{"gene":"PEX7","run_date":"2026-06-10T05:19:53","timeline":{"discoveries":[{"year":1997,"finding":"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).","method":"Complementation assay in RCDP patient fibroblasts; homology cloning; mutation analysis","journal":"Nature genetics","confidence":"High","confidence_rationale":"Tier 2 / Strong — functional complementation in patient cells replicated independently in two simultaneous papers (PMID:9090381 and PMID:9090383), with direct rescue of PTS2 import","pmids":["9090381","9090383"],"is_preprint":false},{"year":1997,"finding":"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.","method":"Complementation assay in RCDP fibroblasts; enzyme activity assay (DHAP-AT); immunofluorescence","journal":"Nature genetics","confidence":"High","confidence_rationale":"Tier 2 / Strong — direct rescue experiment with functional enzyme readout, replicated across two independent labs in the same year","pmids":["9090383","9090381"],"is_preprint":false},{"year":2002,"finding":"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.","method":"Expression of mutant PEX7 alleles in RCDP fibroblasts; PTS2 import assay; Northern analysis; RT-PCR","journal":"Human mutation","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — functional complementation assay with multiple alleles in two independent studies (PMID:12325024, PMID:11781871), single lab each but consistent findings","pmids":["12325024","11781871"],"is_preprint":false},{"year":2002,"finding":"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.","method":"RT-PCR; COS cell expression of luciferase fusion constructs in different reading frames; functional complementation in RCDP fibroblasts","journal":"American journal of human genetics","confidence":"Medium","confidence_rationale":"Tier 1-2 / Moderate — in vitro and cell-based reconstitution of frame restoration with luciferase assay, single lab","pmids":["11781871"],"is_preprint":false},{"year":2003,"finding":"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.","method":"Pex7 knockout mouse generation; biochemical assays (plasmalogen levels, fatty acid oxidation); BrdU neuronal birthdating; histological analysis of bone ossification","journal":"Human molecular genetics","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal biochemical and cellular assays in a defined knockout model, with clear phenotypic readouts","pmids":["12915479"],"is_preprint":false},{"year":2003,"finding":"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.","method":"Linkage analysis; PEX7 sequencing; biochemical peroxisomal function assays (phytanic acid oxidation, plasmalogen synthesis, thiolase activity)","journal":"American journal of human genetics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple biochemical assays with genetic confirmation, single lab","pmids":["12522768"],"is_preprint":false},{"year":2011,"finding":"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.","method":"3D structural modeling; mutational analysis of PTS2 motif; mammalian two-hybrid assay; sequence analysis","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2-3 / Moderate — structural modeling combined with mammalian two-hybrid and cross-complementation mutagenesis in a single lab; no crystal structure","pmids":["22057399"],"is_preprint":false},{"year":2014,"finding":"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.","method":"In vitro co-import/export assays; protease protection assay; organelle fractionation","journal":"Molecular and cellular biology","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — multiple orthogonal in vitro assays (protease protection, co-import/export) dissecting the PEX7 transport cycle in detail, confirmed in follow-up study (PMID:26138649)","pmids":["24865970","26138649"],"is_preprint":false},{"year":2014,"finding":"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.","method":"Modified mammalian two-hybrid assay; overexpression experiments; peroxisomal targeting assay","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2-3 / Moderate — mammalian two-hybrid and targeting assays, single lab, multiple orthogonal approaches","pmids":["25538232"],"is_preprint":false},{"year":2015,"finding":"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.","method":"In vitro co-import/export assays with pre-assembled trimeric complexes; organelle fractionation","journal":"Scientific reports","confidence":"Medium","confidence_rationale":"Tier 1-2 / Moderate — rigorous in vitro reconstitution assays, single lab, extends prior work","pmids":["26138649"],"is_preprint":false},{"year":2014,"finding":"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).","method":"Genetic analysis (pex mutants); cycloheximide chase; polyubiquitination assays; growth condition comparisons in Pichia pastoris","journal":"Molecular biology of the cell","confidence":"Medium","confidence_rationale":"Tier 2-3 / Moderate — multiple genetic and biochemical approaches in yeast model, single lab","pmids":["25009284"],"is_preprint":false},{"year":2013,"finding":"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.","method":"Proteomic analysis (GFP-PEX7 pull-down + mass spectrometry); in vivo Co-IP; immunofluorescence; proteasome inhibitor treatment; genetic analysis of RabE1c mutants","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2-3 / Moderate — multiple orthogonal methods (proteomics, Co-IP, genetics, inhibitor) in Arabidopsis; note this is a plant ortholog study","pmids":["23297417"],"is_preprint":false},{"year":2018,"finding":"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.","method":"Immunoprecipitation/mass spectrometry identification of Pex7-binding partners in mammalian cells","journal":"Sub-cellular biochemistry","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single Co-IP/MS identification reported as a summary chapter, limited mechanistic follow-up described in abstract","pmids":["30378028"],"is_preprint":false},{"year":2013,"finding":"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.","method":"siRNA knockdown; confocal microscopy; immunoelectron microscopy; MALDI-MS proteomic identification of iNOS-EBP50 association; in vivo LPS-treated mouse model","journal":"Nitric oxide : biology and chemistry","confidence":"Medium","confidence_rationale":"Tier 2-3 / Moderate — multiple imaging methods and in vivo confirmation, though mechanistic detail of direct vs indirect PEX7-iNOS interaction is limited","pmids":["23474170"],"is_preprint":false},{"year":2018,"finding":"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.","method":"Co-immunoprecipitation; peroxisomal localization assay; gel-filtration chromatography; atomic force microscopy; sequence/domain analysis","journal":"Journal of biochemistry","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single lab, Co-IP and localization without rigorous mechanistic dissection","pmids":["30204880"],"is_preprint":false},{"year":2009,"finding":"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.","method":"Hypomorphic mouse engineering; biochemical assays (plasmalogen levels, phytanic acid); PTS2 import assay; dietary supplementation experiment","journal":"Molecular genetics and metabolism","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — well-characterized mouse model with multiple biochemical readouts and therapeutic intervention test, single lab","pmids":["20060764"],"is_preprint":false},{"year":2007,"finding":"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.","method":"RNAi knockdown; immunofluorescence; subcellular fractionation; electron microscopy; growth assays in T. brucei","journal":"Biochimica et biophysica acta","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple methods (RNAi, immunofluorescence, fractionation, EM) in a relevant ortholog system","pmids":["17320990"],"is_preprint":false}],"current_model":"PEX7 encodes a cytosolic WD40-repeat PTS2 receptor that binds PTS2-containing peroxisomal matrix proteins via a conserved amphipathic groove, forming a trimeric cargo–PEX7–PEX5L complex whose assembly is stabilized by cargo binding; this complex docks at the peroxisomal membrane docking/translocation machinery (DTM), translocates cargo into the matrix (independent of PTS2 cleavage), and exports PEX7 back to the cytosol in a PEX5-dependent but uncoupled manner, while dysfunctional PEX7 is subject to CRL4A ubiquitin ligase- and proteasome-mediated quality control, with loss of PEX7 function causing defective import of plasmalogen biosynthesis enzymes, phytanoyl-CoA hydroxylase, and peroxisomal thiolase, thereby producing the biochemical and clinical phenotypes of RCDP and Refsum disease."},"narrative":{"mechanistic_narrative":"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].","teleology":[{"year":1997,"claim":"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","pmids":["9090381","9090383"],"confidence":"High","gaps":["Did not define the structural basis of PTS2 recognition","Did not resolve the membrane translocation steps"]},{"year":2002,"claim":"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","pmids":["12325024","11781871"],"confidence":"Medium","gaps":["Quantitative relationship between residual activity and phenotype not fully defined","Single-lab assays per allele"]},{"year":2003,"claim":"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","pmids":["12915479","12522768"],"confidence":"High","gaps":["Mechanism linking import defect to neuronal migration and ossification not resolved","Did not address receptor cycling mechanics"]},{"year":2011,"claim":"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","pmids":["22057399"],"confidence":"Medium","gaps":["No experimental crystal or cryo-EM structure of the PEX7–PTS2 complex","Modeling-based