or PEX19 binding in vitro and impair peroxisomal membrane localisation in vivo. NMR structure determination, competitive binding assays, mutagenesis, in vivo localization The EMBO journal High 19197237
2009 Cargo protein translocation across the peroxisomal membrane occurs downstream of a reversible docking step and upstream of PEX5 ubiquitination (the first ATP-dependent cytosolic step), placing cargo translocation concurrent with PEX5 insertion into the docking/translocation machinery. In vitro peroxisomal import system, protease protection assays, ATP depletion experiments The Journal of biological chemistry High 19632994
2011 PEX5 binds monomeric catalase and potently inhibits its tetramerization; no complex forms with tetrameric catalase. The PEX5-catalase interaction requires domains in both the N- and C-terminal halves of PEX5. The N-terminal domain of PEX14 disrupts the PEX5-catalase interaction, suggesting PEX14 participates in cargo protein release at the docking/translocation machinery. In vitro binding assays, size-exclusion chromatography, PEX5 domain truncation analysis The Journal of biological chemistry High 21976670
2012 USP9X is identified as the primary deubiquitinase acting on the ubiquitin-PEX5 thioester conjugate (Ub-PEX5) in female rat liver and HeLa cells. USP9X can hydrolyze thioester, isopeptide, and peptide bonds and is an elongated monomeric protein. Biochemical fractionation, in vitro deubiquitinase assay, mass spectrometry identification The Journal of biological chemistry High 22371489
2013 PEX5 is monoubiquitinated at a conserved cysteine residue (Cys11 in human PEX5), which is mandatory for ATP-dependent dislocation of PEX5 back into the cytosol. This cysteine functions as a redox switch: exposure to oxidized glutathione yields a ubiquitination-deficient PEX5, and substitution of Cys11 with lysine counteracts this oxidative inactivation. Cell-free in vitro import system, mutagenesis, PEGylation assays for cysteine modification state, human fibroblast experiments Traffic (Copenhagen, Denmark) High 24118911
2013 A novel PEX5-PEX14 interaction site (LVAEF/LVXEF motif) was identified in PEX5 by peptide library screening. NMR structure shows this motif binds PEX14-N in an α-helical orientation similar to WxxxF/Y but with faster dissociation kinetics. Alanine substitution of LVAEF strongly impairs matrix protein import in vivo, and replacing it with the higher-affinity WxxxF/Y motif paradoxically also impairs import, suggesting distinct kinetic properties are required. Peptide library blot analysis, NMR structure determination, surface plasmon resonance, in vivo import assays The Journal of biological chemistry High 24235149
2013 Cargo translocation across the peroxisomal membrane occurs prior to PEX5 ubiquitination, and a reversible docking step precedes irreversible membrane insertion. This positions cargo release upstream of the ATP-dependent PEX5 extraction step. In vitro import system with cargo protein-centered perspective, ATP manipulation, protease protection The Journal of biological chemistry High 23963456
2014 The PEX5 receptor adapts its TPR binding cavity conformation for high-affinity PTS1 binding rather than the cargo signal adapting. Upon ligand binding, the binding cavity shrinks to one-third of its original volume. A bulky side chain in the wild-type cargo blocks this compaction; a single-residue mutation removing this impediment increases peroxisomal import efficiency from 34% to 80%. High-resolution crystal structure, mutagenesis, in vivo import efficiency measurements Traffic (Copenhagen, Denmark) High 25369882
