Existing Annotations Review

GO Term	Evidence	Action	Reason
GO:0005052 peroxisome matrix targeting signal-1 binding	IBA GO_REF:0000033	ACCEPT	Summary: PTS1 binding is the core molecular function of PEX5. The IBA annotation is phylogenetically well-supported and consistent with extensive experimental data showing PEX5 recognizes C-terminal PTS1 tripeptide motifs via its TPR domain (PMID:21976670, PMID:10514471, PMID:12456682). Reason: PTS1 binding is the primary molecular function of PEX5, deeply conserved from yeast to human, and supported by IBA phylogenetic inference as well as numerous IDA/IPI annotations. Supporting Evidence: PMID:21976670 PEX5 protein binds monomeric catalase blocking its tetramerization and releases it upon binding the N-terminal domain of PEX14 PMID:10514471 HsPMP20 bound directly to the human peroxisomal targeting signal 1 receptor, HsPEX5
GO:0005829 cytosol	IBA GO_REF:0000033	ACCEPT	Summary: PEX5 is predominantly cytosolic, cycling between the cytosol and the peroxisomal membrane. The IBA annotation is consistent with experimental localization data (PMID:16314507, PMID:11336669). Reason: PEX5 is a predominantly cytosolic receptor that transiently associates with the peroxisomal membrane during the import cycle. Cytosol localization is well established by IBA and multiple experimental studies. Supporting Evidence: PMID:11336669 human Pex5p does not just bind cargo and deliver it to the peroxisome membrane, but participates in multiple rounds of entry into the peroxisome matrix and export to the cytosol PMID:16314507 Shuttling mechanism of peroxisome targeting signal type 1 receptor Pex5: ATP-independent import and ATP-dependent export
GO:0005778 peroxisomal membrane	IBA GO_REF:0000033	ACCEPT	Summary: PEX5 transiently localizes to the peroxisomal membrane during the import cycle, docking via PEX13/PEX14. The IBA annotation is consistent with the cycling receptor model supported by extensive experimental data (PMID:16314507, PMID:11336669). Reason: Peroxisomal membrane localization is integral to PEX5 function as a cycling receptor. IBA annotation is phylogenetically well-supported. Supporting Evidence: PMID:16314507 Pex5 was in two distinct, 500- and 800-kDa complexes comprising different sets of peroxins, such as Pex14 and Pex2
GO:0016560 protein import into peroxisome matrix, docking	IBA GO_REF:0000033	ACCEPT	Summary: Docking of PEX5 at the peroxisomal membrane via PEX13/PEX14 is a core step in the PTS1 import pathway. The IBA annotation is consistent with the well-characterized docking mechanism (PMID:21976670, PMID:19197237). Reason: Docking is a defined sub-step of the PEX5 import cycle, phylogenetically conserved and well-supported experimentally. Supporting Evidence: PMID:21976670 PEX5 protein binds monomeric catalase blocking its tetramerization and releases it upon binding the N-terminal domain of PEX14
GO:0005782 peroxisomal matrix	IEA GO_REF:0000044	ACCEPT	Summary: PEX5 transiently enters the peroxisomal matrix during the import cycle. This IEA annotation from UniProt subcellular location mapping is consistent with the established cycling mechanism (PMID:11336669). Reason: IEA annotation is consistent with the well-established cycling mechanism where PEX5 enters the peroxisomal matrix to deliver cargo before being recycled. Supporting Evidence: PMID:11336669 human Pex5p does not just bind cargo and deliver it to the peroxisome membrane, but participates in multiple rounds of entry into the peroxisome matrix and export to the cytosol
GO:0005829 cytosol	IEA GO_REF:0000044	ACCEPT	Summary: Cytosol localization of PEX5 is well established. This IEA annotation is broader than the IBA annotation for the same term but consistent. Reason: Redundant with IBA annotation for the same term, but not incorrect. IEA from UniProt subcellular location mapping is consistent with experimental data.
GO:0015031 protein transport	IEA GO_REF:0000043	ACCEPT	Summary: PEX5 mediates protein transport to peroxisomes. This IEA annotation from UniProt keyword mapping is very general. The more specific term GO:0016558 (protein import into peroxisome matrix) is already annotated with multiple experimental evidence codes. Reason: While very general, this IEA annotation is not incorrect. More specific terms are annotated separately with experimental evidence. The IEA-derived broader term does not conflict.
GO:0005515 protein binding	IPI PMID:10562279 PEX12 interacts with PEX5 and PEX10 and acts downstream of r...	MODIFY	Summary: PMID:10562279 demonstrates PEX5 interaction with PEX12 and PEX10 in the peroxisomal import pathway. Protein binding is uninformative; the actual function is involvement in the RING complex interaction during cargo translocation. Reason: Protein binding is too vague. PEX5 interacts with PEX12 as part of the ubiquitin ligase complex interaction during the import cycle. A more specific MF term should capture this. Proposed replacements: peroxisome matrix targeting signal-1 binding Supporting Evidence: PMID:10562279 PEX12 interacts with PEX5 and PEX10 and acts downstream of receptor docking in peroxisomal matrix protein import
GO:0005515 protein binding	IPI PMID:12096124 Analysis of mammalian peroxin interactions using a non-trans...	MARK AS OVER ANNOTATED	Summary: PMID:12096124 used a non-transcription-based bacterial two-hybrid to analyze peroxin interactions including PEX5. Protein binding is uninformative for the actual function. Reason: Protein binding is too vague for a protein whose core function is defined by specific binding activities (PTS1 binding, PEX14 interaction). The peroxin-peroxin interactions are better captured by process and more specific MF terms.
GO:0005515 protein binding	IPI PMID:19197237 Structural basis for competitive interactions of Pex14 with ...	MARK AS OVER ANNOTATED	Summary: PMID:19197237 provides structural basis for competitive interactions of PEX14 with PEX5 and PEX19. This describes the key PEX5-PEX14 docking interaction. Reason: Protein binding is too vague. The PEX5-PEX14 interaction is better captured by GO:0016560 (protein import into peroxisome matrix, docking) which is already annotated.
GO:0005515 protein binding	IPI PMID:21044950 Genome-wide YFP fluorescence complementation screen identifi...	MARK AS OVER ANNOTATED	Summary: PMID:21044950 is a genome-wide YFP fluorescence complementation screen for telomere signaling regulators. The relevance to PEX5 core function is unclear. Reason: High-throughput screen result. Protein binding is uninformative and the telomere signaling context is unlikely to represent a core PEX5 function.
GO:0005515 protein binding	IPI PMID:21525035 PEX14 is required for microtubule-based peroxisome motility ...	MARK AS OVER ANNOTATED	Summary: PMID:21525035 shows PEX14 is required for microtubule-based peroxisome motility. PEX5 may interact with PEX14 in this context but the primary annotation is about PEX14. Reason: Protein binding is too vague. The PEX5-PEX14 interaction is better captured by docking and import terms already annotated.
GO:0005515 protein binding	IPI PMID:25416956 A proteome-scale map of the human interactome network.	MARK AS OVER ANNOTATED	Summary: PMID:25416956 is a proteome-scale map of the human interactome network. High-throughput interaction data. Reason: Protein binding from a high-throughput interactome screen is uninformative for PEX5 whose specific binding functions are well characterized.
GO:0005515 protein binding	IPI P50542-1 PMID:22529745 Molecular requirements for peroxisomal targeting of alanine-...	MARK AS OVER ANNOTATED	Summary: PMID:22529745 examines molecular requirements for peroxisomal targeting of AGT as a determinant in primary hyperoxaluria type 1. PEX5L interaction with AGT is part of its PTS1 receptor function. Reason: Protein binding is too vague. The interaction with AGT represents PEX5 performing its core PTS1 receptor function (cargo recognition), already captured by GO:0005052.
GO:0016558 protein import into peroxisome matrix	IEA GO_REF:0000107	ACCEPT	Summary: IEA annotation for protein import into peroxisome matrix via Ensembl Compara ortholog transfer. Consistent with the well-established core function of PEX5. Reason: Correct IEA annotation consistent with the core function of PEX5 as PTS1 receptor mediating peroxisomal matrix protein import.
GO:0005794 Golgi apparatus	IDA GO_REF:0000052	REMOVE	Summary: Golgi apparatus localization from immunofluorescence data curation. PEX5 is not known to function at the Golgi. This may reflect antibody cross-reactivity or misidentification in high-throughput immunofluorescence studies. Reason: PEX5 is a cytosolic/peroxisomal cycling receptor with no known Golgi function. This localization is not supported by the extensive literature on PEX5 subcellular distribution and is likely an artifact.
GO:0005829 cytosol	IDA GO_REF:0000052	ACCEPT	Summary: Cytosol localization from immunofluorescence data curation. Consistent with the well-established predominantly cytosolic localization of PEX5. Reason: Cytosol localization is well established for PEX5 as a cycling receptor.
GO:0140597 protein carrier chaperone	IDA PMID:28765278 The peroxisomal matrix protein translocon is a large cavity-...	ACCEPT	Summary: PMID:28765278 demonstrates that PEX5 enters a large cavity-forming protein assembly (the translocon) to release its cargo. This supports protein carrier activity as PEX5 physically carries folded cargo into the peroxisome. Reason: Protein carrier activity accurately describes PEX5 function as it physically escorts folded PTS1 cargo from cytosol into the peroxisomal matrix translocon. Supporting Evidence: PMID:28765278 the peroxisomal matrix protein translocon is a large cavity-forming protein assembly into which PEX5 protein enters to release its cargo
GO:0016562 protein import into peroxisome matrix, receptor recycling	IDA PMID:29884772 Peroxisomal monoubiquitinated PEX5 interacts with the AAA AT...	ACCEPT	Summary: PMID:29884772 shows monoubiquitinated PEX5 interacts with PEX1/PEX6 AAA ATPases and is unfolded during dislocation into the cytosol. This directly demonstrates receptor recycling. Reason: Receptor recycling is a core step in the PEX5 import cycle, directly demonstrated by this study. Supporting Evidence: PMID:29884772 Peroxisomal monoubiquitinated PEX5 interacts with the AAA ATPases PEX1 and PEX6 and is unfolded during its dislocation into the cytosol
GO:0000425 pexophagy	IDA PMID:26344566 ATM functions at the peroxisome to induce pexophagy in respo...	KEEP AS NON CORE	Summary: PMID:26344566 shows ATM functions at the peroxisome to induce pexophagy in response to ROS. PEX5 is phosphorylated by ATM and ubiquitinated to recruit autophagy adaptors. PEX5 participates in pexophagy but this is not its primary evolved function. Reason: PEX5 serves as a substrate for ATM-mediated pexophagy signaling, but pexophagy is a secondary quality control process rather than the core evolved function of PEX5 as a PTS1 import receptor. Supporting Evidence: PMID:26344566 ATM functions at the peroxisome to induce pexophagy in response to ROS
GO:0005052 peroxisome matrix targeting signal-1 binding	IDA PMID:26344566 ATM functions at the peroxisome to induce pexophagy in respo...	ACCEPT	Summary: PMID:26344566 also demonstrates PTS1 binding by PEX5 in the context of pexophagy studies. PTS1 binding is the core molecular function of PEX5. Reason: PTS1 binding is the core molecular function of PEX5, demonstrated here in the pexophagy context.
GO:0005782 peroxisomal matrix	IC P50542-1 PMID:24662292 Distinct modes of ubiquitination of peroxisome-targeting sig...	ACCEPT	Summary: Peroxisomal matrix localization by IC (inferred by curator) from PMID:24662292 which studies ubiquitination modes regulating PTS1 receptor Pex5p and PTS1 protein import. PEX5 transiently enters the matrix. Reason: PEX5 enters the peroxisomal matrix during the import cycle. IC from the ubiquitination study is consistent.
GO:0005829 cytosol	IDA P50542-1 PMID:25538232 Mechanistic insights into PTS2-mediated peroxisomal protein ...	ACCEPT	Summary: PMID:25538232 provides mechanistic insights into PTS2-mediated peroxisomal protein import and localizes PEX5L to the cytosol. Reason: Cytosol localization of PEX5L is well established and consistent with its role as a cycling receptor.
GO:0016558 protein import into peroxisome matrix	IDA PMID:26344566 ATM functions at the peroxisome to induce pexophagy in respo...	ACCEPT	Summary: PMID:26344566 demonstrates PEX5-mediated protein import into the peroxisome matrix in the context of pexophagy/ROS studies. Reason: Protein import into peroxisome matrix is the core biological process function of PEX5.
GO:0016558 protein import into peroxisome matrix	IDA P50542-1 PMID:25538232 Mechanistic insights into PTS2-mediated peroxisomal protein ...	ACCEPT	Summary: PMID:25538232 demonstrates PEX5L-mediated peroxisomal matrix protein import via PTS2 pathway with PEX7 as co-receptor. Reason: Core function of PEX5L isoform in PTS2-mediated import.
GO:0044721 protein import into peroxisome matrix, substrate release	IC P50542-1 PMID:25538232 Mechanistic insights into PTS2-mediated peroxisomal protein ...	ACCEPT	Summary: Substrate release is a defined sub-step of the PEX5 import cycle, inferred by curator from PTS2 import mechanistic data. Reason: Substrate release is a necessary step in the PEX5 cycling mechanism.
GO:0140597 protein carrier chaperone	IDA PMID:26344566 ATM functions at the peroxisome to induce pexophagy in respo...	ACCEPT	Summary: Protein carrier activity demonstrated in context of PMID:26344566 pexophagy studies. PEX5 carries PTS1 cargo. Reason: Protein carrier activity is a core molecular function of PEX5.
GO:0140597 protein carrier chaperone	IDA P50542-1 PMID:25538232 Mechanistic insights into PTS2-mediated peroxisomal protein ...	ACCEPT	Summary: Protein carrier activity of PEX5L isoform in PTS2-mediated import. Reason: Core molecular function of PEX5L as a carrier for PTS2 cargo via PEX7.
