{"gene":"PEX13","run_date":"2026-06-10T05:19:53","timeline":{"discoveries":[{"year":1999,"finding":"PEX13 encodes a peroxisomal membrane protein with a cytoplasmically exposed SH3 domain that functions as a docking factor for the PTS1 receptor PEX5; expression of human PEX13 restores peroxisomal matrix protein import in PEX13-deficient cells, and a missense mutation in the SH3 domain (at a conserved position) reduces PEX13 activity.","method":"Complementation rescue in patient fibroblasts and CHO mutant cells; mutagenesis of SH3 domain; cell fusion complementation grouping","journal":"American journal of human genetics","confidence":"High","confidence_rationale":"Tier 2 / Strong — complementation rescue with functional readout replicated across multiple labs (PMID 10441568, 10332040, 10441330)","pmids":["10441568","10332040","10441330"],"is_preprint":false},{"year":1999,"finding":"The I326T missense mutation in the SH3 domain of PEX13 is a temperature-sensitive mutation: PEX13-I326T protein is stable at 30°C but unstable at 37°C, resulting in defective peroxisomal matrix protein import at physiological temperature.","method":"Expression of mutant PEX13 cDNA in PEX13-defective CHO cells at permissive vs. restrictive temperatures; RT-PCR mutation analysis","journal":"Human molecular genetics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — functional rescue assay with temperature-shift experiment in a single lab","pmids":["10332040"],"is_preprint":false},{"year":2003,"finding":"Ubiquitous Pex13 knockout in mouse results in absence of morphologically intact peroxisomes, deficient import of both PTS1 and PTS2 matrix proteins, severe impairment of peroxisomal fatty acid oxidation and plasmalogen synthesis, and neonatal lethality recapitulating Zellweger syndrome.","method":"Conditional Cre/loxP knockout mouse; immunofluorescence for matrix protein import; biochemical assays for fatty acid oxidation and plasmalogen in tissue and cultured fibroblasts","journal":"Molecular and cellular biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — in vivo KO with multiple orthogonal biochemical and cellular phenotypic readouts","pmids":["12897163"],"is_preprint":false},{"year":2005,"finding":"Yeast Pex13 binds Pex14 via two distinct sites: its SH3 domain and a novel intraperoxisomal site. Pex5 also contributes to the Pex13–Pex14 association. Disruption of both the intraperoxisomal Pex14-binding site of Pex13 and the Pex5–Pex14 interaction severely impairs PTS1-dependent import; additionally blocking SH3-mediated Pex13–Pex14 interaction completely abolishes PTS2 import and dissociates Pex13 from the docking complex.","method":"Mutagenesis of interaction sites; co-purification of docking complex; in vivo growth on oleic acid; fluorescence microscopy of matrix protein import","journal":"Molecular and cellular biology","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — multiple interaction-site mutants combined with functional import assays and co-purification in a single rigorous study","pmids":["15798189"],"is_preprint":false},{"year":2010,"finding":"Brain-restricted Pex13 knockout mice exhibit defects in cerebellar fissure and cortical layer formation, granule cell migration, and Purkinje cell layer development; cultured Pex13-null cerebellar neurons show elevated reactive oxygen species, increased mitochondrial superoxide dismutase-2 (MnSOD), enhanced apoptosis, and mitochondrial dysfunction, indicating that PEX13 deficiency leads to mitochondria-mediated oxidative stress and neuronal cell death.","method":"Conditional brain-specific Cre/loxP knockout mouse; ROS measurement; immunostaining for MnSOD; apoptosis assays; mitochondrial function assays in primary cerebellar neurons","journal":"Disease models & mechanisms","confidence":"High","confidence_rationale":"Tier 2 / Strong — in vivo conditional KO with multiple orthogonal cellular and biochemical readouts","pmids":["20959636"],"is_preprint":false},{"year":2013,"finding":"Human PEX13 forms homooligomers at the peroxisomal membrane; the W313 residue in the SH3 domain is required for self-association but not for interaction with PEX14. Disruption of PEX13 homooligomerization specifically impairs PTS1 protein import, and rescue of homooligomerization restores PTS1 import. The N-terminal half of PEX13 is necessary for peroxisomal localization, which is in turn required for homooligomerization.","method":"Live-cell FRET microscopy; co-immunoprecipitation; truncation constructs; complementation assays in patient fibroblasts","journal":"Human molecular genetics","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal Co-IP plus live-cell FRET plus functional rescue with multiple constructs in a single study","pmids":["23716570"],"is_preprint":false},{"year":2016,"finding":"PEX13 is required for selective autophagy (virophagy of Sindbis virus and mitophagy of damaged mitochondria); disease-associated PEX13 mutants I326T and W313G are specifically defective in mitophagy. PEX13's mitophagy function is shared with PEX3 but not with PEX14 or PEX19, which are required for general autophagy.","method":"Loss-of-function (KO/KD) in cultured cells; selective autophagy assays (Sindbis virus clearance, mitochondrial clearance); complementation with disease-mutant constructs; comparison with other peroxin knockdowns","journal":"EMBO reports","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — clean KO with defined selective autophagy phenotypes and pathway comparison, single lab","pmids":["27827795"],"is_preprint":false},{"year":2018,"finding":"PEX13 adopts a Nout–Cin membrane topology in the peroxisomal membrane, exposing its C-terminal SH3 domain to the organelle matrix (intraperoxisomal), not to the cytoplasm as previously believed.","method":"Protease-protection assay on proteoliposomes containing PEX13 and on purified rat liver peroxisomes; mass spectrometry, Edman degradation, and domain-specific western blotting of protected fragments","journal":"The FEBS journal","confidence":"High","confidence_rationale":"Tier 1 / Moderate — reconstituted proteoliposomes plus native peroxisomes, multiple orthogonal detection methods (MS, Edman, western blot), single lab","pmids":["30414318"],"is_preprint":false},{"year":2020,"finding":"PEX13 loss causes accumulation of ubiquitinated PEX5 on peroxisomes; PEX13 protein level is downregulated during amino acid starvation to facilitate pexophagy induction; loss of PEX13 increases peroxisome-dependent