2015 Export-deficient PEX5 proteins bearing bulky C-terminal tags trigger pexophagy in an autophagy-dependent manner. Monoubiquitination of the N-terminal cysteine of peroxisome-associated PEX5 is required for this process. A C-terminal tag does not inhibit PEX5 monoubiquitination but strongly inhibits its export, suggesting that monoubiquitinated PEX5 retained at the membrane serves as a quality control signal for pexophagy. Autophagy assays, PEX5 tagging and export-block experiments, ubiquitination assays in mouse embryonic fibroblasts Autophagy High 26086376
2015 A frameshift mutation in the PEX5L-specific exon 9 (c.722dupA) causes selective loss of the PEX5L isoform, resulting in defective PTS2 protein import only (not PTS1), causing RCDP5 rather than Zellweger syndrome. PEX5L expression in patient fibroblasts restores PTS2 import, confirming the isoform-specific function. Patient genetic analysis, biochemical complementation assays in fibroblasts, isoform-specific functional rescue Human molecular genetics High 26220973
2017 TRIM37 localizes to peroxisomal membranes and ubiquitylates PEX5 at K464 by interacting with PEX5's C-terminal 51 amino acids. This non-degradative ubiquitylation stabilizes PEX5 and promotes peroxisomal matrix protein import. TRIM37 depletion reduces PEX5 abundance via proteasomal degradation and impairs cargo binding and PTS protein import. Co-immunoprecipitation, ubiquitination assays, mutagenesis (K464A), siRNA knockdown, import assays in human cells The Journal of cell biology High 28724525
2017 The DTM (docking/translocation module) is a large cavity-forming protein assembly into which PEX5 enters to release its cargo. Truncated PEX5(1-125) interacts with DTM but remains accessible to exogenously added proteinase K, and multiple PEX5 truncated molecules can be accommodated simultaneously, suggesting a cavity architecture. Truncated PEX5 probing of DTM architecture, proteinase K accessibility assays, competition experiments The Journal of biological chemistry Medium 28765278
2018 DTM-embedded monoubiquitinated PEX5 (Ub-PEX5) interacts directly with both PEX1 and PEX6 through its ubiquitin moiety, and the PEX5 polypeptide chain is globally unfolded during the ATP-dependent extraction event, establishing Ub-PEX5 as a bona fide substrate of the PEX1-PEX6 AAA ATPase complex. Cell-free in vitro system, photoaffinity cross-linking, protein PEGylation assays The Journal of biological chemistry High 29884772
2017 Cys11 of human PEX5 functions as a redox switch modulating import receptor activity in response to oxidative stress. Oxidative stress specifically impairs catalase import more than canonical PTS1 reporters, and PEX5 does not oligomerize in cellulo even under oxidative stress. Cytosolic catalase retained when PEX5 is inactivated can protect against H2O2-mediated redox changes. Live-cell FRET-based import assay, redox manipulation, mutagenesis in human fibroblasts Biochimica et biophysica acta. Molecular cell research High 28760655
2020 PEX5 escorts adipose triglyceride lipase (ATGL) to contact points between peroxisomes and lipid droplets during fasting, facilitating ATGL translocation onto lipid droplets and promoting fasting-induced lipolysis. Adipocyte-specific PEX5 knockout mice show defective ATGL recruitment to lipid droplets and attenuated fasting-induced lipolysis. Conditional knockout mice, live imaging of peroxisome-lipid droplet contacts, coimmunoprecipitation, ATGL localization assays Nature communications High 31996685
2022 PEX5 accompanies cargo completely into the peroxisome lumen in Xenopus egg extract, utilizing WxxxF/Y motifs near its N-terminus to bind a lumenal domain of the docking complex. PEX5 recycling is initiated by an amphipathic helix binding to the lumenal side of the ubiquitin ligase; the N-terminus then emerges in the cytosol for monoubiquitination. PEX5 is extracted from the lumen by unfolding of the receptor, resulting in cargo release. Xenopus egg extract import system, domain mapping, mutagenesis of WxxxF/Y motifs and amphipathic helix Molecular cell High 35931083
