Affinage

PEX7

Peroxisomal targeting signal 2 receptor · UniProt O00628

Length
323 aa
Mass
35.9 kDa
Annotated
2026-06-10
35 papers in source corpus 17 papers cited in narrative 17 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 6/6 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

PEX7 is the cytosolic receptor for peroxisomal matrix proteins bearing a type-2 peroxisome targeting signal (PTS2), and its loss causes the PTS2-import defect underlying rhizomelic chondrodysplasia punctata (RCDP) and a milder Refsum-like phenotype (PMID:9090381, PMID:9090383, PMID:12522768). PEX7 adopts a WD40-repeat β-propeller fold presenting a conserved groove complementary to the amphipathic PTS2 helix, an interface confirmed by compensatory cross-complementation mutagenesis (PMID:22057399). Cargo engagement is the trigger for assembly of a trimeric cargo–PEX7–PEX5L complex: cargo binding is a prerequisite for the PEX7–PEX5L interaction, and the co-receptor PEX5L in turn drastically strengthens cargo binding, so sequential complex formation stabilizes the receptor–cargo unit and is required for import (PMID:25538232). This complex docks at the peroxisomal membrane, where PEX7 enters and becomes exposed to the matrix; cargo is released into the organelle independently of PTS2 cleavage, and PEX7 is subsequently exported back to the cytosol in a PEX5-dependent manner that is not strictly coupled to PEX5 export, with PEX7 retained at the docking/translocation machinery during these steps (PMID:24865970, PMID:26138649). Dysfunctional or excess PEX7 is removed by ubiquitin–proteasome quality control, including CRL4A (DDB1) E3 ligase-mediated turnover (PMID:30378028). Genetically, PEX7 import activity governs plasmalogen biosynthesis, phytanic acid α-oxidation, and very-long-chain fatty acid β-oxidation, and residual receptor activity correlates with milder disease, as shown in patient alleles and Pex7-deficient mouse models that recapitulate plasmalogen depletion, phytanic acid accumulation, defective neuronal migration, and impaired endochondral ossification (PMID:12325024, PMID:11781871, PMID:12915479, PMID:20060764).

Mechanistic history

Synthesis pass · year-by-year structured walk · 8 steps
  1. 1997 High

    Established the molecular identity of the PTS2 import receptor and its disease relevance, answering what protein recognizes PTS2 cargo and why its loss causes RCDP.

    Evidence Complementation of the PTS2-import defect in RCDP patient fibroblasts by human/murine PEX7, with restored thiolase targeting and DHAP-AT activity

    PMID:9090381 PMID:9090383

    Open questions at the time
    • Did not define the structural basis of PTS2 recognition
    • Did not resolve the membrane translocation steps
  2. 2002 Medium

    Linked residual receptor activity to clinical severity, establishing a genotype-activity-phenotype correlation for PEX7 alleles.

    Evidence Functional expression of mutant PEX7 alleles in RCDP fibroblasts with PTS2 import readout; demonstration of ribosomal frame restoration of a frameshift allele

    PMID:11781871 PMID:12325024

    Open questions at the time
    • Quantitative relationship between residual activity and phenotype not fully defined
    • Single-lab assays per allele
  3. 2003 High

    Defined the metabolic and developmental consequences of PEX7 loss in vivo, connecting PTS2 import to specific peroxisomal pathways and broadening the disease spectrum to a Refsum-like phenotype.

    Evidence Pex7 knockout mouse with plasmalogen, fatty acid oxidation, neuronal migration and ossification readouts; linkage and biochemical analysis of Refsum-like patients

    PMID:12522768 PMID:12915479

    Open questions at the time
    • Mechanism linking import defect to neuronal migration and ossification not resolved
    • Did not address receptor cycling mechanics
  4. 2011 Medium

    Provided a structural rationale for cargo recognition, answering how PEX7 physically discriminates the PTS2 motif.

    Evidence WD40 β-propeller structural modeling, PTS2 mutational analysis, mammalian two-hybrid, and compensatory cross-complementation

    PMID:22057399

    Open questions at the time
    • No experimental crystal or cryo-EM structure of the PEX7–PTS2 complex
    • Modeling-based interface
  5. 2014 High

    Dissected the receptor transport cycle, establishing that PEX7 and cargo enter the matrix, release cargo at the trans side, and export back to the cytosol in a PEX5-dependent but uncoupled manner.