ROS, and both ubiquitinated PEX5 accumulation and elevated ROS cooperatively induce pexophagy.","method":"CRISPR gene editing (KO) in cultured cells and zebrafish; quantitative fluorescence microscopy; western blotting for ubiquitinated PEX5; ROS measurements; autophagy flux assays","journal":"Autophagy","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal methods (genetic KO, live imaging, biochemistry) in cell culture and in vivo zebrafish model","pmids":["36541703"],"is_preprint":false},{"year":2024,"finding":"The C-terminal SH3 domain of PEX13 mediates intramolecular interactions with a proximal FxxxF motif, and this intramolecular engagement regulates binding of PEX5 WxxxF/Y motifs to the SH3 domain. Crystal structures reveal recognition of FxxxF and WxxxF/Y motifs by a non-canonical surface of the SH3 domain. The PEX13 FxxxF motif also mediates binding to PEX14. The canonical PxxP-binding surface of the SH3 domain does not bind PEX14 PxxP motifs in humans, unlike in yeast.","method":"Biochemical binding assays; structural biology (crystal structures); mutagenesis of FxxxF and WxxxF motifs","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 1 / Moderate — crystal structure combined with biochemical binding assays and mutagenesis in a single study","pmids":["38632234"],"is_preprint":false},{"year":2025,"finding":"The transcription factor ZBTB17/MIZ1 directly regulates PEX13 expression; knockdown of ZBTB17 reduces PEX13 levels and impairs peroxisomal matrix protein import. Knockdown of ZBTB17 or PEX13 produces similar metabolic alterations including downregulated purine synthesis, placing PEX13 downstream of ZBTB17 in a transcriptional regulatory axis.","method":"CRISPR/Cas9 ubiquitin ligase library screen; siRNA knockdown; reporter assays for transcription factor activity; metabolomic profiling; fluorescence microscopy of peroxisomal enzyme localization","journal":"The Journal of cell biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — CRISPR screen plus orthogonal knockdown with functional and metabolomic readouts, single lab","pmids":["40243840"],"is_preprint":false},{"year":2025,"finding":"PEDV nonstructural protein NSP8 directly interacts with PEX13 (identified by mass spectrometry) and induces dose-dependent degradation of PEX13 via the autophagy-lysosomal pathway. PEX13 downregulation triggers ubiquitination of PEX5, which is recognized by the autophagy receptor NBR1 and ubiquitin ligase PEX2, promoting autophagic peroxisome clearance and suppressing MAVS-dependent IFN-III production.","method":"Mass spectrometry identification of NSP8–PEX13 interaction; western blotting for PEX13 degradation under lysosomal inhibition; ubiquitination assays for PEX5; pexophagy flux assays; IFN-III production assays","journal":"mBio","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — MS-identified interaction plus biochemical pathway dissection, single lab, single paper","pmids":["41186416"],"is_preprint":false},{"year":2026,"finding":"PINK1 is a key regulator of pexophagy induced by PEX13 depletion; PINK1 phosphorylates STUB1, enhancing its E3 ligase activity to ubiquitinate ABCD3, which recruits SQSTM1 for peroxisomal degradation. ATM activates PINK1 under peroxisomal stress, defining an ATM-PINK1-STUB1-ABCD3-SQSTM1 signaling cascade downstream of PEX13 loss.","method":"siRNA screening; epistasis genetic analysis; phosphorylation and ubiquitination assays; autophagy flux assays in cultured cells","journal":"Cell death and differentiation","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — siRNA screen plus biochemical pathway validation, single lab, single paper","pmids":["41927977"],"is_preprint":false},{"year":2020,"finding":"PEX13 loss in mouse hepatocytes leads to reduced hepatic hepcidin expression via increased SMAD7 signaling and endoplasmic reticulum stress, disrupting systemic iron homeostasis.","method":"Conditional hepatocyte-specific Pex13 knockout mouse; siRNA knockdown in HepG2/C3A cells; hepcidin and SMAD7 western blotting; ER stress markers","journal":"Biochimica et biophysica acta. Molecular basis of disease","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vivo conditional KO plus cell-based siRNA with mechanistic pathway markers, single lab","pmids":["32565019"],"is_preprint":false}],"current_model":"PEX13 is an integral peroxisomal membrane protein (Nout–Cin topology) whose intraperoxisomal SH3 domain engages intramolecularly with a proximal FxxxF motif and binds PEX5 WxxxF/Y motifs and PEX14 to form the peroxisomal docking/translocation complex required for import of both PTS1 and PTS2 matrix proteins; PEX13 homooligomerization (mediated by the conserved W313 residue) is specifically required for PTS1 import, while its interactions with PEX14 (via SH3 and a separate intraperoxisomal site) and with PEX5 are each essential for full matrix protein import; beyond import, PEX13 prevents pexophagy by suppressing accumulation of ubiquitinated PEX5 and peroxisomal ROS, and is required for selective autophagy (mitophagy and virophagy); transcriptionally, PEX13 is regulated by the ZBTB17/MIZ1 transcription factor, and its loss activates an ATM-PINK1-STUB1-ABCD3-SQSTM1 pexophagy cascade, while viral hijacking of PEX13 degradation suppresses MAVS-dependent interferon signaling."},"narrative":{"mechanistic_narrative":"PEX13 is an integral peroxisomal membrane protein that serves as a core docking factor of the peroxisomal protein import machinery, required for import of both PTS1- and PTS2-targeted matrix proteins [PMID:10441568, PMID:10332040, PMID:10441330, PMID:12897163]. It adopts a Nout–Cin topology that places its C-terminal SH3 domain inside the peroxisomal matrix rather than facing the cytoplasm [PMID:30414318], where the SH3 domain engages intramolecularly with a proximal FxxxF motif and, through a non-canonical surface, recognizes PEX5 WxxxF/Y motifs; the same FxxxF motif mediates binding to PEX14 [PMID:38632234]. PEX13 contacts PEX14 through two distinct sites—its SH3 domain and a separate intraperoxisomal site—with PEX5 also contributing to the assembly, and these interactions are differentially required for PTS1 versus PTS2 import [PMID:15798189]. Human PEX13 homooligomerizes at the membrane via the conserved W313 residue, an interaction specifically required for PTS1 import [PMID:23716570]. Loss of PEX13 abolishes intact peroxisome assembly and recapitulates Zellweger syndrome, with neonatal lethality, impaired fatty acid β-oxidation