GO:0034614 cellular response to reactive oxygen species	IDA PMID:26344566 ATM functions at the peroxisome to induce pexophagy in respo...	KEEP AS NON CORE	Summary: PMID:26344566 shows PEX5 is involved in cellular response to ROS at peroxisomes, linking ROS to ATM-mediated pexophagy signaling. This is a secondary/downstream role. Reason: PEX5 serves as a substrate in the ROS-ATM-pexophagy signaling axis, but this is not its primary evolved function. It is a consequence of PEX5 being at the peroxisomal membrane where it can be phosphorylated by ATM in response to ROS. Supporting Evidence: PMID:26344566 ATM functions at the peroxisome to induce pexophagy in response to ROS
GO:0044721 protein import into peroxisome matrix, substrate release	IDA PMID:26344566 ATM functions at the peroxisome to induce pexophagy in respo...	ACCEPT	Summary: Substrate release demonstrated by PMID:26344566. PEX5 releases cargo into the peroxisomal matrix. Reason: Substrate release is a defined sub-step of the PEX5 import cycle.
GO:0016562 protein import into peroxisome matrix, receptor recycling	IDA PMID:22371489 Identification of ubiquitin-specific protease 9X (USP9X) as ...	ACCEPT	Summary: PMID:22371489 identifies USP9X as a deubiquitinase acting on ubiquitin-PEX5 thioester conjugate, supporting receptor recycling. Reason: Receptor recycling is a core step in the PEX5 import cycle. USP9X deubiquitination enables PEX5 recycling. Supporting Evidence: PMID:22371489 Identification of ubiquitin-specific protease 9X (USP9X) as a deubiquitinase acting on ubiquitin-peroxin 5 (PEX5) thioester conjugate
GO:0005515 protein binding	IPI PMID:25538232 Mechanistic insights into PTS2-mediated peroxisomal protein ...	MARK AS OVER ANNOTATED	Summary: PMID:25538232 demonstrates that PEX5L drastically increases the interaction strength between cargo protein and receptor PEX7 in PTS2-mediated import. Reason: Protein binding is too vague. The PEX5L-PEX7 co-receptor interaction is better captured by GO:0016558 (protein import into peroxisome matrix) annotations already present.
GO:0005515 protein binding	IPI P50542-1 PMID:11546814 Domain mapping of human PEX5 reveals functional and structur...	MARK AS OVER ANNOTATED	Summary: PMID:11546814 maps PEX5 domains showing functional and structural similarities to yeast Pex18p/Pex21p. Demonstrates PEX5L isoform interaction with PEX7. Reason: Protein binding is too vague. The PEX5-PEX7 interaction for PTS2 import is better captured by process terms already annotated. A more specific MF term would be preferred.
GO:0005782 peroxisomal matrix	IDA P50542-1 PMID:11546814 Domain mapping of human PEX5 reveals functional and structur...	ACCEPT	Summary: PMID:11546814 maps PEX5 domains and localizes PEX5L to peroxisomal matrix. Consistent with the cycling receptor model. Reason: Peroxisomal matrix localization of PEX5 is consistent with its cycling through the matrix during cargo delivery. Supporting Evidence: PMID:11546814 Domain mapping of human PEX5 reveals functional and structural similarities to Saccharomyces cerevisiae Pex18p and Pex21p
GO:0016558 protein import into peroxisome matrix	IDA P50542-1 PMID:11546814 Domain mapping of human PEX5 reveals functional and structur...	ACCEPT	Summary: PMID:11546814 demonstrates PEX5L-mediated peroxisomal matrix protein import. Core function. Reason: Core biological process function of PEX5.
GO:0140597 protein carrier chaperone	IDA P50542-1 PMID:11546814 Domain mapping of human PEX5 reveals functional and structur...	ACCEPT	Summary: PMID:11546814 demonstrates PEX5L protein carrier activity in peroxisomal import. Reason: Core molecular function of PEX5 as a protein carrier.
GO:0005052 peroxisome matrix targeting signal-1 binding	IDA PMID:21976670 PEX5 protein binds monomeric catalase blocking its tetrameri...	ACCEPT	Summary: PMID:21976670 shows PEX5 binds monomeric catalase (a PTS1 cargo) and blocks its tetramerization, releasing it upon PEX14 binding. Directly demonstrates PTS1 binding. Reason: Core molecular function. PTS1 binding is the primary cargo recognition mechanism of PEX5. Supporting Evidence: PMID:21976670 PEX5 protein binds monomeric catalase blocking its tetramerization and releases it upon binding the N-terminal domain of PEX14
GO:0005515 protein binding	IPI PMID:24235149 A novel Pex14 protein-interacting site of human Pex5 is crit...	MARK AS OVER ANNOTATED	Summary: PMID:24235149 identifies a novel PEX14 protein-interacting site on PEX5 critical for matrix protein import. Reason: Protein binding is too vague. The PEX5-PEX14 interaction is the docking step, already captured by GO:0016560.
GO:0005782 peroxisomal matrix	IDA PMID:16314507 Shuttling mechanism of peroxisome targeting signal type 1 re...	ACCEPT	Summary: PMID:16314507 uses cell-free systems to demonstrate PEX5 import into and export from peroxisomes. Directly supports peroxisomal matrix localization. Reason: Directly demonstrated by cell-free translocation assays. Supporting Evidence: PMID:16314507 ATP was not required for (35)S-Pex5 import but was indispensable for export
GO:0005782 peroxisomal matrix	IMP PMID:33389129 A missense allele of PEX5 is responsible for the defective i...	ACCEPT	Summary: PMID:33389129 identifies a PEX5 missense allele responsible for defective PTS2 cargo import. IMP evidence supports PEX5 role in peroxisomal matrix localization via mutant phenotype. Reason: Mutant phenotype analysis demonstrates PEX5 role in peroxisomal matrix protein delivery. Supporting Evidence: PMID:33389129 A missense allele of PEX5 is responsible for the defective import of PTS2 cargo proteins into peroxisomes
GO:0005829 cytosol	IDA PMID:16314507 Shuttling mechanism of peroxisome targeting signal type 1 re...	ACCEPT	Summary: PMID:16314507 demonstrates PEX5 cytosolic localization via cell-free translocation assays showing ATP-dependent export to cytosol. Reason: Cytosol localization directly demonstrated by the shuttling mechanism study.
GO:0016558 protein import into peroxisome matrix	IDA PMID:16314507 Shuttling mechanism of peroxisome targeting signal type 1 re...	ACCEPT	Summary: PMID:16314507 directly demonstrates PEX5-mediated protein import into peroxisome matrix using cell-free systems. Reason: Core biological process function of PEX5, directly demonstrated. Supporting Evidence: PMID:16314507 ATP was not required for (35)S-Pex5 import but was indispensable for export
GO:0016558 protein import into peroxisome matrix	IDA PMID:21976670 PEX5 protein binds monomeric catalase blocking its tetrameri...	ACCEPT	Summary: PMID:21976670 demonstrates PEX5-mediated peroxisomal import in context of catalase tetramerization study. Reason: Core function of PEX5.
GO:0016558 protein import into peroxisome matrix	IDA PMID:24235149 A novel Pex14 protein-interacting site of human Pex5 is crit...	ACCEPT	Summary: PMID:24235149 identifies a novel PEX14-interacting site on PEX5 critical for matrix protein import. Reason: Core biological process function of PEX5.
GO:0016558 protein import into peroxisome matrix	IMP PMID:33389129 A missense allele of PEX5 is responsible for the defective i...	ACCEPT	Summary: PMID:33389129 demonstrates that a PEX5 missense allele causes defective PTS2 cargo protein import. Reason: Mutant phenotype directly links PEX5 to peroxisomal matrix protein import. Supporting Evidence: PMID:33389129 A missense allele of PEX5 is responsible for the defective import of PTS2 cargo proteins into peroxisomes
GO:0016562 protein import into peroxisome matrix, receptor recycling	IDA PMID:11336669 The human peroxisomal targeting signal receptor, Pex5p, is t...	ACCEPT	Summary: PMID:11336669 demonstrates PEX5 is translocated into the peroxisomal matrix and recycled to the cytosol, directly showing receptor recycling. Reason: Receptor recycling is a core step in the PEX5 cycling mechanism. This landmark paper directly demonstrates the shuttling/recycling mechanism. Supporting Evidence: PMID:11336669 human Pex5p does not just bind cargo and deliver it to the peroxisome membrane, but participates in multiple rounds of entry into the peroxisome matrix and export to the cytosol
GO:0044721 protein import into peroxisome matrix, substrate release	ISS GO_REF:0000024	ACCEPT	Summary: ISS annotation for substrate release from orthologs. Substrate release is a well-established step in the PEX5 import cycle. Reason: Substrate release is a conserved step in the cycling mechanism.
GO:0140597 protein carrier chaperone	IDA PMID:16314507 Shuttling mechanism of peroxisome targeting signal type 1 re...	ACCEPT	Summary: PMID:16314507 demonstrates PEX5 protein carrier activity in cell-free translocation systems. Reason: Core molecular function of PEX5 as a protein carrier.
GO:0140597 protein carrier chaperone	IDA PMID:21976670 PEX5 protein binds monomeric catalase blocking its tetrameri...	ACCEPT	Summary: PMID:21976670 demonstrates PEX5 carrier activity for catalase. Reason: Core molecular function of PEX5.
GO:0140597 protein carrier chaperone	IDA PMID:24235149 A novel Pex14 protein-interacting site of human Pex5 is crit...	ACCEPT	Summary: PMID:24235149 supports PEX5 protein carrier activity via PEX14 interaction site critical for import. Reason: Core molecular function of PEX5.
GO:0140597 protein carrier chaperone	IMP PMID:33389129 A missense allele of PEX5 is responsible for the defective i...	ACCEPT	Summary: PMID:33389129 mutant phenotype supports PEX5 protein carrier activity for PTS2 cargo proteins. Reason: Core molecular function of PEX5 demonstrated by mutant phenotype.
GO:0005052 peroxisome matrix targeting signal-1 binding	IDA PMID:17157249 Recognition of a functional peroxisome type 1 target by the ...	ACCEPT	Summary: PMID:17157249 demonstrates recognition of a functional PTS1 target by the dynamic import receptor PEX5. Reason: Core molecular function. PTS1 binding demonstrated experimentally.
GO:0005782 peroxisomal matrix	IDA PMID:24662292 Distinct modes of ubiquitination of peroxisome-targeting sig...	ACCEPT	Summary: PMID:24662292 studies distinct modes of PEX5 ubiquitination regulating PTS1 import, supporting peroxisomal matrix localization. Reason: Peroxisomal matrix localization consistent with PEX5 cycling mechanism.
GO:0016558 protein import into peroxisome matrix	IDA PMID:17157249 Recognition of a functional peroxisome type 1 target by the ...	ACCEPT	Summary: PMID:17157249 demonstrates PEX5-mediated peroxisomal matrix protein import. Reason: Core biological process function of PEX5.
GO:0016558 protein import into peroxisome matrix	IDA PMID:24662292 Distinct modes of ubiquitination of peroxisome-targeting sig...	ACCEPT	Summary: PMID:24662292 demonstrates PEX5-mediated peroxisomal import in context of ubiquitination studies. Reason: Core biological process function of PEX5.
GO:0140597 protein carrier chaperone	IDA PMID:17157249 Recognition of a functional peroxisome type 1 target by the ...	ACCEPT	Summary: PMID:17157249 supports PEX5 protein carrier activity. Reason: Core molecular function of PEX5.
GO:0140597 protein carrier chaperone	IDA PMID:24662292 Distinct modes of ubiquitination of peroxisome-targeting sig...	ACCEPT	Summary: PMID:24662292 supports PEX5 protein carrier activity in context of ubiquitination regulation. Reason: Core molecular function of PEX5.
GO:0005515 protein binding	IPI PMID:12488033 Mammalian Pex14p: membrane topology and characterisation of ...	MARK AS OVER ANNOTATED	Summary: PMID:12488033 characterizes PEX14 membrane topology and PEX14-PEX14 interaction, with PEX5 as an interacting partner. Reason: Protein binding is too vague. PEX5-PEX14 docking interaction is captured by more specific terms.
GO:0031333 negative regulation of protein-containing complex assembly	IDA PMID:21976670 PEX5 protein binds monomeric catalase blocking its tetrameri...	KEEP AS NON CORE	Summary: PMID:21976670 shows PEX5 binds monomeric catalase and blocks its tetramerization. This negative regulation of complex assembly is a mechanistic consequence of PEX5 binding monomeric PTS1 cargo to prevent premature oligomerization before import. Reason: This is a mechanistic consequence of PEX5 binding monomeric catalase for import, not an independent function. The anti-tetramerization effect ensures catalase is imported as a monomer. It is a secondary effect of the primary PTS1 cargo binding function. Supporting Evidence: PMID:21976670 PEX5 protein binds monomeric catalase blocking its tetramerization and releases it upon binding the N-terminal domain of PEX14
GO:0033328 peroxisome membrane targeting sequence binding	IPI PMID:21976670 PEX5 protein binds monomeric catalase blocking its tetrameri...	UNDECIDED	Summary: PMID:21976670 shows PEX5 binds the peroxisome membrane targeting sequence in the context of PEX14 interaction. However, PEX5 is the PTS1 receptor, not a PMP targeting sequence receptor. The annotation may reflect PEX5 interaction with PEX14 N-terminal domain. Reason: PEX5 recognizes PTS1 signals, not peroxisome membrane targeting sequences (mPTS). PEX19 is the mPTS receptor. This annotation may be a mis-annotation or may refer to PEX5 binding a specific motif on PEX14 that overlaps with mPTS-like sequences. Needs clarification.
GO:0005778 peroxisomal membrane	TAS Reactome:R-HSA-9664855	ACCEPT	Summary: Reactome TAS annotation for peroxisomal membrane localization. PEX5 transiently associates with the peroxisomal membrane during the import cycle via docking with PEX13/PEX14. Multiple Reactome reactions represent different steps of the import and recycling cycle at the membrane. Reason: Peroxisomal membrane localization is correct for PEX5 as a cycling receptor. Reactome models different steps of the cycle (docking, ubiquitination, cargo release, recycling, pexophagy) that all involve PEX5 at the peroxisomal membrane.
GO:0005778 peroxisomal membrane	TAS Reactome:R-HSA-9664862	ACCEPT	Summary: Reactome TAS annotation for peroxisomal membrane localization. PEX5 transiently associates with the peroxisomal membrane during the import cycle via docking with PEX13/PEX14. Multiple Reactome reactions represent different steps of the import and recycling cycle at the membrane. Reason: Peroxisomal membrane localization is correct for PEX5 as a cycling receptor. Reactome models different steps of the cycle (docking, ubiquitination, cargo release, recycling, pexophagy) that all involve PEX5 at the peroxisomal membrane.