interface"]},{"year":2014,"claim":"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","pmids":["24865970","26138649"],"confidence":"High","gaps":["Molecular trigger of cargo release at the matrix not defined","Mechanism uncoupling PEX7 and PEX5 export unclear"]},{"year":2014,"claim":"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","pmids":["25538232"],"confidence":"Medium","gaps":["Stoichiometry and kinetics of complex assembly not quantified","Single-lab two-hybrid evidence"]},{"year":2015,"claim":"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","pmids":["26138649"],"confidence":"Medium","gaps":["Conformational changes in PEX5 inferred, not directly observed","Single-lab in vitro system"]},{"year":2018,"claim":"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","pmids":["30378028"],"confidence":"Low","gaps":["Single Co-IP/MS report in a summary chapter without rigorous mechanistic follow-up","Ubiquitination sites and substrate-recognition mechanism undefined"]},{"year":null,"claim":"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.","evidence":"","pmids":[],"confidence":"Low","gaps":["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":{"molecular_activity":[{"term_id":"GO:0038024","term_label":"cargo receptor activity","supporting_discovery_ids":[0,1,6,8]},{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[8,9]}],"localization":[{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[0,7]},{"term_id":"GO:0005777","term_label":"peroxisome","supporting_discovery_ids":[7,9,13]}],"pathway":[{"term_id":"R-HSA-9609507","term_label":"Protein localization","supporting_discovery_ids":[0,7,9]},{"term_id":"R-HSA-1430728","term_label":"Metabolism","supporting_discovery_ids":[4,5,15]},{"term_id":"R-HSA-1852241","term_label":"Organelle biogenesis and maintenance","supporting_discovery_ids":[16]}],"complexes":["cargo-PEX7-PEX5L trimeric import complex","peroxisomal docking/translocation machinery (DTM)"],"partners":["PEX5","PEX5L","DDB1","P7BP2","PEX20","RABE1C"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"O00628","full_name":"Peroxisomal targeting signal 2 receptor","aliases":["Peroxin-7"],"length_aa":323,"mass_kda":35.9,"function":"Receptor required for the peroxisomal import of proteins containing a C-terminal PTS2-type peroxisomal targeting signal (PubMed:11931631, PubMed:22057399, PubMed:25538232, PubMed:9090381). Specifically binds to cargo proteins containing a PTS2 peroxisomal targeting signal in the cytosol (PubMed:11931631, PubMed:22057399, PubMed:25538232). Cargo protein-binding triggers interaction with PEX5 and formation of a ternary complex composed of PEX5 and PEX7 along with PTS2-containing cargo proteins, which is tranlocated into peroxisomes by passing through the PEX13-PEX14 docking complex (PubMed:11546814, PubMed:25538232)","subcellular_location":"Cytoplasm, cytosol; Peroxisome matrix","url":"https://www.uniprot.org/uniprotkb/O00628/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/PEX7","classification":"Not Classified","n_dependent_lines":19,"n_total_lines":1208,"dependency_fraction":0.015728476821192054},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/PEX7","total_profiled":1310},"omim":[{"mim_id":"621410","title":"PEROXISOME BIOGENESIS FACTOR 39; PEX39","url":"https://www.omim.org/entry/621410"},{"mim_id":"616716","title":"RHIZOMELIC CHONDRODYSPLASIA PUNCTATA, TYPE 5; RCDP5","url":"https://www.omim.org/entry/616716"},{"mim_id":"614879","title":"PEROXISOME BIOGENESIS DISORDER 9B; PBD9B","url":"https://www.omim.org/entry/614879"},{"mim_id":"608666","title":"PEROXISOME BIOGENESIS FACTOR 26; PEX26","url":"https://www.omim.org/entry/608666"},{"mim_id":"607622","title":"PHOSPHOMEVALONATE KINASE; PMVK","url":"https://www.omim.org/entry/607622"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Supported","locations":[{"location":"Nucleoplasm","reliability":"Supported"},{"location":"Vesicles","reliability":"Supported"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/PEX7"},"hgnc":{"alias_symbol":["PTS2R","RD"],"prev_symbol":[]},"alphafold":{"accession":"O00628","domains":[{"cath_id":"2.130.10.10","chopping":"11-321","consensus_level":"high","plddt":96.7364,"start":11,"end":321}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/O00628","model_url":"https://alphafold.ebi.ac.uk/files/AF-O00628-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-O00628-F1-predicted_aligned_error_v6.png","plddt_mean":95.0},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=PEX7","jax_strain_url":"https://www.jax.org/strain/search?query=PEX7"},"sequence":{"accession":"O00628","fasta_url":"https://rest.uniprot.org/uniprotkb/O00628.