and plasmalogen synthesis in mouse models, and disease-causing SH3-domain missense mutations in patients [PMID:10441568, PMID:10332040, PMID:10441330, PMID:12897163]. Beyond import, PEX13 restrains pexophagy by limiting accumulation of ubiquitinated PEX5 and peroxisomal ROS [PMID:36541703], and its loss activates an ATM–PINK1–STUB1–ABCD3–SQSTM1 cascade that drives selective peroxisome degradation [PMID:41927977]; PEX13 is also required for selective autophagy including mitophagy and virophagy, functions disrupted by the disease mutants I326T and W313G [PMID:27827795]. PEX13 expression is controlled transcriptionally by ZBTB17/MIZ1 [PMID:40243840], and viral hijacking of PEX13 degradation suppresses MAVS-dependent interferon signaling [PMID:41186416].","teleology":[{"year":1999,"claim":"Established PEX13 as a peroxisomal membrane docking factor for the PTS1 receptor PEX5 and linked it causally to a human peroxisome biogenesis disorder.","evidence":"Complementation rescue in patient fibroblasts and CHO mutants with SH3-domain mutagenesis and cell-fusion complementation grouping","pmids":["10441568","10332040","10441330"],"confidence":"High","gaps":["Did not resolve membrane topology of the SH3 domain","Did not define how PEX13 distinguishes PTS1 from PTS2 cargo"]},{"year":1999,"claim":"Showed that an SH3-domain missense mutation acts via protein destabilization, explaining temperature-sensitive import failure.","evidence":"Expression of I326T mutant cDNA in PEX13-defective CHO cells at permissive vs restrictive temperatures with RT-PCR mutation analysis","pmids":["10332040"],"confidence":"Medium","gaps":["Single-lab temperature-shift assay","Did not determine structural basis of destabilization"]},{"year":2003,"claim":"Demonstrated in vivo that PEX13 is essential for assembly of intact peroxisomes and import of both PTS1 and PTS2 matrix proteins, defining the organismal consequences of its loss.","evidence":"Ubiquitous Cre/loxP Pex13 knockout mouse with import immunofluorescence and biochemical assays of fatty acid oxidation and plasmalogen synthesis","pmids":["12897163"],"confidence":"High","gaps":["Did not dissect which molecular interactions drive each import pathway","Mechanism of peroxisome loss versus import failure not separated"]},{"year":2005,"claim":"Resolved that PEX13 uses two distinct PEX14-binding sites and PEX5 contributions to differentially support PTS1 and PTS2 import within the docking complex.","evidence":"Interaction-site mutagenesis, docking-complex co-purification, oleic acid growth, and matrix import microscopy in yeast","pmids":["15798189"],"confidence":"High","gaps":["Performed in yeast; human site usage later shown to differ","Did not provide structural detail of binding surfaces"]},{"year":2010,"claim":"Connected PEX13 deficiency to mitochondria-mediated oxidative stress and neuronal death, extending its role beyond peroxisomal import to brain development.","evidence":"Brain-specific conditional knockout mouse with ROS, MnSOD, apoptosis, and mitochondrial function assays in primary cerebellar neurons","pmids":["20959636"],"confidence":"High","gaps":["Did not establish molecular link between peroxisomal import loss and mitochondrial dysfunction","Did not identify the ROS source pathway"]},{"year":2013,"claim":"Identified PEX13 homooligomerization via W313 as a specific requirement for PTS1 import, separating self-association from PEX14 binding.","evidence":"Live-cell FRET, reciprocal co-immunoprecipitation, truncation constructs, and complementation in patient fibroblasts","pmids":["23716570"],"confidence":"High","gaps":["Did not show how oligomerization mechanistically gates PTS1 cargo","Stoichiometry of the oligomer not defined"]},{"year":2016,"claim":"Revealed a non-import role for PEX13 in selective autophagy, with disease mutants specifically defective in mitophagy.","evidence":"Loss-of-function in cultured cells with Sindbis virophagy and mitophagy assays, disease-mutant complementation, and peroxin comparisons","pmids":["27827795"],"confidence":"Medium","gaps":["Single lab","Molecular mechanism coupling PEX13 to autophagosome targeting not defined"]},{"year":2018,"claim":"Overturned the cytoplasmic-SH3 model by establishing a Nout–Cin topology placing the SH3 domain in the matrix.","evidence":"Protease-protection assays on reconstituted proteoliposomes and native rat liver peroxisomes with MS, Edman degradation, and domain-specific western blotting","pmids":["30414318"],"confidence":"High","gaps":["Single lab","Did not re-map how cargo receptor PEX5 accesses the intraperoxisomal SH3 domain"]},{"year":2020,"claim":"Defined PEX13 as a suppressor of pexophagy that limits ubiquitinated PEX5 accumulation and peroxisomal ROS, and showed its downregulation during starvation.","evidence":"CRISPR knockout in cells and zebrafish with quantitative imaging, ubiquitinated-PEX5 western blotting, ROS measurement, and autophagy flux assays","pmids":["36541703"],"confidence":"High","gaps":["Did not identify the downstream signaling cascade executing pexophagy","How starvation triggers PEX13 downregulation unresolved"]},{"year":2020,"claim":"Linked hepatic PEX13 loss to systemic iron homeostasis through SMAD7-driven hepcidin suppression and ER stress.","evidence":"Hepatocyte-specific conditional knockout mouse and HepG2/C3A siRNA with hepcidin, SMAD7, and ER stress markers","pmids":["32565019"],"confidence":"Medium","gaps":["Single lab","Did not connect peroxisomal import defect to SMAD7 activation mechanistically"]},{"year":2024,"claim":"Provided the structural basis for PEX13 cargo recognition, showing intramolecular FxxxF–SH3 engagement that gates PEX5 WxxxF/Y binding and revealing human-specific divergence from yeast PxxP usage.","evidence":"Crystal structures with biochemical binding assays and FxxxF/WxxxF motif mutagenesis","pmids":["38632234"],"confidence":"High","gaps":["Did not show structure within an assembled docking complex","Dynamics of the intramolecular switch during import not captured"]},{"year":2025,"claim":"Placed PEX13 downstream of the transcription factor ZBTB17/MIZ1, linking its expression to peroxisomal import capacity and purine metabolism.","evidence":"CRISPR ubiquitin-ligase screen, siRNA knockdown, transcription-factor reporter assays, metabolomics, and import microscopy","pmids":["40243840"],"confidence":"Medium","gaps":["Single lab","Direct promoter occupancy by ZBTB17 not fully resolved"]},{"year":2025,"claim":"Showed viral