GO:0005778 peroxisomal membrane	TAS Reactome:R-HSA-9664879	ACCEPT	Summary: Reactome TAS annotation for peroxisomal membrane localization. PEX5 transiently associates with the peroxisomal membrane during the import cycle via docking with PEX13/PEX14. Multiple Reactome reactions represent different steps of the import and recycling cycle at the membrane. Reason: Peroxisomal membrane localization is correct for PEX5 as a cycling receptor. Reactome models different steps of the cycle (docking, ubiquitination, cargo release, recycling, pexophagy) that all involve PEX5 at the peroxisomal membrane.
GO:0005778 peroxisomal membrane	TAS Reactome:R-HSA-9664880	ACCEPT	Summary: Reactome TAS annotation for peroxisomal membrane localization. PEX5 transiently associates with the peroxisomal membrane during the import cycle via docking with PEX13/PEX14. Multiple Reactome reactions represent different steps of the import and recycling cycle at the membrane. Reason: Peroxisomal membrane localization is correct for PEX5 as a cycling receptor. Reactome models different steps of the cycle (docking, ubiquitination, cargo release, recycling, pexophagy) that all involve PEX5 at the peroxisomal membrane.
GO:0005778 peroxisomal membrane	TAS Reactome:R-HSA-9664881	ACCEPT	Summary: Reactome TAS annotation for peroxisomal membrane localization. PEX5 transiently associates with the peroxisomal membrane during the import cycle via docking with PEX13/PEX14. Multiple Reactome reactions represent different steps of the import and recycling cycle at the membrane. Reason: Peroxisomal membrane localization is correct for PEX5 as a cycling receptor. Reactome models different steps of the cycle (docking, ubiquitination, cargo release, recycling, pexophagy) that all involve PEX5 at the peroxisomal membrane.
GO:0005778 peroxisomal membrane	TAS Reactome:R-HSA-9664883	ACCEPT	Summary: Reactome TAS annotation for peroxisomal membrane localization. PEX5 transiently associates with the peroxisomal membrane during the import cycle via docking with PEX13/PEX14. Multiple Reactome reactions represent different steps of the import and recycling cycle at the membrane. Reason: Peroxisomal membrane localization is correct for PEX5 as a cycling receptor. Reactome models different steps of the cycle (docking, ubiquitination, cargo release, recycling, pexophagy) that all involve PEX5 at the peroxisomal membrane.
GO:0005778 peroxisomal membrane	TAS Reactome:R-HSA-9664888	ACCEPT	Summary: Reactome TAS annotation for peroxisomal membrane localization. PEX5 transiently associates with the peroxisomal membrane during the import cycle via docking with PEX13/PEX14. Multiple Reactome reactions represent different steps of the import and recycling cycle at the membrane. Reason: Peroxisomal membrane localization is correct for PEX5 as a cycling receptor. Reactome models different steps of the cycle (docking, ubiquitination, cargo release, recycling, pexophagy) that all involve PEX5 at the peroxisomal membrane.
GO:0005778 peroxisomal membrane	TAS Reactome:R-HSA-9664892	ACCEPT	Summary: Reactome TAS annotation for peroxisomal membrane localization. PEX5 transiently associates with the peroxisomal membrane during the import cycle via docking with PEX13/PEX14. Multiple Reactome reactions represent different steps of the import and recycling cycle at the membrane. Reason: Peroxisomal membrane localization is correct for PEX5 as a cycling receptor. Reactome models different steps of the cycle (docking, ubiquitination, cargo release, recycling, pexophagy) that all involve PEX5 at the peroxisomal membrane.
GO:0005778 peroxisomal membrane	TAS Reactome:R-HSA-9674127	ACCEPT	Summary: Reactome TAS annotation for peroxisomal membrane localization. PEX5 transiently associates with the peroxisomal membrane during the import cycle via docking with PEX13/PEX14. Multiple Reactome reactions represent different steps of the import and recycling cycle at the membrane. Reason: Peroxisomal membrane localization is correct for PEX5 as a cycling receptor. Reactome models different steps of the cycle (docking, ubiquitination, cargo release, recycling, pexophagy) that all involve PEX5 at the peroxisomal membrane.
GO:0005778 peroxisomal membrane	TAS Reactome:R-HSA-9674131	ACCEPT	Summary: Reactome TAS annotation for peroxisomal membrane localization. PEX5 transiently associates with the peroxisomal membrane during the import cycle via docking with PEX13/PEX14. Multiple Reactome reactions represent different steps of the import and recycling cycle at the membrane. Reason: Peroxisomal membrane localization is correct for PEX5 as a cycling receptor. Reactome models different steps of the cycle (docking, ubiquitination, cargo release, recycling, pexophagy) that all involve PEX5 at the peroxisomal membrane.
GO:0005515 protein binding	IPI PMID:10514471 Characterization of human and murine PMP20 peroxisomal prote...	MARK AS OVER ANNOTATED	Summary: PMID:10514471 characterizes PMP20 (PRDX5) as a PTS1 cargo that binds PEX5 via its C-terminal SQL tripeptide. This demonstrates PEX5 PTS1 receptor function rather than generic protein binding. Reason: Protein binding is too vague. This interaction reflects PEX5 recognizing PMP20 as a PTS1 cargo, which is the core PTS1 receptor function already captured by GO:0005052. Supporting Evidence: PMID:10514471 HsPMP20 bound directly to the human peroxisomal targeting signal 1 receptor, HsPEX5. Mutagenesis analysis showed that the C-terminal tripeptide sequence, SQL, of HsPMP20 is necessary for its binding to HsPEX5
GO:0005778 peroxisomal membrane	TAS Reactome:R-HSA-8953917	ACCEPT	Summary: Reactome TAS annotation for peroxisomal membrane localization. PEX5 transiently associates with the peroxisomal membrane during the import cycle via docking with PEX13/PEX14. Multiple Reactome reactions represent different steps of the import and recycling cycle at the membrane. Reason: Peroxisomal membrane localization is correct for PEX5 as a cycling receptor. Reactome models different steps of the cycle (docking, ubiquitination, cargo release, recycling, pexophagy) that all involve PEX5 at the peroxisomal membrane.
GO:0005778 peroxisomal membrane	TAS Reactome:R-HSA-8953946	ACCEPT	Summary: Reactome TAS annotation for peroxisomal membrane localization. PEX5 transiently associates with the peroxisomal membrane during the import cycle via docking with PEX13/PEX14. Multiple Reactome reactions represent different steps of the import and recycling cycle at the membrane. Reason: Peroxisomal membrane localization is correct for PEX5 as a cycling receptor. Reactome models different steps of the cycle (docking, ubiquitination, cargo release, recycling, pexophagy) that all involve PEX5 at the peroxisomal membrane.
GO:0005778 peroxisomal membrane	TAS Reactome:R-HSA-9033235	ACCEPT	Summary: Reactome TAS annotation for peroxisomal membrane localization. PEX5 transiently associates with the peroxisomal membrane during the import cycle via docking with PEX13/PEX14. Multiple Reactome reactions represent different steps of the import and recycling cycle at the membrane. Reason: Peroxisomal membrane localization is correct for PEX5 as a cycling receptor. Reactome models different steps of the cycle (docking, ubiquitination, cargo release, recycling, pexophagy) that all involve PEX5 at the peroxisomal membrane.
GO:0005778 peroxisomal membrane	TAS Reactome:R-HSA-9033485	ACCEPT	Summary: Reactome TAS annotation for peroxisomal membrane localization. PEX5 transiently associates with the peroxisomal membrane during the import cycle via docking with PEX13/PEX14. Multiple Reactome reactions represent different steps of the import and recycling cycle at the membrane. Reason: Peroxisomal membrane localization is correct for PEX5 as a cycling receptor. Reactome models different steps of the cycle (docking, ubiquitination, cargo release, recycling, pexophagy) that all involve PEX5 at the peroxisomal membrane.
GO:0005778 peroxisomal membrane	TAS Reactome:R-HSA-9033499	ACCEPT	Summary: Reactome TAS annotation for peroxisomal membrane localization. PEX5 transiently associates with the peroxisomal membrane during the import cycle via docking with PEX13/PEX14. Multiple Reactome reactions represent different steps of the import and recycling cycle at the membrane. Reason: Peroxisomal membrane localization is correct for PEX5 as a cycling receptor. Reactome models different steps of the cycle (docking, ubiquitination, cargo release, recycling, pexophagy) that all involve PEX5 at the peroxisomal membrane.
GO:0005778 peroxisomal membrane	TAS Reactome:R-HSA-9033514	ACCEPT	Summary: Reactome TAS annotation for peroxisomal membrane localization. PEX5 transiently associates with the peroxisomal membrane during the import cycle via docking with PEX13/PEX14. Multiple Reactome reactions represent different steps of the import and recycling cycle at the membrane. Reason: Peroxisomal membrane localization is correct for PEX5 as a cycling receptor. Reactome models different steps of the cycle (docking, ubiquitination, cargo release, recycling, pexophagy) that all involve PEX5 at the peroxisomal membrane.
GO:0005778 peroxisomal membrane	TAS Reactome:R-HSA-9033516	ACCEPT	Summary: Reactome TAS annotation for peroxisomal membrane localization. PEX5 transiently associates with the peroxisomal membrane during the import cycle via docking with PEX13/PEX14. Multiple Reactome reactions represent different steps of the import and recycling cycle at the membrane. Reason: Peroxisomal membrane localization is correct for PEX5 as a cycling receptor. Reactome models different steps of the cycle (docking, ubiquitination, cargo release, recycling, pexophagy) that all involve PEX5 at the peroxisomal membrane.
GO:0005778 peroxisomal membrane	TAS Reactome:R-HSA-9033527	ACCEPT	Summary: Reactome TAS annotation for peroxisomal membrane localization. PEX5 transiently associates with the peroxisomal membrane during the import cycle via docking with PEX13/PEX14. Multiple Reactome reactions represent different steps of the import and recycling cycle at the membrane. Reason: Peroxisomal membrane localization is correct for PEX5 as a cycling receptor. Reactome models different steps of the cycle (docking, ubiquitination, cargo release, recycling, pexophagy) that all involve PEX5 at the peroxisomal membrane.
GO:0005778 peroxisomal membrane	TAS Reactome:R-HSA-9033533	ACCEPT	Summary: Reactome TAS annotation for peroxisomal membrane localization. PEX5 transiently associates with the peroxisomal membrane during the import cycle via docking with PEX13/PEX14. Multiple Reactome reactions represent different steps of the import and recycling cycle at the membrane. Reason: Peroxisomal membrane localization is correct for PEX5 as a cycling receptor. Reactome models different steps of the cycle (docking, ubiquitination, cargo release, recycling, pexophagy) that all involve PEX5 at the peroxisomal membrane.
GO:0005829 cytosol	TAS Reactome:R-HSA-9033491	ACCEPT	Summary: Reactome TAS annotation for cytosol localization. PEX5 is predominantly cytosolic and returns to the cytosol after each import cycle. Reason: Cytosol localization is correct for PEX5 as a predominantly cytosolic cycling receptor.
GO:0005829 cytosol	TAS Reactome:R-HSA-9033499	ACCEPT	Summary: Reactome TAS annotation for cytosol localization. PEX5 is predominantly cytosolic and returns to the cytosol after each import cycle. Reason: Cytosol localization is correct for PEX5 as a predominantly cytosolic cycling receptor.
GO:0005829 cytosol	TAS Reactome:R-HSA-9033509	ACCEPT	Summary: Reactome TAS annotation for cytosol localization. PEX5 is predominantly cytosolic and returns to the cytosol after each import cycle. Reason: Cytosol localization is correct for PEX5 as a predominantly cytosolic cycling receptor.
GO:0005829 cytosol	TAS Reactome:R-HSA-9033235	ACCEPT	Summary: Reactome TAS annotation for cytosol localization. PEX5 is predominantly cytosolic and returns to the cytosol after each import cycle. Reason: Cytosol localization is correct for PEX5 as a predominantly cytosolic cycling receptor.
GO:0005829 cytosol	TAS Reactome:R-HSA-9033236	ACCEPT	Summary: Reactome TAS annotation for cytosol localization. PEX5 is predominantly cytosolic and returns to the cytosol after each import cycle. Reason: Cytosol localization is correct for PEX5 as a predominantly cytosolic cycling receptor.
GO:0005829 cytosol	TAS Reactome:R-HSA-9033514	ACCEPT	Summary: Reactome TAS annotation for cytosol localization. PEX5 is predominantly cytosolic and returns to the cytosol after each import cycle. Reason: Cytosol localization is correct for PEX5 as a predominantly cytosolic cycling receptor.
GO:0005829 cytosol	TAS Reactome:R-HSA-9664850	ACCEPT	Summary: Reactome TAS annotation for cytosol localization. PEX5 is predominantly cytosolic and returns to the cytosol after each import cycle. Reason: Cytosol localization is correct for PEX5 as a predominantly cytosolic cycling receptor.
GO:0005829 cytosol	TAS Reactome:R-HSA-9664883	ACCEPT	Summary: Reactome TAS annotation for cytosol localization. PEX5 is predominantly cytosolic and returns to the cytosol after each import cycle. Reason: Cytosol localization is correct for PEX5 as a predominantly cytosolic cycling receptor.
GO:0005052 peroxisome matrix targeting signal-1 binding	IDA PMID:11463335 Identification of PEX5p-related novel peroxisome-targeting s...	ACCEPT	Summary: PMID:11463335 identifies PEX5p-related novel PTS1-binding proteins and demonstrates PEX5 PTS1 binding in comparative assays. Reason: Core molecular function of PEX5 demonstrated in comparative binding assays. Supporting Evidence: PMID:11463335 Identification of PEX5p-related novel peroxisome-targeting signal 1 (PTS1)-binding proteins in mammals
GO:0016558 protein import into peroxisome matrix	IMP PMID:11463335 Identification of PEX5p-related novel peroxisome-targeting s...	ACCEPT	Summary: PMID:11463335 demonstrates PEX5 role in peroxisomal matrix protein import via mutant phenotype. Reason: Core biological process function.