2022 The PEX5-linked monoubiquitin is unfolded at a pre-extraction stage and serves as the extraction initiator; the complete ubiquitin-PEX5 conjugate is threaded by PEX1•PEX6. An intra-molecularly cross-linked ubiquitin at position 11 blocks extraction, confirming ubiquitin unfolding is required for the extraction mechanism. Cell-free in vitro system, engineered PEX5 and ubiquitin molecules, cross-linked ubiquitin experiments Journal of molecular biology High 36442669
2011 AWP1/ZFAND6 is a cofactor of PEX6 involved in PEX5 export. AWP1 preferentially binds cysteine-ubiquitinated PEX5 via its A20 zinc-finger domain, stimulates PEX5 export in vitro, and interacts with PEX6 AAA ATPase. AWP1 knockdown reduces PTS1-protein import and decreases PEX5 stability similarly to PEX1/PEX6/PEX26 deficient cells. Biochemical fractionation, in vitro Pex5 export assay, co-immunoprecipitation, siRNA knockdown Traffic (Copenhagen, Denmark) High 21980954
2013 PEX5 in Pichia pastoris functions as a redox-regulated receptor: disulfide bond-linked Pex5 dimers/oligomers show highest affinity for PTS1 cargo; reduction transitions Pex5 to a noncovalent dimer with partial cargo release. A hetero-oligomeric interaction between the Pex5 N-terminal domain (aa 1-110) and the C-terminal motif of Pex8 further facilitates cargo release under reducing conditions. In vitro binding assays, disulfide cross-linking, DTT reduction experiments, Pex5-Pex8 pulldown The Journal of biological chemistry Medium 23902771
2013 Pex5p stabilizes Pex14p; in the absence of Pex5p, Pex14p is unstable due to inefficient translocation to the peroxisomal membrane. The fifth WXXXF/Y motif of Pex5pL is an auxiliary binding site for Pex14p required for Pex14p stability. Pex5p-Pex13p interaction is essential for import of PTS1 proteins and catalase but not PTS2 proteins. CHO cell mutant isolation, complementation with Pex5p domain mutants, western blot stability assays The Biochemical journal Medium 23009329
2024 Monoubiquitination of PEX5 at cysteine 11 is noncanonical (thioester bond) and reversible; this reversibility prevents polyubiquitination of PEX5 at the peroxisomal membrane. A PEX5 variant with lysine at position 11 undergoes polyubiquitination that negatively interferes with extraction. E2-mediated deubiquitination kinetics are faster than PEX5 polyubiquitination, ensuring the transient monoubiquitinated state. Cell-free rat liver in vitro system, engineered PEX5 Cys11Lys mutant, ubiquitination kinetics analysis PLoS biology High 38470934
2018 Chemically synthesized monoubiquitinated PEX5 binds PEX13, PEX14, and the receptor export module components PEX1, PEX6, and PEX26. Interactions with PEX13 and PEX14 are independent of PEX5 ubiquitination status, whereas interactions with PEX1, PEX6, and PEX26 are enhanced by ubiquitination. Monoubiquitinated PEX5 also binds PEX7/PTS2 complexes and restores PTS2 import in ΔPEX5 fibroblasts. Click chemistry synthesis of Ub-PEX5, in vitro pulldown assays, complementation in ΔPEX5 fibroblasts Scientific reports High 30375424
2009 Small angle X-ray scattering reveals that free full-length human Pex5p is monomeric in solution with an elongated, partially unfolded N-terminal domain. The Pex5p:Pex14p complex shows 1:6 stoichiometry. In the complex, the N-terminus of Pex5p remains extended, with Pex14p molecules significantly intermingled with the Pex5p moiety. Small angle X-ray scattering, static light scattering, solution structure modeling The Journal of biological chemistry Medium 19584060
2022 PEX5L is monomeric with compact spherical conformation in solution. Labeled PEX5L accumulates ~100-fold at lipid bilayers and forms ion-conducting membrane channels in electrophysiological recordings. The truncated PEX5L(1-335) lacking the cargo-binding domain does not form channels, suggesting that PEX5L is the pore-forming component of the oligomeric peroxisomal translocon and that membrane surface binding precedes channel assembly. Horizontal lipid bilayer electrophysiology, fluorescence TCSPC, diffusion coefficient measurements Biological chemistry Medium 36260915