    Evidence In vitro co-import/export and protease protection assays with organelle fractionation

    PMID:24865970 PMID:26138649

    Open questions at the time
    • Molecular trigger of cargo release at the matrix not defined
    • Mechanism uncoupling PEX7 and PEX5 export unclear
  6. 2014 Medium

    Defined the assembly logic of the import-competent complex, showing cargo binding precedes and is required for the PEX7–PEX5L interaction, which then stabilizes cargo binding.

    Evidence Modified mammalian two-hybrid and overexpression/peroxisomal targeting assays for trimeric cargo–PEX7–PEX5L complex formation

    PMID:25538232

    Open questions at the time
    • Stoichiometry and kinetics of complex assembly not quantified
    • Single-lab two-hybrid evidence
  7. 2015 Medium

    Showed that the specific PEX5 that transports PEX7 determines its export competence and that cargo release does not require PTS2 cleavage, implying PEX7 retention at the DTM.

    Evidence In vitro reconstitution with pre-assembled trimeric PEX5-PEX7-PTS2 complexes and organelle fractionation

    PMID:26138649

    Open questions at the time
    • Conformational changes in PEX5 inferred, not directly observed
    • Single-lab in vitro system
  8. 2018 Low

    Identified ubiquitin-proteasome quality control of PEX7 via the CRL4A (DDB1) E3 ligase, addressing how dysfunctional receptor is cleared.

    Evidence Immunoprecipitation/mass spectrometry identification of DDB1 as a PEX7 partner in mammalian cells

    PMID:30378028

    Open questions at the time
    • Single Co-IP/MS report in a summary chapter without rigorous mechanistic follow-up
    • Ubiquitination sites and substrate-recognition mechanism undefined

Open questions

Synthesis pass · forward-looking unresolved questions
  • How cargo release and PEX7 recycling are mechanically driven at the docking/translocation machinery, and the role of newly reported partners (P7BP2, EBP50/iNOS targeting) in human cells, remains unresolved.
  • No experimental structure of the receptor–cargo–DTM assembly
  • Direct vs indirect nature of PEX7–iNOS targeting unresolved
  • Functional role of P7BP2 import not established

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0038024 cargo receptor activity 4 GO:0060090 molecular adaptor activity 2
Localization
GO:0005777 peroxisome 3 GO:0005829 cytosol 2
Pathway
R-HSA-1430728 Metabolism 3 R-HSA-9609507 Protein localization 3 R-HSA-1852241 Organelle biogenesis and maintenance 1
Partners
DDB1P7BP2PEX20PEX5PEX5LRABE1C
Complex memberships
cargo-PEX7-PEX5L trimeric import complexperoxisomal docking/translocation machinery (DTM)