GO:0032991 protein-containing complex	IDA PMID:19584060 Solution structure of human Pex5.Pex14.PTS1 protein complexe...	ACCEPT	Summary: PMID:19584060 provides SAXS solution structure of PEX5-PEX14-PTS1 protein complexes. PEX5 forms defined complexes with PEX14 and PTS1 cargo. Reason: PEX5 forms specific protein complexes with PEX14 and cargo as part of the import mechanism. The annotation to protein-containing complex is accurate.
GO:0016560 protein import into peroxisome matrix, docking	IDA PMID:21976670 PEX5 protein binds monomeric catalase blocking its tetrameri...	ACCEPT	Summary: PMID:21976670 shows PEX5 docking at peroxisomal membrane via PEX14 interaction (releasing catalase upon PEX14 NTD binding). Reason: Docking is a core step in the PEX5 import cycle. Supporting Evidence: PMID:21976670 PEX5 protein binds monomeric catalase blocking its tetramerization and releases it upon binding the N-terminal domain of PEX14
GO:0005052 peroxisome matrix targeting signal-1 binding	IPI PMID:21375735 The Peroxisomal Targeting Signal 1 in sterol carrier protein...	ACCEPT	Summary: PMID:21375735 demonstrates that PTS1 in sterol carrier protein 2 is autonomous and essential for PEX5 receptor recognition. Reason: Core molecular function. PTS1 binding demonstrated via IPI with SCP2 cargo.
GO:0005515 protein binding	IPI PMID:19584060 Solution structure of human Pex5.Pex14.PTS1 protein complexe...	MARK AS OVER ANNOTATED	Summary: PMID:19584060 provides solution structure of PEX5-PEX14-PTS1 complexes by SAXS. Reason: Protein binding is too vague. Structural characterization of the PEX5-PEX14 complex supports docking (GO:0016560) already annotated.
GO:0005777 peroxisome	IDA PMID:21375735 The Peroxisomal Targeting Signal 1 in sterol carrier protein...	ACCEPT	Summary: PMID:21375735 localizes PEX5 to peroxisomes. This is broader than peroxisomal membrane (GO:0005778) or matrix (GO:0005782). Reason: PEX5 localizes to peroxisomes (both membrane and transiently matrix). The peroxisome annotation is accurate if less specific than the membrane/matrix annotations.
GO:0006625 protein targeting to peroxisome	IDA P50542-1 PMID:21375735 The Peroxisomal Targeting Signal 1 in sterol carrier protein...	ACCEPT	Summary: PMID:21375735 demonstrates PEX5L-mediated protein targeting to peroxisome with SCP2 as cargo. Reason: Core biological process function of PEX5. Protein targeting to peroxisome is the primary role.
GO:0045046 protein import into peroxisome membrane	IMP PMID:14709540 PEX19 is a predominantly cytosolic chaperone and import rece...	REMOVE	Summary: PMID:14709540 is about PEX19 as chaperone/import receptor for peroxisomal membrane proteins. PEX5 siRNA served as a control in this study demonstrating selective PMP import defects. The annotation of PEX5 to protein import into peroxisome membrane is likely incorrect - PEX5 imports matrix proteins, not membrane proteins. Reason: PEX5 is the PTS1 receptor for matrix protein import, not membrane protein import. PEX19 is the membrane protein import receptor. In PMID:14709540, PEX5 siRNA was used as a control showing selective matrix protein import deficiency, which is the opposite phenotype from PEX19 siRNA. Annotating PEX5 to membrane protein import is incorrect. Supporting Evidence: PMID:14709540 inhibition of PEX5 induced a selective deficit in peroxisomal matrix protein import... Inhibition of PEX19 induced the converse phenotype, a selective defect in PMP import
GO:0000268 peroxisome targeting sequence binding	IDA PMID:18346465 Comparison of the PTS1- and Rab8b-binding properties of Pex5...	ACCEPT	Summary: PMID:18346465 compares PTS1- and Rab8b-binding properties of PEX5 and PEX5Rp/TRIP8b. PEX5 binds peroxisome targeting sequences. GO:0000268 (peroxisome targeting sequence binding) is a parent term that encompasses both PTS1 and PTS2 signal binding. Reason: PEX5 binds peroxisome targeting sequences (primarily PTS1). This is a correct broader annotation consistent with the more specific GO:0005052. Supporting Evidence: PMID:18346465 the TPR domains of Pex5p and Pex5Rp/TRIP8b have distinct but overlapping substrate specificities
GO:0016558 protein import into peroxisome matrix	IGI PMID:18346465 Comparison of the PTS1- and Rab8b-binding properties of Pex5...	ACCEPT	Summary: PMID:18346465 provides genetic interaction evidence for PEX5 role in peroxisomal matrix protein import via comparison with TRIP8b/PEX5Rp. Reason: Core biological process function of PEX5.
GO:0031267 small GTPase binding	IPI PMID:18346465 Comparison of the PTS1- and Rab8b-binding properties of Pex5...	MARK AS OVER ANNOTATED	Summary: PMID:18346465 shows PEX5 binds Rab8b small GTPase. However, this binding was compared to TRIP8b and the biological significance for PEX5 is unclear. PEX5 is not known to function as a Rab8b effector. Reason: Small GTPase binding by PEX5 may be a non-physiological interaction or a minor binding activity. PEX5 is not known to function as a Rab8b effector. TRIP8b is the primary Rab8b-binding TPR protein. Supporting Evidence: PMID:18346465 the TPR domains of Pex5p and Pex5Rp/TRIP8b have distinct but overlapping substrate specificities
GO:0019899 enzyme binding	IPI PMID:11060344 Mitochondrial and peroxisomal targeting of 2-methylacyl-CoA ...	MODIFY	Summary: PMID:11060344 shows in vitro interaction between recombinant racemase (AMACR) and PEX5. AMACR is a PTS1 cargo (C-terminal -KASL), so this interaction reflects PTS1 receptor function. Reason: Enzyme binding is too generic. The interaction with AMACR reflects PEX5 PTS1 receptor function recognizing the KASL targeting signal. Better captured by GO:0005052 (PTS1 binding). Proposed replacements: peroxisome matrix targeting signal-1 binding Supporting Evidence: PMID:11060344 the in vitro interaction between recombinant racemase and recombinant human PTS1 receptor (Pex5p)... we concluded that ASL is a new PTS1 variant
GO:0019899 enzyme binding	IPI PMID:11669066 Identification of a novel human peroxisomal 2,4-dienoyl-CoA ...	MODIFY	Summary: PMID:11669066 identifies a novel human peroxisomal 2,4-dienoyl-CoA reductase via PEX5 interaction using phage display. This likely reflects PTS1 cargo recognition. Reason: Enzyme binding is too generic. The interaction likely reflects PTS1 receptor cargo recognition function, better captured by GO:0005052. Proposed replacements: peroxisome matrix targeting signal-1 binding
GO:0005778 peroxisomal membrane	HDA PMID:21525035 PEX14 is required for microtubule-based peroxisome motility ...	ACCEPT	Summary: PMID:21525035 provides high-throughput direct assay evidence for PEX5 at the peroxisomal membrane. Consistent with PEX5 membrane association during import. Reason: Peroxisomal membrane localization is correct for PEX5 as a cycling receptor.
GO:0016558 protein import into peroxisome matrix	IGI P50542-1 PMID:11931631 Functional studies on human Pex7p: subcellular localization ...	ACCEPT	Summary: PMID:11931631 provides functional studies on human PEX7 including subcellular localization and interaction with PTS2-containing proteins and peroxins including PEX5L. IGI evidence for PEX5L role in peroxisomal matrix protein import. Reason: Core function of PEX5L in PTS2-mediated import via PEX7 co-receptor function.
GO:0016558 protein import into peroxisome matrix	NAS PMID:10514471 Characterization of human and murine PMP20 peroxisomal prote...	ACCEPT	Summary: PMID:10514471 reports PMP20/PRDX5 is imported into peroxisomal matrix via PEX5. NAS evidence supports PEX5 role in import. Reason: Core biological process function of PEX5. NAS evidence from a relevant cargo study. Supporting Evidence: PMID:10514471 these results indicate that HsPMP20 is imported into the peroxisomal matrix via PEX5p
GO:0005052 peroxisome matrix targeting signal-1 binding	IDA PMID:10514471 Characterization of human and murine PMP20 peroxisomal prote...	ACCEPT	Summary: PMID:10514471 directly demonstrates PTS1 binding between PEX5 and PMP20 via C-terminal SQL tripeptide. Reason: Core molecular function. PTS1 binding directly demonstrated. Supporting Evidence: PMID:10514471 HsPMP20 bound directly to the human peroxisomal targeting signal 1 receptor, HsPEX5. Mutagenesis analysis showed that the C-terminal tripeptide sequence, SQL, of HsPMP20 is necessary for its binding to HsPEX5
GO:0005737 cytoplasm	IDA PMID:10514471 Characterization of human and murine PMP20 peroxisomal prote...	ACCEPT	Summary: PMID:10514471 localizes PEX5 to the cytoplasm. This is broader than cytosol (GO:0005829) which is already annotated. Reason: Cytoplasm localization is correct and broader than the more specific cytosol term. Both are valid.
GO:0016020 membrane	IDA PMID:10514471 Characterization of human and murine PMP20 peroxisomal prote...	MARK AS OVER ANNOTATED	Summary: PMID:10514471 reports PEX5 association with a particulate (membrane) fraction. The generic membrane term is very broad. Reason: The generic membrane term (GO:0016020) is too broad and uninformative when more specific localizations (peroxisomal membrane GO:0005778) are already annotated.
GO:0005515 protein binding	IPI PMID:9820813 C-terminal tripeptide Ser-Asn-Leu (SNL) of human D-aspartate...	MARK AS OVER ANNOTATED	Summary: PMID:9820813 shows that the C-terminal tripeptide SNL of D-aspartate oxidase is a functional PTS1 signal that binds PEX5. This is a PTS1 cargo recognition interaction. Reason: Protein binding is too vague. This interaction reflects PTS1 receptor function (GO:0005052) already annotated. Supporting Evidence: PMID:9820813 C-terminal tripeptide Ser-Asn-Leu (SNL) of human D-aspartate oxidase is a functional peroxisome-targeting signal
GO:0005777 peroxisome	IDA PMID:11829486 Pex13, the mouse ortholog of the human peroxisome biogenesis...	ACCEPT	Summary: PMID:11829486 characterizes mouse Pex13 and localizes it to peroxisomes, with PEX5 as an interacting partner localized to peroxisomes. Reason: Peroxisome localization is correct for PEX5.
GO:0005515 protein binding	IPI P50542-1 PMID:8858165 Pex13p is an SH3 protein of the peroxisome membrane and a do...	MARK AS OVER ANNOTATED	Summary: PMID:8858165 shows Pex13p is an SH3 protein of the peroxisome membrane and a docking factor for PEX5. This is the PEX5-PEX13 docking interaction. Reason: Protein binding is too vague. The PEX5-PEX13 interaction is part of the docking mechanism, captured by GO:0016560. Supporting Evidence: PMID:8858165 Pex13p is an SH3 protein of the peroxisome membrane and a docking factor for the predominantly cytoplasmic PTs1 receptor
GO:0005052 peroxisome matrix targeting signal-1 binding	IDA P50542-1 PMID:12456682 PEX5 binds the PTS1 independently of Hsp70 and the peroxin P...	ACCEPT	Summary: PMID:12456682 shows PEX5 binds PTS1 independently of Hsp70 and PEX12. Directly demonstrates PTS1 binding. Reason: Core molecular function. Supporting Evidence: PMID:12456682 PEX5 binds the PTS1 independently of Hsp70 and the peroxin PEX12
GO:0051262 protein tetramerization	IDA P50542-1 PMID:12456682 PEX5 binds the PTS1 independently of Hsp70 and the peroxin P...	KEEP AS NON CORE	Summary: PMID:12456682 reports PEX5 tetramerization. This is a structural observation about PEX5 oligomerization state. Reason: Protein tetramerization is a structural property of PEX5 observed in vitro but not its primary functional role. The biological significance of PEX5 tetramerization for import function is not clearly established.
GO:0005052 peroxisome matrix targeting signal-1 binding	IMP P50542-1 PMID:9668159 An isoform of pex5p, the human PTS1 receptor, is required fo...	ACCEPT	Summary: PMID:9668159 shows PEX5L isoform is required for PTS2 protein import, with PTS1 binding demonstrated by mutant complementation. IMP evidence supports PTS1 binding. Reason: Core molecular function demonstrated by mutant phenotype analysis. Supporting Evidence: PMID:9668159 Transfection of PBD005 cells with PEX5S cDNA restores PTS1 but not PTS2 import; transfection with PXR5L cDNA restores both PTS1 and PTS2 protein import
GO:0006625 protein targeting to peroxisome	IMP P50542-1 PMID:9668159 An isoform of pex5p, the human PTS1 receptor, is required fo...	ACCEPT	Summary: PMID:9668159 demonstrates PEX5L is required for protein targeting to peroxisome (both PTS1 and PTS2 pathways). Reason: Core biological process function of PEX5. Supporting Evidence: PMID:9668159 the long isoform of the Pex5 protein is required for peroxisomal import of PTS2 proteins
GO:0005515 protein binding	IPI PMID:9653144 Identification of a human PTS1 receptor docking protein dire...	MARK AS OVER ANNOTATED	Summary: PMID:9653144 identifies PEX14 as a human PTS1 receptor docking protein directly required for peroxisomal protein import. This is the PEX5-PEX14 docking interaction. Reason: Protein binding is too vague. The PEX5-PEX14 docking interaction is captured by GO:0016560. Supporting Evidence: PMID:9653144 Identification of a human PTS1 receptor docking protein directly required for peroxisomal protein import
GO:0005515 protein binding	IPI PMID:15911627 Peroxisomal import of human alanine:glyoxylate aminotransfer...	MARK AS OVER ANNOTATED	Summary: PMID:15911627 shows peroxisomal import of AGT requires ancillary targeting information remote from its C terminus. Demonstrates PEX5 interaction with AGT cargo. Reason: Protein binding is too vague. PEX5-AGT interaction represents PTS1 receptor cargo recognition function, captured by GO:0005052.
GO:0005515 protein binding	IPI PMID:10837480 Molecular anatomy of the peroxin Pex12p: ring finger domain ...	MARK AS OVER ANNOTATED	Summary: PMID:10837480 shows PEX12 ring finger domain interacts with PEX5 and PEX10. This is part of the ubiquitination machinery interaction during receptor recycling. Reason: Protein binding is too vague. PEX5-PEX12 interaction is part of the receptor recycling/ubiquitination mechanism, captured by GO:0016562. Supporting Evidence: PMID:10837480 ring finger domain is essential for Pex12p function and interacts with the peroxisome-targeting signal type 1-receptor Pex5p and a ring peroxin, Pex10p