2003 Full-length tetrameric PEX5 has high intrinsic affinity for the PTS1 peptide (Kd ~35 nM) as measured by fluorescence anisotropy. PEX5-PTS1 binding kinetics are unaffected by Hsp70 (with or without ATP/ADP) or by the PEX12 zinc RING domain, indicating that initial PTS1 recognition is an autonomous step not regulated by these factors. Fluorescence anisotropy binding assay with purified recombinant proteins The Journal of biological chemistry Medium 12456682
2003 PTS1 variants corresponding to known functional targeting signals bind PEX5 TPR domain within 1.8 kcal/mol of the optimal -SKL sequence. A binding energy threshold determines PTS1 functionality, correlating structural features from the PEX5:PTS1 crystal structure with thermodynamic binding parameters. Fluorescence-based binding assay with synthetic peptide library, thermodynamic analysis Biochemistry Medium 12578380
2021 A missense mutation F218S in PEX5 (within the PEX7-interaction domain) disrupts the trimeric complex formation between PEX5, PEX7, and a PTS2 cargo protein, abolishing PTS2 protein import while leaving PTS1 import, monoubiquitination, and export intact, causing congenital cataracts in affected patients. In vitro import assays, trimeric complex pulldown, patient fibroblast studies, lens-specific mouse KO Human genetics High 33389129
2023 PEX13 loss causes accumulation of ubiquitinated PEX5 on peroxisomes and increased peroxisome-derived ROS, together inducing pexophagy. PEX13 protein levels are downregulated during amino acid starvation to facilitate pexophagy induction, establishing PEX13 as a gatekeeper that prevents premature pexophagy by limiting accumulation of ubiquitinated PEX5. Gene editing, quantitative fluorescence microscopy, zebrafish model, ubiquitination assays Autophagy High 36541703
2025 Cryo-EM structure of yeast Pex5 in complex with cargo protein Eci1 reveals that Eci1 can bind Pex5 and reach peroxisomes in the absence of a canonical PTS1 signal, through additional binding interfaces beyond the PTS1-binding site in the TPR domain. Cryo-electron microscopy structure determination, PTS1-deletion mutant analysis Journal of cell science High 40376748
2021 In mammalian cells, PEX5 depletion under serum starvation leads to downregulation of TSC2, activation of mTORC1 (increased phosphorylation of 70S6K, S6K, and 4E-BP1), and suppression of TFEB nuclear localization. Pharmacological mTOR inhibition upon PEX5 depletion during starvation activates TFEB and recovers peroxisome biogenesis, placing PEX5 upstream of mTORC1-TFEB axis. siRNA knockdown, pharmacological mTOR inhibition, nuclear localization assays, peroxisome biogenesis readouts Experimental & molecular medicine Medium 29622767

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
1995 Mutations in the PTS1 receptor gene, PXR1, define complementation group 2 of the peroxisome biogenesis disorders. Nature genetics 384 7719337
2000 Peroxisomal targeting signal-1 recognition by the TPR domains of human PEX5. Nature structural biology 311 11101887
2001 Mitochondrial alterations caused by defective peroxisomal biogenesis in a mouse model for Zellweger syndrome (PEX5 knockout mouse). The American journal of pathology 177 11583975
1998 Peroxisome targeting signal type 1 (PTS1) receptor is involved in import of both PTS1 and PTS2: studies with PEX5-defective CHO cell mutants. Molecular and cellular biology 177 9418886
2005 Shuttling mechanism of peroxisome targeting signal type 1 receptor Pex5: ATP-independent import and ATP-dependent export. Molecular and cellular biology 175 16314507