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/O00628/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/O00628"}},"corpus_meta":[{"pmid":"9090381","id":"PMC_9090381","title":"Human PEX7 encodes the peroxisomal PTS2 receptor and is responsible for rhizomelic chondrodysplasia punctata.","date":"1997","source":"Nature genetics","url":"https://pubmed.ncbi.nlm.nih.gov/9090381","citation_count":345,"is_preprint":false},{"pmid":"9090383","id":"PMC_9090383","title":"Rhizomelic chondrodysplasia punctata is caused by deficiency of human PEX7, a homologue of the yeast PTS2 receptor.","date":"1997","source":"Nature genetics","url":"https://pubmed.ncbi.nlm.nih.gov/9090383","citation_count":221,"is_preprint":false},{"pmid":"12522768","id":"PMC_12522768","title":"Identification of PEX7 as the second gene involved in Refsum disease.","date":"2003","source":"American journal of human genetics","url":"https://pubmed.ncbi.nlm.nih.gov/12522768","citation_count":113,"is_preprint":false},{"pmid":"12325024","id":"PMC_12325024","title":"Mutation analysis of PEX7 in 60 probands with rhizomelic chondrodysplasia punctata and functional correlations of genotype with phenotype.","date":"2002","source":"Human mutation","url":"https://pubmed.ncbi.nlm.nih.gov/12325024","citation_count":104,"is_preprint":false},{"pmid":"12915479","id":"PMC_12915479","title":"Impaired neuronal migration and endochondral ossification in Pex7 knockout mice: a model for rhizomelic chondrodysplasia punctata.","date":"2003","source":"Human molecular genetics","url":"https://pubmed.ncbi.nlm.nih.gov/12915479","citation_count":91,"is_preprint":false},{"pmid":"14974078","id":"PMC_14974078","title":"Molecular basis of Refsum disease: sequence variations in phytanoyl-CoA hydroxylase (PHYH) and the PTS2 receptor (PEX7).","date":"2004","source":"Human mutation","url":"https://pubmed.ncbi.nlm.nih.gov/14974078","citation_count":77,"is_preprint":false},{"pmid":"11781871","id":"PMC_11781871","title":"Mutational spectrum in the PEX7 gene and functional analysis of mutant alleles in 78 patients with rhizomelic chondrodysplasia punctata type 1.","date":"2002","source":"American journal of human genetics","url":"https://pubmed.ncbi.nlm.nih.gov/11781871","citation_count":69,"is_preprint":false},{"pmid":"17320990","id":"PMC_17320990","title":"Characterization of the role of the receptors PEX5 and PEX7 in the import of proteins into glycosomes of Trypanosoma brucei.","date":"2007","source":"Biochimica et biophysica acta","url":"https://pubmed.ncbi.nlm.nih.gov/17320990","citation_count":62,"is_preprint":false},{"pmid":"20060764","id":"PMC_20060764","title":"A Pex7 hypomorphic mouse model for plasmalogen deficiency affecting the lens and skeleton.","date":"2009","source":"Molecular genetics and metabolism","url":"https://pubmed.ncbi.nlm.nih.gov/20060764","citation_count":51,"is_preprint":false},{"pmid":"16987176","id":"PMC_16987176","title":"The peroxisomal import proteins PEX2, PEX5 and PEX7 are differently involved in Podospora anserina sexual cycle.","date":"2006","source":"Molecular microbiology","url":"https://pubmed.ncbi.nlm.nih.gov/16987176","citation_count":51,"is_preprint":false},{"pmid":"22194815","id":"PMC_22194815","title":"The PEX7-mediated peroxisomal import system is required for fungal development and pathogenicity in Magnaporthe oryzae.","date":"2011","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/22194815","citation_count":50,"is_preprint":false},{"pmid":"22057399","id":"PMC_22057399","title":"Structural requirements for interaction of peroxisomal targeting signal 2 and its receptor PEX7.","date":"2011","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/22057399","citation_count":42,"is_preprint":false},{"pmid":"24801177","id":"PMC_24801177","title":"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.","date":"2014","source":"FEBS letters","url":"https://pubmed.ncbi.nlm.nih.gov/24801177","citation_count":38,"is_preprint":false},{"pmid":"23297417","id":"PMC_23297417","title":"Proteomic analysis reveals that the Rab GTPase RabE1c is involved in the degradation of the peroxisomal protein receptor PEX7 (peroxin 7).","date":"2013","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/23297417","citation_count":36,"is_preprint":false},{"pmid":"24865970","id":"PMC_24865970","title":"A PEX7-centered perspective on the peroxisomal targeting signal type 2-mediated protein import pathway.","date":"2014","source":"Molecular and cellular biology","url":"https://pubmed.ncbi.nlm.nih.gov/24865970","citation_count":36,"is_preprint":false},{"pmid":"25538232","id":"PMC_25538232","title":"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.","date":"2014","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/25538232","citation_count":33,"is_preprint":false},{"pmid":"10673331","id":"PMC_10673331","title":"PEX7 gene structure, alternative transcripts, and evidence for a founder haplotype for the frequent RCDP allele, L292ter.","date":"2000","source":"Genomics","url":"https://pubmed.ncbi.nlm.nih.gov/10673331","citation_count":31,"is_preprint":false},{"pmid":"26138649","id":"PMC_26138649","title":"Revisiting the intraperoxisomal pathway of mammalian PEX7.","date":"2015","source":"Scientific