References

GO_REF:0000024

Manual transfer of experimentally-verified manual GO annotation data to orthologs by curator judgment of sequence similarity

GO_REF:0000033

Annotation inferences using phylogenetic trees

GO_REF:0000043

Gene Ontology annotation based on UniProtKB/Swiss-Prot keyword mapping

GO_REF:0000044

Gene Ontology annotation based on UniProtKB/Swiss-Prot Subcellular Location vocabulary mapping, accompanied by conservative changes to GO terms applied by UniProt

GO_REF:0000052

Gene Ontology annotation based on curation of immunofluorescence data

GO_REF:0000107

Automatic transfer of experimentally verified manual GO annotation data to orthologs using Ensembl Compara

PMID:10514471

Characterization of human and murine PMP20 peroxisomal proteins that exhibit antioxidant activity in vitro.

PMID:10562279

PEX12 interacts with PEX5 and PEX10 and acts downstream of receptor docking in peroxisomal matrix protein import.

PMID:10837480

Molecular anatomy of the peroxin Pex12p: ring finger domain is essential for Pex12p function and interacts with the peroxisome-targeting signal type 1-receptor Pex5p and a ring peroxin, Pex10p.

PMID:11060344

Mitochondrial and peroxisomal targeting of 2-methylacyl-CoA racemase in humans.

PMID:11336669

The human peroxisomal targeting signal receptor, Pex5p, is translocated into the peroxisomal matrix and recycled to the cytosol.

PMID:11463335

Identification of PEX5p-related novel peroxisome-targeting signal 1 (PTS1)-binding proteins in mammals.