exploitation of PEX13: a coronavirus protein degrades PEX13 to trigger pexophagy and dampen antiviral interferon signaling.","evidence":"MS identification of PEDV NSP8–PEX13 interaction, lysosomal-inhibition degradation assays, PEX5 ubiquitination, pexophagy flux, and IFN-III assays","pmids":["41186416"],"confidence":"Medium","gaps":["Single lab, single virus","Did not map the NSP8 binding interface on PEX13"]},{"year":2026,"claim":"Defined the signaling cascade executing pexophagy after PEX13 loss, identifying an ATM–PINK1–STUB1–ABCD3–SQSTM1 axis.","evidence":"siRNA screening, epistasis analysis, phosphorylation and ubiquitination assays, and autophagy flux in cultured cells","pmids":["41927977"],"confidence":"Medium","gaps":["Single lab","How PEX13 depletion is sensed by ATM upstream not defined"]},{"year":null,"claim":"How PEX13's intraperoxisomal SH3 domain physically receives cytosolic PEX5 cargo given the Nout–Cin topology, and how the import and pexophagy-suppressing functions are mechanistically coordinated, remain unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["Topology-versus-cargo-access paradox unresolved","No integrated structure of the human docking/translocation complex","Switch between import support and pexophagy suppression undefined"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[0,3,5,9]},{"term_id":"GO:0008092","term_label":"cytoskeletal protein binding","supporting_discovery_ids":[3,9]}],"localization":[{"term_id":"GO:0005777","term_label":"peroxisome","supporting_discovery_ids":[0,5,7,8]}],"pathway":[{"term_id":"R-HSA-9609507","term_label":"Protein localization","supporting_discovery_ids":[0,2,3]},{"term_id":"R-HSA-9612973","term_label":"Autophagy","supporting_discovery_ids":[6,8,12]},{"term_id":"R-HSA-1430728","term_label":"Metabolism","supporting_discovery_ids":[2,10]}],"complexes":["peroxisomal docking/translocation complex"],"partners":["PEX5","PEX14","PEX3"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q92968","full_name":"Peroxisomal membrane protein PEX13","aliases":["Peroxin-13"],"length_aa":403,"mass_kda":44.1,"function":"Component of the PEX13-PEX14 docking complex, a translocon channel that specifically mediates the import of peroxisomal cargo proteins bound to PEX5 receptor (PubMed:28765278, PubMed:8858165, PubMed:9653144). The PEX13-PEX14 docking complex forms a large import pore which can be opened to a diameter of about 9 nm (By similarity). Mechanistically, PEX5 receptor along with cargo proteins associates with the PEX14 subunit of the PEX13-PEX14 docking complex in the cytosol, leading to the insertion of the receptor into the organelle membrane with the concomitant translocation of the cargo into the peroxisome matrix (PubMed:28765278, PubMed:8858165, PubMed:9653144). Involved in the import of PTS1- and PTS2-type containing proteins (PubMed:8858165, PubMed:9653144)","subcellular_location":"Peroxisome membrane","url":"https://www.uniprot.org/uniprotkb/Q92968/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/PEX13","classification":"Not Classified","n_dependent_lines":66,"n_total_lines":1208,"dependency_fraction":0.054635761589403975},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/PEX13","total_profiled":1310},"omim":[{"mim_id":"621410","title":"PEROXISOME BIOGENESIS FACTOR 39; PEX39","url":"https://www.omim.org/entry/621410"},{"mim_id":"614885","title":"PEROXISOME BIOGENESIS DISORDER 11B; PBD11B","url":"https://www.omim.org/entry/614885"},{"mim_id":"614883","title":"PEROXISOME BIOGENESIS DISORDER 11A (ZELLWEGER); PBD11A","url":"https://www.omim.org/entry/614883"},{"mim_id":"614870","title":"PEROXISOME BIOGENESIS DISORDER 6A (ZELLWEGER); PBD6A","url":"https://www.omim.org/entry/614870"},{"mim_id":"602859","title":"PEROXISOME BIOGENESIS FACTOR 10; PEX10","url":"https://www.omim.org/entry/602859"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Supported","locations":[{"location":"Peroxisomes","reliability":"Supported"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/PEX13"},"hgnc":{"alias_symbol":[],"prev_symbol":[]},"alphafold":{"accession":"Q92968","domains":[{"cath_id":"2.30.30.40","chopping":"266-350","consensus_level":"high","plddt":85.2149,"start":266,"end":350},{"cath_id":"1.20.5","chopping":"117-199","consensus_level":"medium","plddt":83.1688,"start":117,"end":199}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q92968","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q92968-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q92968-F1-predicted_aligned_error_v6.png","plddt_mean":64.94},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=PEX13","jax_strain_url":"https://www.jax.org/strain/search?query=PEX13"},"sequence":{"accession":"Q92968","fasta_url":"https://rest.uniprot.org/uniprotkb/Q92968.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q92968/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q92968"}},"corpus_meta":[{"pmid":"12897163","id":"PMC_12897163","title":"Pex13 inactivation in the mouse disrupts peroxisome biogenesis and leads to a Zellweger syndrome phenotype.","date":"2003","source":"Molecular and cellular biology","url":"https://pubmed.ncbi.nlm.nih.gov/12897163","citation_count":93,"is_preprint":false},{"pmid":"10332040","id":"PMC_10332040","title":"Nonsense and temperature-sensitive mutations in PEX13 are the cause of complementation group H of peroxisome biogenesis disorders.","date":"1999","source":"Human molecular genetics","url":"https://pubmed.ncbi.nlm.nih.gov/10332040","citation_count":70,"is_preprint":false},{"pmid":"10441568","id":"PMC_10441568","title":"PEX13 is mutated in complementation group 13 of the peroxisome-biogenesis disorders.","date":"1999","source":"American journal of human genetics","url":"https://pubmed.ncbi.nlm.nih.gov/10441568","citation_count":56,"is_preprint":false},{"pmid":"20959636","id":"PMC_20959636","title":"PEX13 deficiency in mouse brain as a model of Zellweger syndrome: abnormal cerebellum formation, reactive gliosis and oxidative stress.","date":"2010","source":"Disease models & mechanisms","url":"https://pubmed.ncbi.nlm.nih.gov/20959636","citation_count":54,"is_preprint":false},{"pmid":"36541703","id":"PMC_36541703","title":"PEX13 prevents pexophagy by regulating ubiquitinated PEX5 and peroxisomal ROS.","date":"2023","source":"Autophagy","url":"https://pubmed.ncbi.nlm.nih.gov/36541703","citation_count":50,"is_preprint":false},{"pmid":"20192831","id":"PMC_20192831","title":"Peroxisome biogenesis factor PEX13 is required