reports","url":"https://pubmed.ncbi.nlm.nih.gov/26138649","citation_count":21,"is_preprint":false},{"pmid":"25009284","id":"PMC_25009284","title":"The unique degradation pathway of the PTS2 receptor, Pex7, is dependent on the PTS receptor/coreceptor, Pex5 and Pex20.","date":"2014","source":"Molecular biology of the cell","url":"https://pubmed.ncbi.nlm.nih.gov/25009284","citation_count":21,"is_preprint":false},{"pmid":"23474170","id":"PMC_23474170","title":"PEX7 and EBP50 target iNOS to the peroxisome in hepatocytes.","date":"2013","source":"Nitric oxide : biology and chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/23474170","citation_count":21,"is_preprint":false},{"pmid":"30389805","id":"PMC_30389805","title":"Distinct Roles for Peroxisomal Targeting Signal Receptors Pex5 and Pex7 in Drosophila.","date":"2018","source":"Genetics","url":"https://pubmed.ncbi.nlm.nih.gov/30389805","citation_count":19,"is_preprint":false},{"pmid":"34260798","id":"PMC_34260798","title":"Different contributions of the peroxisomal import protein Pex5 and Pex7 to development, stress response and virulence of insect fungal pathogen Beauveria bassiana.","date":"2021","source":"Journal of applied microbiology","url":"https://pubmed.ncbi.nlm.nih.gov/34260798","citation_count":11,"is_preprint":false},{"pmid":"35898397","id":"PMC_35898397","title":"A Pex7 Deficient Mouse Series Correlates Biochemical and Neurobehavioral Markers to Genotype Severity-Implications for the Disease Spectrum of Rhizomelic Chondrodysplasia Punctata Type 1.","date":"2022","source":"Frontiers in cell and developmental biology","url":"https://pubmed.ncbi.nlm.nih.gov/35898397","citation_count":10,"is_preprint":false},{"pmid":"10083738","id":"PMC_10083738","title":"A novel nonsense mutation of the PEX7 gene in a patient with rhizomelic chondrodysplasia punctata.","date":"1999","source":"Journal of human genetics","url":"https://pubmed.ncbi.nlm.nih.gov/10083738","citation_count":10,"is_preprint":false},{"pmid":"12054588","id":"PMC_12054588","title":"Isolation of Chinese hamster ovary cell pex mutants: two PEX7-defective mutants.","date":"2002","source":"Biochemical and biophysical research 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endocrinology","url":"https://pubmed.ncbi.nlm.nih.gov/25800479","citation_count":3,"is_preprint":false},{"pmid":"30204880","id":"PMC_30204880","title":"A newly isolated Pex7-binding, atypical PTS2 protein P7BP2 is a novel dynein-type AAA+ protein.","date":"2018","source":"Journal of biochemistry","url":"https://pubmed.ncbi.nlm.nih.gov/30204880","citation_count":3,"is_preprint":false},{"pmid":"34742890","id":"PMC_34742890","title":"Pex7 selectively imports PTS2 target proteins to peroxisomes and is required for anthracnose disease development in Colletotrichum scovillei.","date":"2021","source":"Fungal genetics and biology : FG & B","url":"https://pubmed.ncbi.nlm.nih.gov/34742890","citation_count":3,"is_preprint":false},{"pmid":"33586206","id":"PMC_33586206","title":"Twins with PEX7 related intellectual disability and cataract: Highlighting phenotypes of peroxisome biogenesis disorder 9B.","date":"2021","source":"American journal of medical genetics. Part A","url":"https://pubmed.ncbi.nlm.nih.gov/33586206","citation_count":3,"is_preprint":false},{"pmid":"26587300","id":"PMC_26587300","title":"Whole Exome Sequencing Reveals Compound Heterozygosity for Ethnically Distinct PEX7 Mutations Responsible for Rhizomelic Chondrodysplasia Punctata, Type 1.","date":"2015","source":"Case reports in genetics","url":"https://pubmed.ncbi.nlm.nih.gov/26587300","citation_count":3,"is_preprint":false},{"pmid":"41594547","id":"PMC_41594547","title":"Metabolomic Profiling Reveals Brain Lipid Alterations in PEX7-Deficient Models of Rhizomelic Chondrodysplasia Punctata.","date":"2025","source":"Biomolecules","url":"https://pubmed.ncbi.nlm.nih.gov/41594547","citation_count":1,"is_preprint":false},{"pmid":"23357221","id":"PMC_23357221","title":"Identification of a novel missense mutation of PEX7 gene in an Iranian patient with rhizomelic chondrodysplasia punctata type 1.","date":"2013","source":"Gene","url":"https://pubmed.ncbi.nlm.nih.gov/23357221","citation_count":1,"is_preprint":false},{"pmid":"28742517","id":"PMC_28742517","title":"Type 1 rhizomelic chondrodysplasia punctata with a homozygous PEX7 mutation.","date":"2017","source":"Journal of pediatric endocrinology & metabolism : JPEM","url":"https://pubmed.ncbi.nlm.nih.gov/28742517","citation_count":0,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":18402,"output_tokens":4601,"usd":0.06211,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":12613,"output_tokens":3101,"usd":0.070295,"stage2_stop_reason":"end_turn"},"total_usd":0.132405,"stage1_batch_id":"msgbatch_013a8chtv3AWyTqv4z4sEF4C","stage2_batch_id":"msgbatch_01AHsuW63vinsvuTgzmQ3n62","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 1997,\n      \"finding\": \"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).