1999 Recombinant human peroxisomal targeting signal receptor PEX5. Structural basis for interaction of PEX5 with PEX14. The Journal of biological chemistry 154 10026185
2004 The Arabidopsis peroxisomal targeting signal type 2 receptor PEX7 is necessary for peroxisome function and dependent on PEX5. Molecular biology of the cell 119 15548601
1999 PEX12 interacts with PEX5 and PEX10 and acts downstream of receptor docking in peroxisomal matrix protein import. The Journal of cell biology 115 10562279
2001 Domain mapping of human PEX5 reveals functional and structural similarities to Saccharomyces cerevisiae Pex18p and Pex21p. The Journal of biological chemistry 102 11546814
2001 The di-aromatic pentapeptide repeats of the human peroxisome import receptor PEX5 are separate high affinity binding sites for the peroxisomal membrane protein PEX14. The Journal of biological chemistry 100 11438541
2000 Disruption of the interaction of the longer isoform of Pex5p, Pex5pL, with Pex7p abolishes peroxisome targeting signal type 2 protein import in mammals. Study with a novel Pex5-impaired Chinese hamster ovary cell mutant. The Journal of biological chemistry 91 10767287
2007 Glaucoma-causing myocilin mutants require the Peroxisomal targeting signal-1 receptor (PTS1R) to elevate intraocular pressure. Human molecular genetics 89 17317787
2012 Identification of ubiquitin-specific protease 9X (USP9X) as a deubiquitinase acting on ubiquitin-peroxin 5 (PEX5) thioester conjugate. The Journal of biological chemistry 84 22371489
2020 Spatiotemporal contact between peroxisomes and lipid droplets regulates fasting-induced lipolysis via PEX5. Nature communications 79 31996685
2015 Export-deficient monoubiquitinated PEX5 triggers peroxisome removal in SV40 large T antigen-transformed mouse embryonic fibroblasts. Autophagy 78 26086376
2011 PEX5 protein binds monomeric catalase blocking its tetramerization and releases it upon binding the N-terminal domain of PEX14. The Journal of biological chemistry 74 21976670
2009 Structural basis for competitive interactions of Pex14 with the import receptors Pex5 and Pex19. The EMBO journal 73 19197237
2013 PEX5, the shuttling import receptor for peroxisomal matrix proteins, is a redox-sensitive protein. Traffic (Copenhagen, Denmark) 71 24118911
2013 Redox-regulated cargo binding and release by the peroxisomal targeting signal receptor, Pex5. The Journal of biological chemistry 66 23902771
2017 TRIM37, a novel E3 ligase for PEX5-mediated peroxisomal matrix protein import. The Journal of cell biology 65 28724525
2017 The peroxisomal import receptor PEX5 functions as a stress sensor, retaining catalase in the cytosol in times of oxidative stress. Biochimica et biophysica acta. Molecular cell research 63 28760655
2007 Characterization of the role of the receptors PEX5 and PEX7 in the import of proteins into glycosomes of Trypanosoma brucei. Biochimica et biophysica acta 61 17320990
2015 A novel type of rhizomelic chondrodysplasia punctata, RCDP5, is caused by loss of the PEX5 long isoform. Human molecular genetics 60 26220973
1999 Functional heterogeneity of C-terminal peroxisome targeting signal 1 in PEX5-defective patients. Biochemical and biophysical research communications 52 10462504
2006 The peroxisomal import proteins PEX2, PEX5 and PEX7 are differently involved in Podospora anserina sexual cycle. Molecular microbiology 51 16987176
2017 Role of PEX5 ubiquitination in maintaining peroxisome dynamics and homeostasis. Cell cycle (Georgetown, Tex.) 50 28933989
2013 A novel Pex14 protein-interacting site of human Pex5 is critical for matrix protein import into peroxisomes. The Journal of biological chemistry 50 24235149
2023 PEX13 prevents pexophagy by regulating ubiquitinated PEX5 and peroxisomal ROS. Autophagy 49 36541703
2022 PEX5 translocation into and out of peroxisomes drives matrix protein import. Molecular cell 49 35931083