Evidence

Reading pass · 17 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1997 Human PEX7 encodes the cytosolic receptor for peroxisomal matrix proteins containing the type-2 peroxisome targeting signal (PTS2). Expression of human or murine PEX7 in RCDP patient fibroblasts corrects the PTS2-import defect, establishing PEX7 as the functional PTS2 receptor responsible for RCDP (PBD CG11). Complementation assay in RCDP patient fibroblasts; homology cloning; mutation analysis Nature genetics High 9090381 9090383
1997 Expression of human PEX7 in RCDP fibroblasts rescues PTS2 targeting of peroxisomal 3-ketoacyl thiolase and restores some activity of DHAP-AT (a plasmalogen biosynthesis enzyme), demonstrating that multiple peroxisomal enzymes are PTS2-targeted and their deficiency in RCDP results from loss of the PTS2 receptor. Complementation assay in RCDP fibroblasts; enzyme activity assay (DHAP-AT); immunofluorescence Nature genetics High 9090381 9090383
2002 Residual PEX7 protein activity and reduced amounts of normal Pex7p are associated with milder RCDP phenotypes. Functional expression assays showed that severe RCDP alleles fail to restore PTS2 import in patient fibroblasts, whereas mild-disease alleles complement the targeting defect upon overexpression, establishing a genotype-activity-phenotype correlation. Expression of mutant PEX7 alleles in RCDP fibroblasts; PTS2 import assay; Northern analysis; RT-PCR Human mutation Medium 11781871 12325024
2002 A frameshift PEX7 allele (8-nucleotide duplication at codons 45-52) predicted to abolish function was found in mild RCDP patients; in vitro luciferase fusion experiments confirmed that ribosomal frame restoration occurs, producing full-length functional peroxin 7 and explaining the mild phenotype. RT-PCR; COS cell expression of luciferase fusion constructs in different reading frames; functional complementation in RCDP fibroblasts American journal of human genetics Medium 11781871
2003 Pex7 knockout mice exhibit severe plasmalogen depletion, impaired phytanic acid alpha-oxidation, and impaired very-long-chain fatty acid beta-oxidation, directly linking Pex7-mediated PTS2 import to these peroxisomal metabolic pathways. Additionally, Pex7-null mice show delayed neuronal migration in the developing cerebral cortex and defective endochondral ossification. Pex7 knockout mouse generation; biochemical assays (plasmalogen levels, fatty acid oxidation); BrdU neuronal birthdating; histological analysis of bone ossification Human molecular genetics High 12915479
2003 Mutations in PEX7 cause not only severe RCDP but also a milder condition resembling Refsum disease, characterized by phytanic acid accumulation. Biochemical analyses confirmed defects in phytanoyl-CoA hydroxylase (a PTS2-targeted enzyme) import, plasmalogen synthesis, and peroxisomal thiolase, broadening the functional consequences of PEX7 loss. Linkage analysis; PEX7 sequencing; biochemical peroxisomal function assays (phytanic acid oxidation, plasmalogen synthesis, thiolase activity) American journal of human genetics Medium 12522768
2011 Structural modeling of PEX7 reveals a WD40-repeat beta-propeller with a conserved groove complementary to PTS2 signals. PTS2 forms an amphipathic helix with conserved residues on one face. Mammalian two-hybrid assays and cross-complementation of a PTS2 mutation by a compensatory PEX7 mutation confirmed the direct interaction interface between PTS2 and PEX7. 3D structural modeling; mutational analysis of PTS2 motif; mammalian two-hybrid assay; sequence analysis The Journal of biological chemistry Medium 22057399
2014 PEX7 is targeted to the peroxisome in a PEX5- and cargo-dependent manner. Entry of PEX7 and its PTS2 cargo into the peroxisome occurs upstream of monoubiquitination of PEX5. PEX7 becomes partially or completely exposed to the peroxisome matrix (demonstrated by protease protection assay), suggesting cargo release at the trans side of the membrane. Export of PEX7 back to the cytosol requires PEX5 export but the two events are not strictly coupled, indicating they leave the peroxisome separately. In vitro co-import/export assays; protease protection assay; organelle fractionation Molecular and cellular biology High 24865970 26138649
2014 The co-receptor PEX5L drastically increases the interaction strength between PTS2 cargo and PEX7. Cargo binding by PEX7 is a prerequisite for the PEX7-PEX5L interaction. Overexpression of PTS2 cargo stimulates formation of trimeric cargo-PEX7-PEX5L complexes and peroxisomal transfer of PEX7, establishing that sequential formation of this trimeric complex stabilizes cargo binding and is required for PTS2-mediated import. Modified mammalian two-hybrid assay; overexpression experiments; peroxisomal targeting assay The Journal of biological chemistry Medium 25538232