PMID:11546814

Domain mapping of human PEX5 reveals functional and structural similarities to Saccharomyces cerevisiae Pex18p and Pex21p.

PMID:11669066

Identification of a novel human peroxisomal 2,4-dienoyl-CoA reductase related protein using the M13 phage protein VI phage display technology.

PMID:11829486

Pex13, the mouse ortholog of the human peroxisome biogenesis disorder PEX13 gene: gene structure, tissue expression, and localization of the protein to peroxisomes.

PMID:11931631

Functional studies on human Pex7p: subcellular localization and interaction with proteins containing a peroxisome-targeting signal type 2 and other peroxins.

PMID:12096124

Analysis of mammalian peroxin interactions using a non-transcription-based bacterial two-hybrid assay.

PMID:12456682

PEX5 binds the PTS1 independently of Hsp70 and the peroxin PEX12.

PMID:12488033

Mammalian Pex14p: membrane topology and characterisation of the Pex14p-Pex14p interaction.

PMID:14709540

PEX19 is a predominantly cytosolic chaperone and import receptor for class 1 peroxisomal membrane proteins.

PMID:15911627

Peroxisomal import of human alanine:glyoxylate aminotransferase requires ancillary targeting information remote from its C terminus.

PMID:16314507

Shuttling mechanism of peroxisome targeting signal type 1 receptor Pex5: ATP-independent import and ATP-dependent export.

PMID:17157249

Recognition of a functional peroxisome type 1 target by the dynamic import receptor pex5p.

PMID:18346465

Comparison of the PTS1- and Rab8b-binding properties of Pex5p and Pex5Rp/TRIP8b.

PMID:19197237

Structural basis for competitive interactions of Pex14 with the import receptors Pex5 and Pex19.

PMID:19584060

Solution structure of human Pex5.Pex14.PTS1 protein complexes obtained by small angle X-ray scattering.

PMID:21044950

Genome-wide YFP fluorescence complementation screen identifies new regulators for telomere signaling in human cells.

PMID:21375735

The Peroxisomal Targeting Signal 1 in sterol carrier protein 2 is autonomous and essential for receptor recognition.

PMID:21525035

PEX14 is required for microtubule-based peroxisome motility in human cells.

PMID:21976670

PEX5 protein binds monomeric catalase blocking its tetramerization and releases it upon binding the N-terminal domain of PEX14.

PMID:22371489

Identification of ubiquitin-specific protease 9X (USP9X) as a deubiquitinase acting on ubiquitin-peroxin 5 (PEX5) thioester conjugate.

PMID:22529745

Molecular requirements for peroxisomal targeting of alanine-glyoxylate aminotransferase as an essential determinant in primary hyperoxaluria type 1.

PMID:24235149

A novel Pex14 protein-interacting site of human Pex5 is critical for matrix protein import into peroxisomes.

PMID:24662292

Distinct modes of ubiquitination of peroxisome-targeting signal type 1 (PTS1) receptor Pex5p regulate PTS1 protein import.

PMID:25416956

A proteome-scale map of the human interactome network.

PMID:25538232

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.

PMID:26344566

ATM functions at the peroxisome to induce pexophagy in response to ROS.

PMID:28765278

The peroxisomal matrix protein translocon is a large cavity-forming protein assembly into which PEX5 protein enters to release its cargo.

PMID:29884772

Peroxisomal monoubiquitinated PEX5 interacts with the AAA ATPases PEX1 and PEX6 and is unfolded during its dislocation into the cytosol.

PMID:33389129

A missense allele of PEX5 is responsible for the defective import of PTS2 cargo proteins into peroxisomes.

PMID:8858165

Pex13p is an SH3 protein of the peroxisome membrane and a docking factor for the predominantly cytoplasmic PTs1 receptor.

PMID:9653144

Identification of a human PTS1 receptor docking protein directly required for peroxisomal protein import.

PMID:9668159

An isoform of pex5p, the human PTS1 receptor, is required for the import of PTS2 proteins into peroxisomes.

PMID:9820813

C-terminal tripeptide Ser-Asn-Leu (SNL) of human D-aspartate oxidase is a functional peroxisome-targeting signal.

Reactome:R-HSA-8953917

PEX2:PEX10:PEX12 binds PEX5S,L (in PEX5S:PEX13:PEX14) and Ub:UBE2D1,2,3

Reactome:R-HSA-8953946

PEX2:PEX10:PEX12 monoubiquitinates PEX5S,L at cysteine-11

Reactome:R-HSA-9033235

Cargo of PEX5S,L translocates from the cytosol to the peroxisomal matrix

Reactome:R-HSA-9033236

PEX5S,L:Cargo binds PEX13:PEX14:PEX2:PEX10:PEX12 (Docking and Translocation Module)

Reactome:R-HSA-9033485

PEX2:PEX10:PEX12 monoubiquitinates PEX5L at cysteine-11

Reactome:R-HSA-9033491

USP9X hydrolyzes Ub:PEX5L yielding PEX5L and Ubiquitin

Reactome:R-HSA-9033499

PEX1:PEX6:PEX26:ZFAND6 dissociates Ub:PEX5L and PEX7 from PEX14:PEX13:PEX2:PEX10:PEX12 and translocates PEX5L and PEX7 from the peroxisomal membrane to the cytosol

Reactome:R-HSA-9033509

USP9X binds Ub:PEX5L

Reactome:R-HSA-9033514

Cargo of PEX5L:PEX7 translocates from the cytosol to the peroxisomal matrix

Reactome:R-HSA-9033516

PEX2:PEX10:PEX12:Ub:PEX5L:PEX7:PEX13:PEX14 binds PEX1:PEX6:PEX26 and ZFAND6

Reactome:R-HSA-9033527

PEX2:PEX10:PEX12 binds PEX5L (in PEX5L:PEX7:PEX13:PEX14:PEX2:PEX10:PEX12) and Ub:UBE2D1,2,3

Reactome:R-HSA-9033533

PEX2:PEX10:PEX12:Ub:PEX5S,L:PEX13:PEX14 binds PEX1:PEX6:PEX26 and ZFAND6

Reactome:R-HSA-9664850

ATM binds PEX5

Reactome:R-HSA-9664855

MAP1LC3B binds ATM dimer:Ub-p-PEX5:SQSTM1

Reactome:R-HSA-9664862

ATM dimer:PEX5 phosphorylates PEX5

Reactome:R-HSA-9664879

ATM:PEX5 binds ATM

Reactome:R-HSA-9664880

MAP1LC3B binds ATM dimer:Ub-p-PEX5:SQSTM1:NBR1

Reactome:R-HSA-9664881

NBR1 binds ATM:Ub-p-PEX5:SQSTM1

Reactome:R-HSA-9664883

ATM:PEX5 translocates from cytosol to peroxisomal membrane

Reactome:R-HSA-9664888

ATM dimer:p-PEX5 ubiquitinates to form ATM dimer:Ub-p-PEX5

Reactome:R-HSA-9664892

SQSTM1 binds ATM dimer:Ub-p-PEX5

Reactome:R-HSA-9674127

USP30 deubiquitinates ATM dimer:Ub-p-PEX5

Reactome:R-HSA-9674131

USP30 binds ATM dimer:Ub-p-PEX5

Deep Research

Falcon

(PEX5-deep-research-falcon.md)

Research Report: Human **PEX5** (UniProt **P50542**) — Functional Annotation and Current Understanding Falcon Edison Scientific Literature 27 citations 2026-03-05T00:33:23.497598

The research report should be a detailed narrative explaining the function, biological processes, and localization of the gene product. Citations should be given for all claims.

You should prioritize authoritative reviews and primary scientific literature when conducting research. You can supplement
this with annotations you find in gene/protein databases, but these can be outdated or inaccurate.

We are specifically interested in the primary function of the gene - for enzymes, what reaction is catalyzed, and what is the substrate specificity? For transporters, what is the substrate? For structural proteins or adapters, what is the broader structural role? For signaling molecules, what is the role in the pathway.

We are interested in where in or outside the cell the gene product carries out its function.

We are also interested in the signaling or biochemical pathways in which the gene functions. We are less interested in broad pleiotropic effects, except where these elucidate the precise role.

Include evidence where possible. We are interested in both experimental evidence as well as inference from structure, evolution, or bioinformatic analysis. Precise studies should be prioritized over high-throughput, where available.

Research Report: Human PEX5 (UniProt P50542) — Functional Annotation and Current Understanding

0. Target verification (critical identity check)

The literature synthesized here explicitly addresses human PEX5 (UniProt: P50542) as the peroxisomal targeting signal 1 (PTS1) receptor / peroxin-5, a soluble cycling receptor required for import of peroxisomal matrix proteins, and analyzes hallmark features matching UniProt (C‑terminal TPR cargo-binding domain; N‑terminal Wxxx(F/Y) docking motifs; conserved Cys11 ubiquitination site). (skowyra2024towardssolvingthe pages 1-3, gopalswamy2023distinctconformationaland pages 3-4, francisco2024noncanonicalandreversible pages 2-3)

1. Key concepts and definitions (current understanding)

1.1 Peroxisomal targeting signals and receptors

Most peroxisomal matrix proteins are synthesized on free cytosolic ribosomes and carry a PTS1, typically a C‑terminal tripeptide such as SKL, which is recognized by the shuttling receptor PEX5. (bajdzienko2024mammalianpexophagyat pages 2-3)

A smaller set of matrix proteins use an N‑terminal PTS2 recognized by PEX7, which in mammals requires PEX5 as a co-receptor to deliver PTS2 cargo to the membrane import machinery. (bajdzienko2024mammalianpexophagyat pages 2-3)

1.2 PEX5 as a cycling receptor: “importomer” model and ATP usage

PEX5 binds PTS1 cargo in the cytosol and delivers it to the peroxisomal membrane docking/translocation module (DTM). Notably, peroxisomes can import folded and oligomeric proteins, a distinctive feature among organelles. (bajdzienko2024mammalianpexophagyat pages 2-3, skowyra2024towardssolvingthe pages 1-3)

A key mechanistic distinction is that matrix protein import itself does not require ATP hydrolysis, whereas PEX5 export/recycling back to the cytosol does require ATP, consumed by AAA ATPases. (kumar2024theperoxisomean pages 11-13)

1.3 Domain architecture and motifs (definition-level)

PEX5 has:
- a C‑terminal TPR domain that directly binds the PTS1 peptide; and
- a long intrinsically disordered N‑terminal region containing multiple short (di)aromatic motifs that mediate docking to peroxisomal membrane proteins (notably PEX14 and PEX13). (skowyra2024towardssolvingthe pages 1-3, gopalswamy2023distinctconformationaland pages 1-3)

2. Mechanism of action: molecular function, pathway placement, localization

2.1 Cargo recognition and delivery

PEX5 binds PTS1-containing cargo through its TPR domain, forming a receptor–cargo complex in the cytosol, then targets the complex to peroxisomes. (skowyra2024towardssolvingthe pages 1-3, bajdzienko2024mammalianpexophagyat pages 2-3)

2.2 Docking/translocation at the peroxisomal membrane

Docking/translocation module (DTM): PEX5 engages a transmembrane complex that includes PEX13 and PEX14; PEX14’s N‑terminal domain recognizes PEX5’s Wxxx(F/Y)-type motifs. (bajdzienko2024mammalianpexophagyat pages 2-3, gopalswamy2023distinctconformationaland pages 3-4)

Selective phase / hydrogel conduit model (PEX13): A major modern mechanistic model proposes that PEX13 YG-repeat intrinsically disordered regions form a selective phase (hydrogel/droplet-like), reminiscent of nucleoporin FG repeats, into which PEX5 (via WxxxF/Y motifs) can partition to deliver cargo. This provides a framework for how folded cargo traverses a membrane-associated conduit without a classical protein channel. (skowyra2024towardssolvingthe pages 3-4, kumar2024theperoxisomean pages 10-11)