2010 Interdependence of the peroxisome-targeting receptors in Arabidopsis thaliana: PEX7 facilitates PEX5 accumulation and import of PTS1 cargo into peroxisomes. Molecular biology of the cell 48 20130089
2000 Peroxisomal targeting signal-1 receptor protein PEX5 from Leishmania donovani. Molecular, biochemical, and immunocytochemical characterization. The Journal of biological chemistry 47 10788481
2011 AWP1/ZFAND6 functions in Pex5 export by interacting with cys-monoubiquitinated Pex5 and Pex6 AAA ATPase. Traffic (Copenhagen, Denmark) 46 21980954
2013 A cargo-centered perspective on the PEX5 receptor-mediated peroxisomal protein import pathway. The Journal of biological chemistry 44 23963456
2010 pex5 Mutants that differentially disrupt PTS1 and PTS2 peroxisomal matrix protein import in Arabidopsis. Plant physiology 44 20974890
2020 PEX5, a novel target of microRNA-31-5p, increases radioresistance in hepatocellular carcinoma by activating Wnt/β-catenin signaling and homologous recombination. Theranostics 43 32373215
2009 Mapping the cargo protein membrane translocation step into the PEX5 cycling pathway. The Journal of biological chemistry 42 19632994
2003 Correlating structure and affinity for PEX5:PTS1 complexes. Biochemistry 42 12578380
2018 Peroxisomal monoubiquitinated PEX5 interacts with the AAA ATPases PEX1 and PEX6 and is unfolded during its dislocation into the cytosol. The Journal of biological chemistry 39 29884772
2001 An unexpected extended conformation for the third TPR motif of the peroxin PEX5 from Trypanosoma brucei. Journal of molecular biology 39 11243819
2002 The neuronal migration defect in mice with Zellweger syndrome (Pex5 knockout) is not caused by the inactivity of peroxisomal beta-oxidation. Journal of neuropathology and experimental neurology 37 11939592
2018 PEX5 regulates autophagy via the mTORC1-TFEB axis during starvation. Experimental & molecular medicine 35 29622767
2009 Solution structure of human Pex5.Pex14.PTS1 protein complexes obtained by small angle X-ray scattering. The Journal of biological chemistry 35 19584060
2014 Ligand-induced compaction of the PEX5 receptor-binding cavity impacts protein import efficiency into peroxisomes. Traffic (Copenhagen, Denmark) 34 25369882
2006 Cloning of two splice variants of the rice PTS1 receptor, OsPex5pL and OsPex5pS, and their functional characterization using pex5-deficient yeast and Arabidopsis. The Plant journal : for cell and molecular biology 32 16792693
2002 PEX5 binds the PTS1 independently of Hsp70 and the peroxin PEX12. The Journal of biological chemistry 30 12456682
2000 A proposed model for the PEX5-peroxisomal targeting signal-1 recognition complex. Proteins 28 10713985
2017 The peroxisomal matrix protein translocon is a large cavity-forming protein assembly into which PEX5 protein enters to release its cargo. The Journal of biological chemistry 27 28765278
2013 Ubiquitination of the glycosomal matrix protein receptor PEX5 in Trypanosoma brucei by PEX4 displays novel features. Biochimica et biophysica acta 27 23994617
2021 Membrane Interactions of the Peroxisomal Proteins PEX5 and PEX14. Frontiers in cell and developmental biology 23 33937250
2014 A viable Arabidopsis pex13 missense allele confers severe peroxisomal defects and decreases PEX5 association with peroxisomes. Plant molecular biology 22 25008153
2023 The rice peroxisomal receptor PEX5 negatively regulates resistance to rice blast fungus Magnaporthe oryzae. Cell reports 21 37862164
2014 The unique degradation pathway of the PTS2 receptor, Pex7, is dependent on the PTS receptor/coreceptor, Pex5 and Pex20. Molecular biology of the cell 21 25009284
2015 Elevated growth temperature decreases levels of the PEX5 peroxisome-targeting signal receptor and ameliorates defects of Arabidopsis mutants with an impaired PEX4 ubiquitin-conjugating enzyme. BMC plant biology 19 26377801