2015 In vitro co-import/export assays using pre-assembled trimeric PEX5-PEX7-PTS2 complexes showed that the export competence of peroxisomal PEX7 is determined by the specific PEX5 molecule that transported it to the peroxisome, indicating PEX7 is retained at the docking/translocation machinery (DTM) during peroxisomal steps. Cargo release into the organelle matrix does not require PTS2 cleavage. DTM insertion likely induces conformational alterations in PEX5 to allow PTS2 protein release. In vitro co-import/export assays with pre-assembled trimeric complexes; organelle fractionation Scientific reports Medium 26138649
2014 In Pichia pastoris, Pex7 is constitutively degraded in wild-type cells via polyubiquitination and proteasomal degradation. This degradation requires Pex7 to shuttle into and out of peroxisomes and depends on the receptor recycling pathways of Pex5 and Pex20, and on a direct interaction between Pex7 and Pex20. Pex7 degradation is regulated by growth conditions (more prevalent in methanol vs. oleate medium). Genetic analysis (pex mutants); cycloheximide chase; polyubiquitination assays; growth condition comparisons in Pichia pastoris Molecular biology of the cell Medium 25009284
2013 In Arabidopsis, the Rab GTPase RabE1c binds to PEX7 in a GTP-dependent manner. A subset of RabE1c localizes to peroxisomes and interacts with PEX7 at the peroxisomal membrane. RabE1c facilitates proteasomal degradation of PEX7; mutation of RabE1c restored PEX7 protein levels and PTS2 import activity, as well as peroxisomal beta-oxidation. Proteomic analysis (GFP-PEX7 pull-down + mass spectrometry); in vivo Co-IP; immunofluorescence; proteasome inhibitor treatment; genetic analysis of RabE1c mutants The Journal of biological chemistry Medium 23297417
2018 DDB1 (damage-specific DNA-binding protein 1), a component of the CRL4A (Cullin4A-RING ubiquitin ligase) E3 complex, was identified as a PEX7-interacting protein. CRL4A-mediated quality control of PEX7 prevents accumulation of dysfunctional PEX7 and is important for PTS2 protein import. Immunoprecipitation/mass spectrometry identification of Pex7-binding partners in mammalian cells Sub-cellular biochemistry Low 30378028
2013 siRNA knockdown of PEX7 in hepatocytes reduced iNOS colocalization with the peroxisomal marker PMP70, identifying PEX7 as required for iNOS targeting to peroxisomes. EBP50 associates with peroxisomes in a PEX5- and PEX7-dependent manner, and iNOS localization to peroxisomes is contingent on EBP50 expression. siRNA knockdown; confocal microscopy; immunoelectron microscopy; MALDI-MS proteomic identification of iNOS-EBP50 association; in vivo LPS-treated mouse model Nitric oxide : biology and chemistry Medium 23474170
2018 A novel PEX7-binding protein, P7BP2, is imported into peroxisomes via a cleavable PTS2 in its N-terminal region, requiring binding to PEX7 and the long isoform of PEX5 (PEX5L). P7BP2 is a novel dynein-type AAA+ protein that behaves as a monomer and forms a pseudo-hexameric disc-like ring structure observed by atomic force microscopy. Co-immunoprecipitation; peroxisomal localization assay; gel-filtration chromatography; atomic force microscopy; sequence/domain analysis Journal of biochemistry Low 30204880
2009 A Pex7 hypomorphic mouse model (Pex7 transcript <5% of wild-type) displays tissue plasmalogen deficiency, phytanic acid accumulation, and reduced import of Pex7 ligands, confirming that reduced Pex7 function directly impairs plasmalogen biosynthesis and phytanic acid oxidation. Dietary supplementation with batyl alcohol (a plasmalogen precursor) recovered ether phospholipids in blood but did not alter clinical phenotype. Hypomorphic mouse engineering; biochemical assays (plasmalogen levels, phytanic acid); PTS2 import assay; dietary supplementation experiment Molecular genetics and metabolism Medium 20060764
2007 In Trypanosoma brucei, TbPEX7 binds to TbPEX5. RNAi depletion of PEX7 in bloodstream-form trypanosomes led to mislocalization of PTS2 proteins to the cytosol, while in procyclic cells it affected both PTS1, PTS2, and internal PTS (I-PTS) signal-containing protein import. PEX7 depletion was lethal in both life-cycle stages, indicating it is essential for glycosome biogenesis. RNAi knockdown; immunofluorescence; subcellular fractionation; electron microscopy; growth assays in T. brucei Biochimica et biophysica acta Medium 17320990