Subcellular localization and cycling: PEX5 is primarily a cytosolic soluble receptor that cycles to the peroxisomal membrane and (in some models) into the lumen during cargo delivery, then returns to the cytosol after ATP-dependent extraction. (bajdzienko2024mammalianpexophagyat pages 2-3, kumar2024theperoxisomean pages 10-11, francisco2024noncanonicalandreversible pages 1-2)

2.3 Recycling (receptor export module) and ubiquitin switch

After cargo release, PEX5 is recycled by a defined ubiquitin- and ATP-dependent pathway:

Monoubiquitination of PEX5 on Cys11: a conserved N‑terminal cysteine (Cys11 in mammals) is monoubiquitinated at the peroxisomal membrane. This modification is described as mandatory for subsequent extraction. (francisco2024noncanonicalandreversible pages 1-2, bajdzienko2024mammalianpexophagyat pages 2-3)
E3 ligase complex: monoubiquitination is mediated by a membrane-embedded RING E3 complex formed by PEX2/PEX10/PEX12. (skowyra2024towardssolvingthe pages 1-3, bajdzienko2024mammalianpexophagyat pages 2-3)
AAA ATPase extraction: monoubiquitinated PEX5 is extracted from the DTM by the receptor export module (REM), the PEX1–PEX6 AAA ATPase complex (anchored to peroxisomes by PEX26 in mammals), resetting the receptor to the cytosol after deubiquitination. (francisco2024noncanonicalandreversible pages 1-2, bajdzienko2024mammalianpexophagyat pages 2-3)
RADAR pathway (quality control): when recycling fails, PEX5 can be polyubiquitinated on lysines and targeted for proteasomal degradation (RADAR: receptor accumulation and degradation in the absence of recycling). (kumar2024theperoxisomean pages 11-13)

3. Recent developments (prioritizing 2023–2024)

3.1 2024: Why Cys11 is used—reversible noncanonical cysteine ubiquitination

A major 2024 advance (Francisco et al., PLOS Biology, Mar 2024, URL: https://doi.org/10.1371/journal.pbio.3002567) is a mechanistic explanation for why PEX5 is monoubiquitinated on a cysteine rather than lysine.

Key findings:
- Substituting the native acceptor Cys11 with Lys (PEX5 C11K) caused robust polyubiquitination at the peroxisomal membrane, which impairs extraction, consistent with a need to avoid accumulation of polyubiquitinated receptor at the translocon. (francisco2024noncanonicalandreversible pages 1-2)
- The authors show cysteine ubiquitination is reversible and highly dynamic, via E2-mediated deubiquitination that is faster than polyubiquitination, ensuring PEX5 remains primarily mono-ubiquitinated and avoiding “clogging” of the import machinery. (francisco2024noncanonicalandreversible pages 2-3)
- The in vitro work highlights how crowding differs from cytosol, noting cytosolic protein concentration ~175 g/L vs ~4 g/L used in vitro (≈44-fold difference), which is relevant for interpreting kinetics and ubiquitin-chain formation tendencies. (francisco2024noncanonicalandreversible pages 2-3)

3.2 2024: Import mechanism frameworks and “mystery-solving” synthesis (expert analysis)

Skowyra, Feng & Rapoport (Trends in Cell Biology, May 2024, URL: https://doi.org/10.1016/j.tcb.2023.08.005) synthesize and advance models where:
- PEX5 is the soluble PTS1 receptor with an unstructured N‑terminus and a C‑terminal TPR cargo-binding domain.
- The import machinery involves PEX13/PEX14 docking and a ubiquitin/AAA ATPase recycling cycle. (skowyra2024towardssolvingthe pages 1-3)

The review also emphasizes a conceptual model in which cargo import is coupled to receptor export, and draws mechanistic parallels to selective barriers (nuclear pore-like concepts), consistent with the PEX13 YG selective phase evidence. (skowyra2024towardssolvingthe pages 1-3, skowyra2024towardssolvingthe pages 3-4)

3.3 2023: Quantitative, motif-resolved PEX5–PEX14 interaction landscape

Gopalswamy et al. (Biological Chemistry, Nov 2023, URL: https://doi.org/10.1515/hsz-2022-0177) provide a refined and quantitative map of how PEX14 recognizes multiple motifs in the human PEX5 N‑terminus.

Key results:
- Human PEX5 contains eight PEX14-binding motifs in its N‑terminus: seven canonical Wxxx(F/Y) motifs plus one noncanonical LVxEF motif. (gopalswamy2023distinctconformationaland pages 3-4, gopalswamy2023distinctconformationaland pages 1-3)
- Individual motif affinities span roughly ~60 nM to ~6 µM (ITC-derived dissociation constants), demonstrating that not all motifs contribute equally. (gopalswamy2023distinctconformationaland pages 3-4)
- The work proposes a refined higher-affinity consensus ExWΦxE(F/Y)Φ for PEX14 NTD binding. (gopalswamy2023distinctconformationaland pages 3-4)

4. Current applications and real-world implementations

4.1 Clinical genetics and diagnostic sequencing for peroxisome biogenesis disorders

PEX5 is one of the peroxin genes whose pathogenic variants cause peroxisome biogenesis disorders (PBDs), including Zellweger spectrum disorders (ZSD). A practical implementation is clinical exome sequencing used to establish molecular diagnoses in patients with atypical presentations. (khalilian2025spectrumofgenetic pages 1-2, khalilian2025spectrumofgenetic pages 4-6)

4.2 Peroxisome quality control and pexophagy as translational context

Peroxisome homeostasis depends on the balance between biogenesis and selective degradation (pexophagy). A 2024 “Cell Science at a Glance” synthesis states that the DTM (PEX13/PEX14) interfaces with the RING E3 ligase complex (PEX2/PEX10/PEX12) that initiates receptor recycling via Cys11 monoubiquitination—linking the import cycle to ubiquitin signaling that also features in pexophagy pathways. (bajdzienko2024mammalianpexophagyat pages 2-3)

Additionally, updated peroxisome biology synthesis notes that loss of PEX13 can increase ubiquitinated PEX5 and ROS, promoting pexophagy, indicating that import components contribute to peroxisome quality control. (kumar2024theperoxisomean pages 10-11)

5. Expert opinions and authoritative analysis (interpretive synthesis)

5.1 Mechanistic “state of the field” (2024 reviews)

Two 2024 syntheses highlight unresolved but converging themes:
- Peroxisomal import likely uses intrinsically disordered regions and selective phase/condensate-like behavior (PEX13 YG repeats; PEX5 WxxxF/Y motifs), offering an explanation for translocation of folded proteins. (kumar2024theperoxisomean pages 10-11, skowyra2024towardssolvingthe pages 3-4)
- The receptor export/recycling system resembles ubiquitin-directed extraction by AAA ATPases, drawing parallels to ERAD/p97/Cdc48 logic and emphasizing that ubiquitin can be the immediate mechanical “handle” for unfoldase engagement (reviewed as part of recycling discussion). (kumar2024theperoxisomean pages 11-13)

5.2 Why the 2024 cysteine-ubiquitination work is influential

The 2024 PLOS Biology study provides a specific biochemical rationale for a long-standing feature (cysteine ubiquitination at Cys11): reversibility and avoidance of extraction-resistant polyubiquitination. This directly addresses a mechanistic vulnerability of the importomer—translocon obstruction by stalled receptors—and thus re-frames Cys11 as a design principle for maintaining throughput and preventing inappropriate degradation. (francisco2024noncanonicalandreversible pages 2-3)

6. Relevant statistics and quantitative data (recent studies emphasized)

6.1 Quantitative interaction strengths

PEX5–PEX14 (full-length/fragment) binding: SPR measurements reported KD values in the low-nanomolar range for interaction of human PEX5 (long/short isoforms and fragments) with PEX14(1–78), e.g. ~0.7 nM (PEX5L) and ~3.3 nM (PEX5S). (Schliebs et al., 1999; URL not available in retrieved text) (schliebs1999recombinanthumanperoxisomal pages 5-7)
Motif-resolved affinities (2023): individual human PEX5 N‑terminal motifs bind PEX14 NTD with KDs spanning ~60 nM to ~6.3 µM, indicating a broad energetic hierarchy across motifs. (gopalswamy2023distinctconformationaland pages 3-4)

6.2 Physical parameters of the selective phase model

In vitro, PEX13 YG hydrogels can assemble at YG-domain concentrations up to ~40 mg/mL; mutation of tyrosines disrupts import, supporting tyrosine-driven cohesion in the selective phase. (skowyra2024towardssolvingthe pages 3-4)

6.3 Cell/organellar turnover metric relevant to pathway perturbation

Peroxisomes have been reported to have an approximate half-life of ~2 days in cultured CHO cells under basal growth conditions, underscoring that altered import/recycling and pexophagy can plausibly remodel peroxisome abundance on day timescales. (bajdzienko2024mammalianpexophagyat pages 2-3)

6.4 Recent clinical case-series statistic for PEX5

A 2025 Iranian ZSD case series (Khalilian et al., BMC Medical Genomics, Apr 2025, URL: https://doi.org/10.1186/s12920-025-02126-3) examined 14 patients evaluated during 2018–2024 and found variants across multiple PEX genes; PEX5 variants were detected in 1/14 cases. (khalilian2025spectrumofgenetic pages 1-2, khalilian2025spectrumofgenetic pages 4-6)

7. Human disease relevance (PEX5-specific)

7.1 Example pathogenic PEX5 variant and phenotype

In the 2025 case series, the PEX5-associated case carried c.1775C>T (p.Pro592Leu) and was classified as pathogenic (ACMG/ClinVar noted in the table). The patient presentation included severe neurodevelopmental features (reported as hypotonia and developmental delay) and additional findings such as seizures and hearing loss in the cohort table context. (khalilian2025spectrumofgenetic pages 3-4)

7.2 Mechanistic link between molecular defect and phenotype

Given PEX5’s central role as the PTS1 receptor and co-receptor for PTS2 import (via PEX7), loss-of-function is expected to cause a broad failure of peroxisomal matrix enzyme import, producing systemic metabolic dysfunction characteristic of PBD/ZSD. Mechanistically, disruption at any step—cargo binding, docking to PEX13/PEX14, Cys11 monoubiquitination, or PEX1/PEX6/PEX26 extraction—can impair receptor cycling and collapse import capacity. (skowyra2024towardssolvingthe pages 1-3, francisco2024noncanonicalandreversible pages 1-2, bajdzienko2024mammalianpexophagyat pages 2-3)