\",\n      \"method\": \"Complementation assay in RCDP patient fibroblasts; homology cloning; mutation analysis\",\n      \"journal\": \"Nature genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — functional complementation in patient cells replicated independently in two simultaneous papers (PMID:9090381 and PMID:9090383), with direct rescue of PTS2 import\",\n      \"pmids\": [\"9090381\", \"9090383\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1997,\n      \"finding\": \"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.\",\n      \"method\": \"Complementation assay in RCDP fibroblasts; enzyme activity assay (DHAP-AT); immunofluorescence\",\n      \"journal\": \"Nature genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — direct rescue experiment with functional enzyme readout, replicated across two independent labs in the same year\",\n      \"pmids\": [\"9090383\", \"9090381\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"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.\",\n      \"method\": \"Expression of mutant PEX7 alleles in RCDP fibroblasts; PTS2 import assay; Northern analysis; RT-PCR\",\n      \"journal\": \"Human mutation\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — functional complementation assay with multiple alleles in two independent studies (PMID:12325024, PMID:11781871), single lab each but consistent findings\",\n      \"pmids\": [\"12325024\", \"11781871\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"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.\",\n      \"method\": \"RT-PCR; COS cell expression of luciferase fusion constructs in different reading frames; functional complementation in RCDP fibroblasts\",\n      \"journal\": \"American journal of human genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1-2 / Moderate — in vitro and cell-based reconstitution of frame restoration with luciferase assay, single lab\",\n      \"pmids\": [\"11781871\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"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.\",\n      \"method\": \"Pex7 knockout mouse generation; biochemical assays (plasmalogen levels, fatty acid oxidation); BrdU neuronal birthdating; histological analysis of bone ossification\",\n      \"journal\": \"Human molecular genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal biochemical and cellular assays in a defined knockout model, with clear phenotypic readouts\",\n      \"pmids\": [\"12915479\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"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.\",\n      \"method\": \"Linkage analysis; PEX7 sequencing; biochemical peroxisomal function assays (phytanic acid oxidation, plasmalogen synthesis, thiolase activity)\",\n      \"journal\": \"American journal of human genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple biochemical assays with genetic confirmation, single lab\",\n      \"pmids\": [\"12522768\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"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.\",\n      \"method\": \"3D structural modeling; mutational analysis of PTS2 motif; mammalian two-hybrid assay; sequence analysis\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 / Moderate — structural modeling combined with mammalian two-hybrid and cross-complementation mutagenesis in a single lab; no crystal structure\",\n      \"pmids\": [\"22057399\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"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.\",\n      \"method\": \"In vitro co-import/export assays; protease protection assay; organelle fractionation\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — multiple orthogonal in vitro assays (protease protection, co-import/export) dissecting the PEX7 transport cycle in detail, confirmed in follow-up study (PMID:26138649)\",\n      \"pmids\": [\"24865970\", \"26138649\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"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.\",\n      \"method\": \"Modified mammalian two-hybrid assay; overexpression experiments; peroxisomal targeting assay\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 / Moderate — mammalian two-hybrid and targeting assays, single lab, multiple orthogonal approaches\",\n      \"pmids\": [\"25538232\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"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.\",\n      \"method\": \"In vitro co-import/export assays with pre-assembled trimeric complexes; organelle fractionation\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1-2 / Moderate — rigorous in vitro reconstitution assays, single lab, extends prior work\",\n      \"pmids\": [\"26138649\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"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).