2014 PEX14 binding to Arabidopsis PEX5 has differential effects on PTS1 and PTS2 cargo occupancy of the receptor. FEBS letters 19 24879895
2009 Genotype-phenotype correlation in PEX5-deficient peroxisome biogenesis defective cell lines. Human mutation 19 18712838
2023 SIRT3 improved peroxisomes-mitochondria interplay and prevented cardiac hypertrophy via preserving PEX5 expression. Redox biology 18 36906951
2018 Distinct Roles for Peroxisomal Targeting Signal Receptors Pex5 and Pex7 in Drosophila. Genetics 18 30389805
2001 The tetratricopeptide repeat domains of human, tobacco, and nematode PEX5 proteins are functionally interchangeable with the analogous native domain for peroxisomal import of PTS1-terminated proteins in yeast. Molecular genetics and genomics : MGG 18 11361338
2018 A pex1 missense mutation improves peroxisome function in a subset of Arabidopsis pex6 mutants without restoring PEX5 recycling. Proceedings of the National Academy of Sciences of the United States of America 17 29555730
2014 PEX5 and ubiquitin dynamics on mammalian peroxisome membranes. PLoS computational biology 16 24453954
2013 Pex5p stabilizes Pex14p: a study using a newly isolated pex5 CHO cell mutant, ZPEG101. The Biochemical journal 16 23009329
2003 A review of morphological techniques for detection of peroxisomal (and mitochondrial) proteins and their corresponding mRNAs during ontogenesis in mice: application to the PEX5-knockout mouse with Zellweger syndrome. Microscopy research and technique 16 12740819
2012 Peroxisome deficient aP2-Pex5 knockout mice display impaired white adipocyte and muscle function concomitant with reduced adrenergic tone. Molecular genetics and metabolism 15 23141464
2020 Structure-Activity Relationship in Pyrazolo[4,3-c]pyridines, First Inhibitors of PEX14-PEX5 Protein-Protein Interaction with Trypanocidal Activity. Journal of medicinal chemistry 13 31860309
2019 Ceramide regulates interaction of Hsd17b4 with Pex5 and function of peroxisomes. Biochimica et biophysica acta. Molecular and cell biology of lipids 12 31176039
2022 The Extraction Mechanism of Monoubiquitinated PEX5 from the Peroxisomal Membrane. Journal of molecular biology 10 36442669
2021 Different contributions of the peroxisomal import protein Pex5 and Pex7 to development, stress response and virulence of insect fungal pathogen Beauveria bassiana. Journal of applied microbiology 10 34260798
2018 Chemically monoubiquitinated PEX5 binds to the components of the peroxisomal docking and export machinery. Scientific reports 10 30375424
2023 Loss of pex5 sensitizes zebrafish to fasting due to deregulated mitochondria, mTOR, and autophagy. Cellular and molecular life sciences : CMLS 9 36821008
2022 Diffusion and interaction dynamics of the cytosolic peroxisomal import receptor PEX5. Biophysical reports 9 36299769
2022 Pre-meiotic deletion of PEX5 causes spermatogenesis failure and infertility in mice. Cell proliferation 9 36433756
2014 Microporation is an efficient method for siRNA-induced knockdown of PEX5 in HepG2 cells: evaluation of the transfection efficiency, the PEX5 mRNA and protein levels and induction of peroxisomal deficiency. Histochemistry and cell biology 9 25224142
2021 A missense allele of PEX5 is responsible for the defective import of PTS2 cargo proteins into peroxisomes. Human genetics 8 33389129
2000 Peroxisomal remnant structures in Hansenula polymorpha Pex5 cells can develop into normal peroxisomes upon induction of the PTS2 protein amine oxidase. The Journal of biological chemistry 8 11050097
2021 Acyl-CoA oxidase ACOX-1 interacts with a peroxin PEX-5 to play roles in larval development of Haemonchus contortus. PLoS pathogens 7 34270617
2005 AtLACS7 interacts with the TPR domains of the PTS1 receptor PEX5. Archives of biochemistry and biophysics 7 16256065
2020 Aging lowers PEX5 levels in cortical neurons in male and female mouse brains. Molecular and cellular neurosciences 6 32777345