for appressorium-mediated plant infection by the anthracnose fungus Colletotrichum orbiculare.","date":"2010","source":"Molecular plant-microbe interactions : MPMI","url":"https://pubmed.ncbi.nlm.nih.gov/20192831","citation_count":42,"is_preprint":false},{"pmid":"27827795","id":"PMC_27827795","title":"Peroxisomal protein PEX13 functions in selective autophagy.","date":"2016","source":"EMBO 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oryzae.","date":"2019","source":"Virulence","url":"https://pubmed.ncbi.nlm.nih.gov/30905264","citation_count":30,"is_preprint":false},{"pmid":"23716570","id":"PMC_23716570","title":"Functional analysis of PEX13 mutation in a Zellweger syndrome spectrum patient reveals novel homooligomerization of PEX13 and its role in human peroxisome biogenesis.","date":"2013","source":"Human molecular genetics","url":"https://pubmed.ncbi.nlm.nih.gov/23716570","citation_count":26,"is_preprint":false},{"pmid":"22641036","id":"PMC_22641036","title":"Trypanosomes contain two highly different isoforms of peroxin PEX13 involved in glycosome biogenesis.","date":"2012","source":"FEBS letters","url":"https://pubmed.ncbi.nlm.nih.gov/22641036","citation_count":23,"is_preprint":false},{"pmid":"19449432","id":"PMC_19449432","title":"Zellweger syndrome caused by PEX13 deficiency: report of two novel mutations.","date":"2009","source":"American journal of medical genetics. Part A","url":"https://pubmed.ncbi.nlm.nih.gov/19449432","citation_count":15,"is_preprint":false},{"pmid":"9878256","id":"PMC_9878256","title":"Genomic structure of PEX13, a candidate peroxisome biogenesis disorder gene.","date":"1998","source":"Genomics","url":"https://pubmed.ncbi.nlm.nih.gov/9878256","citation_count":13,"is_preprint":false},{"pmid":"34517131","id":"PMC_34517131","title":"PEX13 is required for thermogenesis of white adipose tissue in cold-exposed mice.","date":"2021","source":"Biochimica et biophysica acta. Molecular and cell biology of lipids","url":"https://pubmed.ncbi.nlm.nih.gov/34517131","citation_count":11,"is_preprint":false},{"pmid":"38632234","id":"PMC_38632234","title":"Modulation of peroxisomal import by the PEX13 SH3 domain and a proximal FxxxF binding motif.","date":"2024","source":"Nature communications","url":"https://pubmed.ncbi.nlm.nih.gov/38632234","citation_count":11,"is_preprint":false},{"pmid":"32075879","id":"PMC_32075879","title":"Trypanosoma brucei Pex13.2 Is an Accessory Peroxin That Functions in the Import of Peroxisome Targeting Sequence Type 2 Proteins and Localizes to Subdomains of the Glycosome.","date":"2020","source":"mSphere","url":"https://pubmed.ncbi.nlm.nih.gov/32075879","citation_count":10,"is_preprint":false},{"pmid":"11829486","id":"PMC_11829486","title":"Pex13, the mouse ortholog of the human peroxisome biogenesis disorder PEX13 gene: gene structure, tissue expression, and localization of the protein to peroxisomes.","date":"2002","source":"Genomics","url":"https://pubmed.ncbi.nlm.nih.gov/11829486","citation_count":8,"is_preprint":false},{"pmid":"32565019","id":"PMC_32565019","title":"Hepatocyte-specific deletion of peroxisomal protein PEX13 results in disrupted iron homeostasis.","date":"2020","source":"Biochimica et biophysica acta. 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expression of human PEX13 restores peroxisomal matrix protein import in PEX13-deficient cells, and a missense mutation in the SH3 domain (at a conserved position) reduces PEX13 activity.\",\n      \"method\": \"Complementation rescue in patient fibroblasts and CHO mutant cells; mutagenesis of SH3 domain; cell fusion complementation grouping\",\n      \"journal\": \"American journal of human genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — complementation rescue with functional readout replicated across multiple labs (PMID 10441568, 10332040, 10441330)\",\n      \"pmids\": [\"10441568\", \"10332040\", \"10441330\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1999,\n      \"finding\": \"The I326T missense mutation in the SH3 domain of PEX13 is a temperature-sensitive mutation: PEX13-I326T protein is stable at 30°C but unstable at 37°C, resulting in defective peroxisomal matrix protein import at physiological temperature.\",\n      \"method\": \"Expression of mutant PEX13 cDNA in PEX13-defective CHO cells at permissive vs. restrictive temperatures; RT-PCR mutation analysis\",\n      \"journal\": \"Human molecular genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — functional rescue assay with temperature-shift experiment in a single lab\",\n      \"pmids\": [\"10332040\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"Ubiquitous Pex13 knockout in mouse results in absence of morphologically intact peroxisomes, deficient import of both PTS1 and PTS2 matrix proteins, severe impairment of peroxisomal fatty acid oxidation and plasmalogen synthesis, and neonatal lethality recapitulating Zellweger syndrome.\",\n      \"method\": \"Conditional Cre/loxP knockout mouse; immunofluorescence for matrix protein import; biochemical assays for fatty acid oxidation and plasmalogen in tissue and cultured fibroblasts\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — in vivo KO with multiple orthogonal biochemical and cellular phenotypic readouts\",\n      \"pmids\": [\"12897163\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"Yeast Pex13 binds Pex14 via two distinct sites: its SH3 domain and a novel intraperoxisomal site. Pex5 also contributes to the Pex13–Pex14 association. Disruption of both the intraperoxisomal Pex14-binding site of Pex13 and the Pex5–Pex14 interaction severely impairs PTS1-dependent import; additionally blocking SH3-mediated Pex13–Pex14 interaction completely abolishes PTS2 import and dissociates Pex13 from the docking complex.\",\n      \"method\": \"Mutagenesis of interaction sites; co-purification of docking complex; in vivo growth on oleic acid; fluorescence microscopy of matrix protein import\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — multiple interaction-site mutants combined with functional import assays and co-purification in a single rigorous study\",\n      \"pmids\": [\"15798189\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"Brain-restricted Pex13 knockout mice exhibit defects in cerebellar fissure and cortical layer formation, granule cell migration, and Purkinje cell layer development; cultured Pex13-null cerebellar neurons show elevated reactive oxygen species, increased mitochondrial superoxide dismutase-2 (MnSOD), enhanced apoptosis, and mitochondrial dysfunction, indicating that PEX13 deficiency leads to mitochondria-mediated oxidative stress and neuronal cell death.