\",\n      \"method\": \"Genetic analysis (pex mutants); cycloheximide chase; polyubiquitination assays; growth condition comparisons in Pichia pastoris\",\n      \"journal\": \"Molecular biology of the cell\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 / Moderate — multiple genetic and biochemical approaches in yeast model, single lab\",\n      \"pmids\": [\"25009284\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"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.\",\n      \"method\": \"Proteomic analysis (GFP-PEX7 pull-down + mass spectrometry); in vivo Co-IP; immunofluorescence; proteasome inhibitor treatment; genetic analysis of RabE1c mutants\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 / Moderate — multiple orthogonal methods (proteomics, Co-IP, genetics, inhibitor) in Arabidopsis; note this is a plant ortholog study\",\n      \"pmids\": [\"23297417\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"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.\",\n      \"method\": \"Immunoprecipitation/mass spectrometry identification of Pex7-binding partners in mammalian cells\",\n      \"journal\": \"Sub-cellular biochemistry\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single Co-IP/MS identification reported as a summary chapter, limited mechanistic follow-up described in abstract\",\n      \"pmids\": [\"30378028\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"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.\",\n      \"method\": \"siRNA knockdown; confocal microscopy; immunoelectron microscopy; MALDI-MS proteomic identification of iNOS-EBP50 association; in vivo LPS-treated mouse model\",\n      \"journal\": \"Nitric oxide : biology and chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 / Moderate — multiple imaging methods and in vivo confirmation, though mechanistic detail of direct vs indirect PEX7-iNOS interaction is limited\",\n      \"pmids\": [\"23474170\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"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.\",\n      \"method\": \"Co-immunoprecipitation; peroxisomal localization assay; gel-filtration chromatography; atomic force microscopy; sequence/domain analysis\",\n      \"journal\": \"Journal of biochemistry\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single lab, Co-IP and localization without rigorous mechanistic dissection\",\n      \"pmids\": [\"30204880\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"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.\",\n      \"method\": \"Hypomorphic mouse engineering; biochemical assays (plasmalogen levels, phytanic acid); PTS2 import assay; dietary supplementation experiment\",\n      \"journal\": \"Molecular genetics and metabolism\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — well-characterized mouse model with multiple biochemical readouts and therapeutic intervention test, single lab\",\n      \"pmids\": [\"20060764\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"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.\",\n      \"method\": \"RNAi knockdown; immunofluorescence; subcellular fractionation; electron microscopy; growth assays in T. brucei\",\n      \"journal\": \"Biochimica et biophysica acta\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple methods (RNAi, immunofluorescence, fractionation, EM) in a relevant ortholog system\",\n      \"pmids\": [\"17320990\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"PEX7 encodes a cytosolic WD40-repeat PTS2 receptor that binds PTS2-containing peroxisomal matrix proteins via a conserved amphipathic groove, forming a trimeric cargo–PEX7–PEX5L complex whose assembly is stabilized by cargo binding; this complex docks at the peroxisomal membrane docking/translocation machinery (DTM), translocates cargo into the matrix (independent of PTS2 cleavage), and exports PEX7 back to the cytosol in a PEX5-dependent but uncoupled manner, while dysfunctional PEX7 is subject to CRL4A ubiquitin ligase- and proteasome-mediated quality control, with loss of PEX7 function causing defective import of plasmalogen biosynthesis enzymes, phytanoyl-CoA hydroxylase, and peroxisomal thiolase, thereby producing the biochemical and clinical phenotypes of RCDP and Refsum disease.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"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 [#0, #5]. 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 [#6]. 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 [#8]. 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 [#7, #9]. Dysfunctional or excess PEX7 is removed by ubiquitin–proteasome quality control, including CRL4A (DDB1) E3 ligase-mediated turnover [#12]. 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 [#2, #4, #15].\",\n  \"teleology\": [\n    {\n      \"year\": 1997,\n      \"claim\": \"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.