2019 A PEX5 missense allele preferentially disrupts PTS1 cargo import into Arabidopsis peroxisomes. Plant direct 6 31236542
2007 Molecular characterization of the PEX5 gene encoding peroxisomal targeting signal 1 receptor from the methylotrophic yeast Pichia methanolica. Yeast (Chichester, England) 6 17506110
2022 Structure-based design, synthesis and evaluation of a novel family of PEX5-PEX14 interaction inhibitors against Trypanosoma. European journal of medicinal chemistry 5 36194937
2022 Membrane binding and pore forming insertion of PEX5 into horizontal lipid bilayer. Biological chemistry 5 36260915
2023 Development of novel PEX5-PEX14 protein-protein interaction (PPI) inhibitors based on an oxopiperazine template. European journal of medicinal chemistry 4 37406382
2022 Two Pex5 Proteins With Different Cargo Specificity Are Critical for Peroxisome Function in Ustilago maydis. Frontiers in cell and developmental biology 4 35646929
2022 Small molecule mediated inhibition of protein cargo recognition by peroxisomal transport receptor PEX5 is toxic to Trypanosoma. Scientific reports 4 36038611
2021 Versatile allosteric properties in Pex5-like tetratricopeptide repeat proteins to induce diverse downstream function. Traffic (Copenhagen, Denmark) 4 33580581
2021 PEX5 prevents cardiomyocyte hypertrophy via suppressing the redox-sensitive signaling pathways MAPKs and STAT3. European journal of pharmacology 4 34174269
2001 Temperature-sensitive phenotype of Chinese hamster ovary cells defective in PEX5 gene. Biochemical and biophysical research communications 4 11606046
2025 PEX5 deficiency enhances radiosensitivity via MGST1-GSH detoxifying function and promotes ferroptosis in liver cancer. Science China. Life sciences 3 40614015
2024 Noncanonical and reversible cysteine ubiquitination prevents the overubiquitination of PEX5 at the peroxisomal membrane. PLoS biology 3 38470934
2021 Association of genetic variants of TMEM135 and PEX5 in the peroxisome pathway with cutaneous melanoma-specific survival. Annals of translational medicine 3 33842617
2018 Identification of Peroxisomal Protein Complexes with PTS Receptors, Pex5 and Pex7, in Mammalian Cells. Sub-cellular biochemistry 3 30378028
2012 Processing of the glycosomal matrix-protein import receptor PEX5 of Trypanosoma brucei. Biochemical and biophysical research communications 3 23266609
1998 Cloning and sequence of a 3.835 kbp DNA fragment containing the HIS4 gene and a fragment of a PEX5-like gene from Candida albicans. Yeast (Chichester, England) 3 9778800
2024 Polymorphism in the Hsa-miR-4274 seed region influences the expression of PEX5 and enhances radiotherapy resistance in colorectal cancer. Frontiers of medicine 2 39190270
2024 Structural dynamics of the TPR domain of the peroxisomal cargo receptor Pex5 in Trypanosoma. International journal of biological macromolecules 2 39304044
1995 The gene for the peroxisomal targeting signal import receptor (PXR1) is located on human chromosome 12p13, flanked by TPI1 and D12S1089. Genomics 2 8586442
2025 A cryo-electron microscopy structure of yeast Pex5 in complex with a cargo uncovers a novel binding interface. Journal of cell science 1 40376748
2025 TRIM37-mediated stabilization of PEX5 via monoubiquitination attenuates oxidative stress and demyelination in multiple sclerosis insights from EAE and LPC-induced experimental models. PloS one 1 41134761
2022 Studying the interaction between PEX5 and its full-length cargo proteins in living cells by a novel Försteŕs resonance energy transfer-based competition assay. Frontiers in cell and developmental biology 1 36407094
2025 PEX5 acts as a negative regulator of RANKL-induced osteoclastogenesis in vitro and inflammatory calvarial bone destruction in vivo. Biochemical and biophysical research communications 0 40319819