\",\n      \"method\": \"Conditional brain-specific Cre/loxP knockout mouse; ROS measurement; immunostaining for MnSOD; apoptosis assays; mitochondrial function assays in primary cerebellar neurons\",\n      \"journal\": \"Disease models & mechanisms\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — in vivo conditional KO with multiple orthogonal cellular and biochemical readouts\",\n      \"pmids\": [\"20959636\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"Human PEX13 forms homooligomers at the peroxisomal membrane; the W313 residue in the SH3 domain is required for self-association but not for interaction with PEX14. Disruption of PEX13 homooligomerization specifically impairs PTS1 protein import, and rescue of homooligomerization restores PTS1 import. The N-terminal half of PEX13 is necessary for peroxisomal localization, which is in turn required for homooligomerization.\",\n      \"method\": \"Live-cell FRET microscopy; co-immunoprecipitation; truncation constructs; complementation assays in patient fibroblasts\",\n      \"journal\": \"Human molecular genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal Co-IP plus live-cell FRET plus functional rescue with multiple constructs in a single study\",\n      \"pmids\": [\"23716570\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"PEX13 is required for selective autophagy (virophagy of Sindbis virus and mitophagy of damaged mitochondria); disease-associated PEX13 mutants I326T and W313G are specifically defective in mitophagy. PEX13's mitophagy function is shared with PEX3 but not with PEX14 or PEX19, which are required for general autophagy.\",\n      \"method\": \"Loss-of-function (KO/KD) in cultured cells; selective autophagy assays (Sindbis virus clearance, mitochondrial clearance); complementation with disease-mutant constructs; comparison with other peroxin knockdowns\",\n      \"journal\": \"EMBO reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — clean KO with defined selective autophagy phenotypes and pathway comparison, single lab\",\n      \"pmids\": [\"27827795\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"PEX13 adopts a Nout–Cin membrane topology in the peroxisomal membrane, exposing its C-terminal SH3 domain to the organelle matrix (intraperoxisomal), not to the cytoplasm as previously believed.\",\n      \"method\": \"Protease-protection assay on proteoliposomes containing PEX13 and on purified rat liver peroxisomes; mass spectrometry, Edman degradation, and domain-specific western blotting of protected fragments\",\n      \"journal\": \"The FEBS journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — reconstituted proteoliposomes plus native peroxisomes, multiple orthogonal detection methods (MS, Edman, western blot), single lab\",\n      \"pmids\": [\"30414318\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"PEX13 loss causes accumulation of ubiquitinated PEX5 on peroxisomes; PEX13 protein level is downregulated during amino acid starvation to facilitate pexophagy induction; loss of PEX13 increases peroxisome-dependent ROS, and both ubiquitinated PEX5 accumulation and elevated ROS cooperatively induce pexophagy.\",\n      \"method\": \"CRISPR gene editing (KO) in cultured cells and zebrafish; quantitative fluorescence microscopy; western blotting for ubiquitinated PEX5; ROS measurements; autophagy flux assays\",\n      \"journal\": \"Autophagy\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal methods (genetic KO, live imaging, biochemistry) in cell culture and in vivo zebrafish model\",\n      \"pmids\": [\"36541703\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"The C-terminal SH3 domain of PEX13 mediates intramolecular interactions with a proximal FxxxF motif, and this intramolecular engagement regulates binding of PEX5 WxxxF/Y motifs to the SH3 domain. Crystal structures reveal recognition of FxxxF and WxxxF/Y motifs by a non-canonical surface of the SH3 domain. The PEX13 FxxxF motif also mediates binding to PEX14. The canonical PxxP-binding surface of the SH3 domain does not bind PEX14 PxxP motifs in humans, unlike in yeast.\",\n      \"method\": \"Biochemical binding assays; structural biology (crystal structures); mutagenesis of FxxxF and WxxxF motifs\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — crystal structure combined with biochemical binding assays and mutagenesis in a single study\",\n      \"pmids\": [\"38632234\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"The transcription factor ZBTB17/MIZ1 directly regulates PEX13 expression; knockdown of ZBTB17 reduces PEX13 levels and impairs peroxisomal matrix protein import. Knockdown of ZBTB17 or PEX13 produces similar metabolic alterations including downregulated purine synthesis, placing PEX13 downstream of ZBTB17 in a transcriptional regulatory axis.\",\n      \"method\": \"CRISPR/Cas9 ubiquitin ligase library screen; siRNA knockdown; reporter assays for transcription factor activity; metabolomic profiling; fluorescence microscopy of peroxisomal enzyme localization\",\n      \"journal\": \"The Journal of cell biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — CRISPR screen plus orthogonal knockdown with functional and metabolomic readouts, single lab\",\n      \"pmids\": [\"40243840\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"PEDV nonstructural protein NSP8 directly interacts with PEX13 (identified by mass spectrometry) and induces dose-dependent degradation of PEX13 via the autophagy-lysosomal pathway. PEX13 downregulation triggers ubiquitination of PEX5, which is recognized by the autophagy receptor NBR1 and ubiquitin ligase PEX2, promoting autophagic peroxisome clearance and suppressing MAVS-dependent IFN-III production.\",\n      \"method\": \"Mass spectrometry identification of NSP8–PEX13 interaction; western blotting for PEX13 degradation under lysosomal inhibition; ubiquitination assays for PEX5; pexophagy flux assays; IFN-III production assays\",\n      \"journal\": \"mBio\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — MS-identified interaction plus biochemical pathway dissection, single lab, single paper\",\n      \"pmids\": [\"41186416\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"PINK1 is a key regulator of pexophagy induced by PEX13 depletion; PINK1 phosphorylates STUB1, enhancing its E3 ligase activity to ubiquitinate ABCD3, which recruits SQSTM1 for peroxisomal degradation. ATM activates PINK1 under peroxisomal stress, defining an ATM-PINK1-STUB1-ABCD3-SQSTM1 signaling cascade downstream of PEX13 loss.