\",\n      \"evidence\": \"Complementation of the PTS2-import defect in RCDP patient fibroblasts by human/murine PEX7, with restored thiolase targeting and DHAP-AT activity\",\n      \"pmids\": [\"9090381\", \"9090383\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not define the structural basis of PTS2 recognition\", \"Did not resolve the membrane translocation steps\"]\n    },\n    {\n      \"year\": 2002,\n      \"claim\": \"Linked residual receptor activity to clinical severity, establishing a genotype-activity-phenotype correlation for PEX7 alleles.\",\n      \"evidence\": \"Functional expression of mutant PEX7 alleles in RCDP fibroblasts with PTS2 import readout; demonstration of ribosomal frame restoration of a frameshift allele\",\n      \"pmids\": [\"12325024\", \"11781871\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Quantitative relationship between residual activity and phenotype not fully defined\", \"Single-lab assays per allele\"]\n    },\n    {\n      \"year\": 2003,\n      \"claim\": \"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.\",\n      \"evidence\": \"Pex7 knockout mouse with plasmalogen, fatty acid oxidation, neuronal migration and ossification readouts; linkage and biochemical analysis of Refsum-like patients\",\n      \"pmids\": [\"12915479\", \"12522768\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism linking import defect to neuronal migration and ossification not resolved\", \"Did not address receptor cycling mechanics\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Provided a structural rationale for cargo recognition, answering how PEX7 physically discriminates the PTS2 motif.\",\n      \"evidence\": \"WD40 β-propeller structural modeling, PTS2 mutational analysis, mammalian two-hybrid, and compensatory cross-complementation\",\n      \"pmids\": [\"22057399\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No experimental crystal or cryo-EM structure of the PEX7–PTS2 complex\", \"Modeling-based interface\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"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.\",\n      \"evidence\": \"In vitro co-import/export and protease protection assays with organelle fractionation\",\n      \"pmids\": [\"24865970\", \"26138649\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Molecular trigger of cargo release at the matrix not defined\", \"Mechanism uncoupling PEX7 and PEX5 export unclear\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"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.\",\n      \"evidence\": \"Modified mammalian two-hybrid and overexpression/peroxisomal targeting assays for trimeric cargo–PEX7–PEX5L complex formation\",\n      \"pmids\": [\"25538232\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Stoichiometry and kinetics of complex assembly not quantified\", \"Single-lab two-hybrid evidence\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"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.\",\n      \"evidence\": \"In vitro reconstitution with pre-assembled trimeric PEX5-PEX7-PTS2 complexes and organelle fractionation\",\n      \"pmids\": [\"26138649\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Conformational changes in PEX5 inferred, not directly observed\", \"Single-lab in vitro system\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Identified ubiquitin-proteasome quality control of PEX7 via the CRL4A (DDB1) E3 ligase, addressing how dysfunctional receptor is cleared.\",\n      \"evidence\": \"Immunoprecipitation/mass spectrometry identification of DDB1 as a PEX7 partner in mammalian cells\",\n      \"pmids\": [\"30378028\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"Single Co-IP/MS report in a summary chapter without rigorous mechanistic follow-up\", \"Ubiquitination sites and substrate-recognition mechanism undefined\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"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.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"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\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0038024\", \"supporting_discovery_ids\": [0, 1, 6, 8]},\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [8, 9]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [0, 7]},\n      {\"term_id\": \"GO:0005777\", \"supporting_discovery_ids\": [7, 9, 13]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-9609507\", \"supporting_discovery_ids\": [0, 7, 9]},\n      {\"term_id\": \"R-HSA-1430728\", \"supporting_discovery_ids\": [4, 5, 15]},\n      {\"term_id\": \"R-HSA-1852241\", \"supporting_discovery_ids\": [16]}\n    ],\n    \"complexes\": [\"cargo-PEX7-PEX5L trimeric import complex\", \"peroxisomal docking/translocation machinery (DTM)\"],\n    \"partners\": [\"PEX5\", \"PEX5L\", \"DDB1\", \"P7BP2\", \"PEX20\", \"RabE1c\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":6,"faith_total":6,"faith_pct":100.0}}