Source papers

Stage 0 corpus · 35 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
1997 Human PEX7 encodes the peroxisomal PTS2 receptor and is responsible for rhizomelic chondrodysplasia punctata. Nature genetics 345 9090381
1997 Rhizomelic chondrodysplasia punctata is caused by deficiency of human PEX7, a homologue of the yeast PTS2 receptor. Nature genetics 221 9090383
2003 Identification of PEX7 as the second gene involved in Refsum disease. American journal of human genetics 113 12522768
2002 Mutation analysis of PEX7 in 60 probands with rhizomelic chondrodysplasia punctata and functional correlations of genotype with phenotype. Human mutation 104 12325024
2003 Impaired neuronal migration and endochondral ossification in Pex7 knockout mice: a model for rhizomelic chondrodysplasia punctata. Human molecular genetics 91 12915479
2004 Molecular basis of Refsum disease: sequence variations in phytanoyl-CoA hydroxylase (PHYH) and the PTS2 receptor (PEX7). Human mutation 77 14974078
2002 Mutational spectrum in the PEX7 gene and functional analysis of mutant alleles in 78 patients with rhizomelic chondrodysplasia punctata type 1. American journal of human genetics 69 11781871
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 62 17320990
2009 A Pex7 hypomorphic mouse model for plasmalogen deficiency affecting the lens and skeleton. Molecular genetics and metabolism 51 20060764
2006 The peroxisomal import proteins PEX2, PEX5 and PEX7 are differently involved in Podospora anserina sexual cycle. Molecular microbiology 51 16987176
2011 The PEX7-mediated peroxisomal import system is required for fungal development and pathogenicity in Magnaporthe oryzae. PloS one 50 22194815
2011 Structural requirements for interaction of peroxisomal targeting signal 2 and its receptor PEX7. The Journal of biological chemistry 42 22057399
2014 Peroxisomal plant nitric oxide synthase (NOS) protein is imported by peroxisomal targeting signal type 2 (PTS2) in a process that depends on the cytosolic receptor PEX7 and calmodulin. FEBS letters 38 24801177
2014 A PEX7-centered perspective on the peroxisomal targeting signal type 2-mediated protein import pathway. Molecular and cellular biology 36 24865970
2013 Proteomic analysis reveals that the Rab GTPase RabE1c is involved in the degradation of the peroxisomal protein receptor PEX7 (peroxin 7). The Journal of biological chemistry 36 23297417
2014 Mechanistic insights into PTS2-mediated peroxisomal protein import: the co-receptor PEX5L drastically increases the interaction strength between the cargo protein and the receptor PEX7. The Journal of biological chemistry 33 25538232
2000 PEX7 gene structure, alternative transcripts, and evidence for a founder haplotype for the frequent RCDP allele, L292ter. Genomics 31 10673331
2015 Revisiting the intraperoxisomal pathway of mammalian PEX7. Scientific reports 21 26138649
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
2013 PEX7 and EBP50 target iNOS to the peroxisome in hepatocytes. Nitric oxide : biology and chemistry 21 23474170
2018 Distinct Roles for Peroxisomal Targeting Signal Receptors Pex5 and Pex7 in Drosophila. Genetics 19 30389805
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 11 34260798
2022 A Pex7 Deficient Mouse Series Correlates Biochemical and Neurobehavioral Markers to Genotype Severity-Implications for the Disease Spectrum of Rhizomelic Chondrodysplasia Punctata Type 1. Frontiers in cell and developmental biology 10 35898397
1999 A novel nonsense mutation of the PEX7 gene in a patient with rhizomelic chondrodysplasia punctata. Journal of human genetics 10 10083738
2002 Isolation of Chinese hamster ovary cell pex mutants: two PEX7-defective mutants. Biochemical and biophysical research communications 7 12054588
2022 Fusarium verticillioides Pex7/20 mediates peroxisomal PTS2 pathway import, pathogenicity, and fumonisin B1 biosynthesis. Applied microbiology and biotechnology 4 36121485
2021 Twins with PEX7 related intellectual disability and cataract: Highlighting phenotypes of peroxisome biogenesis disorder 9B. American journal of medical genetics. Part A 3 33586206
2021 Pex7 selectively imports PTS2 target proteins to peroxisomes and is required for anthracnose disease development in Colletotrichum scovillei. Fungal genetics and biology : FG & B 3 34742890
2018 A newly isolated Pex7-binding, atypical PTS2 protein P7BP2 is a novel dynein-type AAA+ protein. Journal of biochemistry 3 30204880
2018 Identification of Peroxisomal Protein Complexes with PTS Receptors, Pex5 and Pex7, in Mammalian Cells. Sub-cellular biochemistry 3 30378028
2015 Rhizomelic Chondrodysplasia Punctata Type 1 Caused by a Novel Mutation in the PEX7 Gene. Journal of clinical research in pediatric endocrinology 3 25800479
2015 Whole Exome Sequencing Reveals Compound Heterozygosity for Ethnically Distinct PEX7 Mutations Responsible for Rhizomelic Chondrodysplasia Punctata, Type 1. Case reports in genetics 3 26587300
2025 Metabolomic Profiling Reveals Brain Lipid Alterations in PEX7-Deficient Models of Rhizomelic Chondrodysplasia Punctata. Biomolecules 1 41594547
2013 Identification of a novel missense mutation of PEX7 gene in an Iranian patient with rhizomelic chondrodysplasia punctata type 1. Gene 1 23357221
2017 Type 1 rhizomelic chondrodysplasia punctata with a homozygous PEX7 mutation. Journal of pediatric endocrinology & metabolism : JPEM 0 28742517

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