\",\n      \"method\": \"siRNA screening; epistasis genetic analysis; phosphorylation and ubiquitination assays; autophagy flux assays in cultured cells\",\n      \"journal\": \"Cell death and differentiation\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — siRNA screen plus biochemical pathway validation, single lab, single paper\",\n      \"pmids\": [\"41927977\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"PEX13 loss in mouse hepatocytes leads to reduced hepatic hepcidin expression via increased SMAD7 signaling and endoplasmic reticulum stress, disrupting systemic iron homeostasis.\",\n      \"method\": \"Conditional hepatocyte-specific Pex13 knockout mouse; siRNA knockdown in HepG2/C3A cells; hepcidin and SMAD7 western blotting; ER stress markers\",\n      \"journal\": \"Biochimica et biophysica acta. Molecular basis of disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vivo conditional KO plus cell-based siRNA with mechanistic pathway markers, single lab\",\n      \"pmids\": [\"32565019\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"PEX13 is an integral peroxisomal membrane protein (Nout–Cin topology) whose intraperoxisomal SH3 domain engages intramolecularly with a proximal FxxxF motif and binds PEX5 WxxxF/Y motifs and PEX14 to form the peroxisomal docking/translocation complex required for import of both PTS1 and PTS2 matrix proteins; PEX13 homooligomerization (mediated by the conserved W313 residue) is specifically required for PTS1 import, while its interactions with PEX14 (via SH3 and a separate intraperoxisomal site) and with PEX5 are each essential for full matrix protein import; beyond import, PEX13 prevents pexophagy by suppressing accumulation of ubiquitinated PEX5 and peroxisomal ROS, and is required for selective autophagy (mitophagy and virophagy); transcriptionally, PEX13 is regulated by the ZBTB17/MIZ1 transcription factor, and its loss activates an ATM-PINK1-STUB1-ABCD3-SQSTM1 pexophagy cascade, while viral hijacking of PEX13 degradation suppresses MAVS-dependent interferon signaling.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"PEX13 is an integral peroxisomal membrane protein that serves as a core docking factor of the peroxisomal protein import machinery, required for import of both PTS1- and PTS2-targeted matrix proteins [#0, #2]. It adopts a Nout–Cin topology that places its C-terminal SH3 domain inside the peroxisomal matrix rather than facing the cytoplasm [#7], where the SH3 domain engages intramolecularly with a proximal FxxxF motif and, through a non-canonical surface, recognizes PEX5 WxxxF/Y motifs; the same FxxxF motif mediates binding to PEX14 [#9]. PEX13 contacts PEX14 through two distinct sites—its SH3 domain and a separate intraperoxisomal site—with PEX5 also contributing to the assembly, and these interactions are differentially required for PTS1 versus PTS2 import [#3]. Human PEX13 homooligomerizes at the membrane via the conserved W313 residue, an interaction specifically required for PTS1 import [#5]. Loss of PEX13 abolishes intact peroxisome assembly and recapitulates Zellweger syndrome, with neonatal lethality, impaired fatty acid β-oxidation and plasmalogen synthesis in mouse models, and disease-causing SH3-domain missense mutations in patients [#0, #2]. Beyond import, PEX13 restrains pexophagy by limiting accumulation of ubiquitinated PEX5 and peroxisomal ROS [#8], and its loss activates an ATM–PINK1–STUB1–ABCD3–SQSTM1 cascade that drives selective peroxisome degradation [#12]; PEX13 is also required for selective autophagy including mitophagy and virophagy, functions disrupted by the disease mutants I326T and W313G [#6]. PEX13 expression is controlled transcriptionally by ZBTB17/MIZ1 [#10], and viral hijacking of PEX13 degradation suppresses MAVS-dependent interferon signaling [#11].\",\n  \"teleology\": [\n    {\n      \"year\": 1999,\n      \"claim\": \"Established PEX13 as a peroxisomal membrane docking factor for the PTS1 receptor PEX5 and linked it causally to a human peroxisome biogenesis disorder.\",\n      \"evidence\": \"Complementation rescue in patient fibroblasts and CHO mutants with SH3-domain mutagenesis and cell-fusion complementation grouping\",\n      \"pmids\": [\"10441568\", \"10332040\", \"10441330\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not resolve membrane topology of the SH3 domain\", \"Did not define how PEX13 distinguishes PTS1 from PTS2 cargo\"]\n    },\n    {\n      \"year\": 1999,\n      \"claim\": \"Showed that an SH3-domain missense mutation acts via protein destabilization, explaining temperature-sensitive import failure.\",\n      \"evidence\": \"Expression of I326T mutant cDNA in PEX13-defective CHO cells at permissive vs restrictive temperatures with RT-PCR mutation analysis\",\n      \"pmids\": [\"10332040\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single-lab temperature-shift assay\", \"Did not determine structural basis of destabilization\"]\n    },\n    {\n      \"year\": 2003,\n      \"claim\": \"Demonstrated in vivo that PEX13 is essential for assembly of intact peroxisomes and import of both PTS1 and PTS2 matrix proteins, defining the organismal consequences of its loss.\",\n      \"evidence\": \"Ubiquitous Cre/loxP Pex13 knockout mouse with import immunofluorescence and biochemical assays of fatty acid oxidation and plasmalogen synthesis\",\n      \"pmids\": [\"12897163\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not dissect which molecular interactions drive each import pathway\", \"Mechanism of peroxisome loss versus import failure not separated\"]\n    },\n    {\n      \"year\": 2005,\n      \"claim\": \"Resolved that PEX13 uses two distinct PEX14-binding sites and PEX5 contributions to differentially support PTS1 and PTS2 import within the docking complex.\",\n      \"evidence\": \"Interaction-site mutagenesis, docking-complex co-purification, oleic acid growth, and matrix import microscopy in yeast\",\n      \"pmids\": [\"15798189\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Performed in yeast; human site usage later shown to differ\", \"Did not provide structural detail of binding surfaces\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Connected PEX13 deficiency to mitochondria-mediated oxidative stress and neuronal death, extending its role beyond peroxisomal import to brain development.\",\n      \"evidence\": \"Brain-specific conditional knockout mouse with ROS, MnSOD, apoptosis, and mitochondrial function assays in primary cerebellar neurons\",\n      \"pmids\": [\"20959636\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not establish molecular link between peroxisomal import loss and mitochondrial dysfunction\", \"Did not identify the ROS source pathway\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Identified PEX13 homooligomerization via W313 as a specific requirement for PTS1 import, separating self-association from PEX14 binding.\",\n      \"evidence\": \"Live-cell FRET, reciprocal co-immunoprecipitation, truncation constructs, and complementation in patient fibroblasts\",\n      \"pmids\": [\"23716570\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not show how oligomerization mechanistically gates PTS1 cargo\", \"Stoichiometry of the oligomer not defined\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Revealed a non-import role for PEX13 in selective autophagy, with disease mutants specifically defective in mitophagy.\",\n      \"evidence\": \"Loss-of-function in cultured cells with Sindbis virophagy and mitophagy assays, disease-mutant complementation, and peroxin comparisons\",\n      \"pmids\": [\"27827795\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single lab\", \"Molecular mechanism coupling PEX13 to autophagosome targeting not defined\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Overturned the cytoplasmic-SH3 model by establishing a Nout–Cin topology placing the SH3 domain in the matrix.\",\n      \"evidence\": \"Protease-protection assays on reconstituted proteoliposomes and native rat liver peroxisomes with MS, Edman degradation, and domain-specific western blotting\",\n      \"pmids\": [\"30414318\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Single lab\", \"Did not re-map how cargo receptor PEX5 accesses the intraperoxisomal SH3 domain\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Defined PEX13 as a suppressor of pexophagy that limits ubiquitinated PEX5 accumulation and peroxisomal ROS, and showed its downregulation during starvation.\",\n      \"evidence\": \"CRISPR knockout in cells and zebrafish with quantitative imaging, ubiquitinated-PEX5 western blotting, ROS measurement, and autophagy flux assays\",\n      \"pmids\": [\"36541703\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not identify the downstream signaling cascade executing pexophagy\", \"How starvation triggers PEX13 downregulation unresolved\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Linked hepatic PEX13 loss to systemic iron homeostasis through SMAD7-driven hepcidin suppression and ER stress.\",\n      \"evidence\": \"Hepatocyte-specific conditional knockout mouse and HepG2/C3A siRNA with hepcidin, SMAD7, and ER stress markers\",\n      \"pmids\": [\"32565019\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single lab\", \"Did not connect peroxisomal import defect to SMAD7 activation mechanistically\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Provided the structural basis for PEX13 cargo recognition, showing intramolecular FxxxF–SH3 engagement that gates PEX5 WxxxF/Y binding and revealing human-specific divergence from yeast PxxP usage.\",\n      \"evidence\": \"Crystal structures with biochemical binding assays and FxxxF/WxxxF motif mutagenesis\",\n      \"pmids\": [\"38632234\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not show structure within an assembled docking complex\", \"Dynamics of the intramolecular switch during import not captured\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Placed PEX13 downstream of the transcription factor ZBTB17/MIZ1, linking its expression to peroxisomal import capacity and purine metabolism.\",\n      \"evidence\": \"CRISPR ubiquitin-ligase screen, siRNA knockdown, transcription-factor reporter assays, metabolomics, and import microscopy\",\n      \"pmids\": [\"40243840\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single lab\", \"Direct promoter occupancy by ZBTB17 not fully resolved\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Showed viral exploitation of PEX13: a coronavirus protein degrades PEX13 to trigger pexophagy and dampen antiviral interferon signaling.\",\n      \"evidence\": \"MS identification of PEDV NSP8–PEX13 interaction, lysosomal-inhibition degradation assays, PEX5 ubiquitination, pexophagy flux, and IFN-III assays\",\n      \"pmids\": [\"41186416\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single lab, single virus\", \"Did not map the NSP8 binding interface on PEX13\"]\n    },\n    {\n      \"year\": 2026,\n      \"claim\": \"Defined the signaling cascade executing pexophagy after PEX13 loss, identifying an ATM–PINK1–STUB1–ABCD3–SQSTM1 axis.\",\n      \"evidence\": \"siRNA screening, epistasis analysis, phosphorylation and ubiquitination assays, and autophagy flux in cultured cells\",\n      \"pmids\": [\"41927977\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single lab\", \"How PEX13 depletion is sensed by ATM upstream not defined\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How PEX13's intraperoxisomal SH3 domain physically receives cytosolic PEX5 cargo given the Nout–Cin topology, and how the import and pexophagy-suppressing functions are mechanistically coordinated, remain unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Topology-versus-cargo-access paradox unresolved\", \"No integrated structure of the human docking/translocation complex\", \"Switch between import support and pexophagy suppression undefined\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [0, 3, 5, 9]},\n      {\"term_id\": \"GO:0008092\", \"supporting_discovery_ids\": [3, 9]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005777\", \"supporting_discovery_ids\": [0, 5, 7, 8]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-9609507\", \"supporting_discovery_ids\": [0, 2, 3]},\n      {\"term_id\": \"R-HSA-9612973\", \"supporting_discovery_ids\": [6, 8, 12]},\n      {\"term_id\": \"R-HSA-1430728\", \"supporting_discovery_ids\": [2, 10]}\n    ],\n    \"complexes\": [\"peroxisomal docking/translocation complex\"],\n    \"partners\": [\"PEX5\", \"PEX14\", \"PEX3\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"loss","faith_supported":7,"faith_total":7,"faith_pct":100.0}}