8. Summary table (functional annotation snapshot)

Category	Key facts (w/ citations)
Identity/domains	Human PEX5 (UniProt P50542) is the soluble PTS1 receptor (peroxin-5) with a C‑terminal TPR domain that binds PTS1 peptides and an ~320 aa intrinsically disordered N‑terminus harboring eight PEX14‑binding (di)aromatic motifs (7 WxxxF/Y plus 1 LVxEF) (skowyra2024towardssolvingthe pages 1-3, gopalswamy2023distinctconformationaland pages 1-3).
Cargo recognition	PEX5 recognizes C‑terminal PTS1 signals via its TPR domain and transports folded and even oligomeric matrix proteins; PEX7 uses PEX5 as co‑receptor for PTS2 cargo (bajdzienko2024mammalianpexophagyat pages 2-3, skowyra2024towardssolvingthe pages 1-3).
Docking/translocation interactions	Cargo‑loaded PEX5 docks at the peroxisomal membrane via PEX13/PEX14; the PEX14 N‑terminal domain binds PEX5 WxxxF/Y motifs, while PEX13 YG repeats can form a selective phase/hydrogel that partitions PEX5‑cargo, suggesting a phase‑separation–like translocation conduit (gopalswamy2023distinctconformationaland pages 3-4, skowyra2024towardssolvingthe pages 3-4, kumar2024theperoxisomean pages 10-11).
Recycling/ubiquitination	After cargo release, PEX5 is monoubiquitinated on conserved Cys11 by the membrane RING E3 complex (PEX2/PEX10/PEX12) and extracted to cytosol by the AAA ATPase REM (PEX1/PEX6 anchored by PEX26); impaired recycling triggers RADAR with lysine‑linked polyubiquitination and proteasomal degradation (francisco2024noncanonicalandreversible pages 1-2, kumar2024theperoxisomean pages 11-13, ghosh2024molecularcharacterizationof pages 28-31, bajdzienko2024mammalianpexophagyat pages 2-3).
Recent 2023–2024 advances	Cys11 monoubiquitination is noncanonical and reversible: an E2‑mediated deubiquitination outpaces polyubiquitination, preventing translocon clogging; refined PEX14‑binding consensus ExWΦxE(F/Y)Φ and motif‑specific affinities/energetics were delineated; mechanistic evidence supports PEX13 YG‑mediated selective phase as a translocation medium (francisco2024noncanonicalandreversible pages 2-3, gopalswamy2023distinctconformationaland pages 3-4, skowyra2024towardssolvingthe pages 3-4, kumar2024theperoxisomean pages 10-11).
Pexophagy link	Ubiquitin on peroxisomal membrane proteins recruits NBR1/p62 to drive pexophagy; loss of PEX13 increases ubiquitinated PEX5 and ROS, promoting pexophagy—highlighting import machinery in peroxisome quality control (bajdzienko2024mammalianpexophagyat pages 2-3, kumar2024theperoxisomean pages 10-11).
Disease/clinical genetics	PEX5 pathogenic variants cause peroxisome biogenesis disorders; an Iranian 2018–2024 case series identified 1/14 ZSD patients with homozygous PEX5 c.1775C>T (p.Pro592Leu), classified pathogenic and associated with developmental delay, hypotonia, seizures, hearing loss (khalilian2025spectrumofgenetic pages 3-4).
Quantitative data	PEX5–PEX14 binding: full‑length/fragment KD ~0.7–3.3 nM by SPR (PEX14 1–78 with PEX5L/S); individual PEX5 N‑terminal motifs bind PEX14 with KDs ~60 nM to ~6.3 μM (motif‑specific); PEX13 YG hydrogels assemble up to ~40 mg/mL; peroxisome half‑life ~2 days in CHO cells (schliebs1999recombinanthumanperoxisomal pages 5-7, gopalswamy2023distinctconformationaland pages 3-4, skowyra2024towardssolvingthe pages 3-4, bajdzienko2024mammalianpexophagyat pages 2-3).

Table: Concise, citation-backed overview of the human PEX5 receptor covering domains, cargo recognition, membrane interactions, recycling/ubiquitination, recent advances, pexophagy links, clinical genetics, and key quantitative measurements. Useful for rapid verification of mechanism and for integrating 2023–2024 insights into PEX5 biology.

9. Key sources (with URLs and publication dates)

Francisco T. et al. Noncanonical and reversible cysteine ubiquitination prevents the overubiquitination of PEX5 at the peroxisomal membrane. PLOS Biology (Mar 2024). https://doi.org/10.1371/journal.pbio.3002567 (francisco2024noncanonicalandreversible pages 2-3, francisco2024noncanonicalandreversible pages 1-2)
Skowyra ML, Feng P, Rapoport TA. Towards solving the mystery of peroxisomal matrix protein import. Trends in Cell Biology (May 2024). https://doi.org/10.1016/j.tcb.2023.08.005 (skowyra2024towardssolvingthe pages 1-3, skowyra2024towardssolvingthe pages 3-4)
Kumar R. et al. The peroxisome: an update on mysteries 3.0. Histochemistry and Cell Biology (Jan 2024). https://doi.org/10.1007/s00418-023-02259-5 (kumar2024theperoxisomean pages 10-11, kumar2024theperoxisomean pages 11-13)
Bajdzienko J, Bremm A. Mammalian pexophagy at a glance. Journal of Cell Science (May 2024). https://doi.org/10.1242/jcs.259775 (bajdzienko2024mammalianpexophagyat pages 2-3)
Gopalswamy M. et al. Distinct conformational and energetic features define the specific recognition of (di)aromatic peptide motifs by PEX14. Biological Chemistry (Nov 2023). https://doi.org/10.1515/hsz-2022-0177 (gopalswamy2023distinctconformationaland pages 3-4, gopalswamy2023distinctconformationaland pages 1-3)
Khalilian S. et al. Spectrum of genetic alterations in patients with peroxisome biogenesis defects in the Iranian population: a case series study. BMC Medical Genomics (Apr 2025). https://doi.org/10.1186/s12920-025-02126-3 (khalilian2025spectrumofgenetic pages 1-2, khalilian2025spectrumofgenetic pages 3-4)

References

(skowyra2024towardssolvingthe pages 1-3): Michael L. Skowyra, Peiqiang Feng, and Tom A. Rapoport. Towards solving the mystery of peroxisomal matrix protein import. Trends in Cell Biology, 34:388-405, May 2024. URL: https://doi.org/10.1016/j.tcb.2023.08.005, doi:10.1016/j.tcb.2023.08.005. This article has 27 citations and is from a domain leading peer-reviewed journal.
(gopalswamy2023distinctconformationaland pages 3-4): Mohanraj Gopalswamy, Chen Zheng, Stefan Gaussmann, Hamed Kooshapur, Eva Hambruch, Wolfgang Schliebs, Ralf Erdmann, Iris Antes, and Michael Sattler. Distinct conformational and energetic features define the specific recognition of (di)aromatic peptide motifs by pex14. Biological Chemistry, 404:179-194, Nov 2023. URL: https://doi.org/10.1515/hsz-2022-0177, doi:10.1515/hsz-2022-0177. This article has 10 citations and is from a peer-reviewed journal.
(francisco2024noncanonicalandreversible pages 2-3): Tânia Francisco, Ana G. Pedrosa, Tony A. Rodrigues, Tarad Abalkhail, Hongli Li, Maria J. Ferreira, Gerbrand J. van der Heden van Noort, Marc Fransen, Ewald H. Hettema, and Jorge E. Azevedo. Noncanonical and reversible cysteine ubiquitination prevents the overubiquitination of pex5 at the peroxisomal membrane. PLOS Biology, 22:e3002567, Mar 2024. URL: https://doi.org/10.1371/journal.pbio.3002567, doi:10.1371/journal.pbio.3002567. This article has 4 citations and is from a highest quality peer-reviewed journal.
(bajdzienko2024mammalianpexophagyat pages 2-3): Justyna Bajdzienko and Anja Bremm. Mammalian pexophagy at a glance. Journal of Cell Science, May 2024. URL: https://doi.org/10.1242/jcs.259775, doi:10.1242/jcs.259775. This article has 14 citations and is from a domain leading peer-reviewed journal.
(kumar2024theperoxisomean pages 11-13): Rechal Kumar, Markus Islinger, Harley Worthy, Ruth Carmichael, and Michael Schrader. The peroxisome: an update on mysteries 3.0. Histochemistry and Cell Biology, 161:99-132, Jan 2024. URL: https://doi.org/10.1007/s00418-023-02259-5, doi:10.1007/s00418-023-02259-5. This article has 73 citations and is from a peer-reviewed journal.
(gopalswamy2023distinctconformationaland pages 1-3): Mohanraj Gopalswamy, Chen Zheng, Stefan Gaussmann, Hamed Kooshapur, Eva Hambruch, Wolfgang Schliebs, Ralf Erdmann, Iris Antes, and Michael Sattler. Distinct conformational and energetic features define the specific recognition of (di)aromatic peptide motifs by pex14. Biological Chemistry, 404:179-194, Nov 2023. URL: https://doi.org/10.1515/hsz-2022-0177, doi:10.1515/hsz-2022-0177. This article has 10 citations and is from a peer-reviewed journal.
(skowyra2024towardssolvingthe pages 3-4): Michael L. Skowyra, Peiqiang Feng, and Tom A. Rapoport. Towards solving the mystery of peroxisomal matrix protein import. Trends in Cell Biology, 34:388-405, May 2024. URL: https://doi.org/10.1016/j.tcb.2023.08.005, doi:10.1016/j.tcb.2023.08.005. This article has 27 citations and is from a domain leading peer-reviewed journal.
(kumar2024theperoxisomean pages 10-11): Rechal Kumar, Markus Islinger, Harley Worthy, Ruth Carmichael, and Michael Schrader. The peroxisome: an update on mysteries 3.0. Histochemistry and Cell Biology, 161:99-132, Jan 2024. URL: https://doi.org/10.1007/s00418-023-02259-5, doi:10.1007/s00418-023-02259-5. This article has 73 citations and is from a peer-reviewed journal.
(francisco2024noncanonicalandreversible pages 1-2): Tânia Francisco, Ana G. Pedrosa, Tony A. Rodrigues, Tarad Abalkhail, Hongli Li, Maria J. Ferreira, Gerbrand J. van der Heden van Noort, Marc Fransen, Ewald H. Hettema, and Jorge E. Azevedo. Noncanonical and reversible cysteine ubiquitination prevents the overubiquitination of pex5 at the peroxisomal membrane. PLOS Biology, 22:e3002567, Mar 2024. URL: https://doi.org/10.1371/journal.pbio.3002567, doi:10.1371/journal.pbio.3002567. This article has 4 citations and is from a highest quality peer-reviewed journal.
(khalilian2025spectrumofgenetic pages 1-2): Sheyda Khalilian, Mohadeseh Fathi, Sanaz Jamshidi, Rasoul Madannejad, Arezou Sayad, Soudeh Ghafouri-Fard, and Mohammad Miryounesi. Spectrum of genetic alterations in patients with peroxisome biogenesis defects in the iranian population: a case series study. BMC Medical Genomics, Apr 2025. URL: https://doi.org/10.1186/s12920-025-02126-3, doi:10.1186/s12920-025-02126-3. This article has 1 citations and is from a peer-reviewed journal.
(khalilian2025spectrumofgenetic pages 4-6): Sheyda Khalilian, Mohadeseh Fathi, Sanaz Jamshidi, Rasoul Madannejad, Arezou Sayad, Soudeh Ghafouri-Fard, and Mohammad Miryounesi. Spectrum of genetic alterations in patients with peroxisome biogenesis defects in the iranian population: a case series study. BMC Medical Genomics, Apr 2025. URL: https://doi.org/10.1186/s12920-025-02126-3, doi:10.1186/s12920-025-02126-3. This article has 1 citations and is from a peer-reviewed journal.
(schliebs1999recombinanthumanperoxisomal pages 5-7): W Schliebs, J Saidowsky, B Agianian, and G Dodt. Recombinant human peroxisomal targeting signal receptor pex5: structural basis for interaction of pex5 with pex14. Unknown journal, 1999.
(khalilian2025spectrumofgenetic pages 3-4): Sheyda Khalilian, Mohadeseh Fathi, Sanaz Jamshidi, Rasoul Madannejad, Arezou Sayad, Soudeh Ghafouri-Fard, and Mohammad Miryounesi. Spectrum of genetic alterations in patients with peroxisome biogenesis defects in the iranian population: a case series study. BMC Medical Genomics, Apr 2025. URL: https://doi.org/10.1186/s12920-025-02126-3, doi:10.1186/s12920-025-02126-3. This article has 1 citations and is from a peer-reviewed journal.
(ghosh2024molecularcharacterizationof pages 28-31): Mausumi Ghosh. Molecular characterization of protein translocation pores. ArXiv, 2024. URL: https://doi.org/10.53846/goediss-10355, doi:10.53846/goediss-10355. This article has 0 citations.

Citations

bajdzienko2024mammalianpexophagyat pages 2-3
kumar2024theperoxisomean pages 11-13
francisco2024noncanonicalandreversible pages 1-2
francisco2024noncanonicalandreversible pages 2-3
skowyra2024towardssolvingthe pages 1-3
gopalswamy2023distinctconformationaland pages 3-4
kumar2024theperoxisomean pages 10-11
schliebs1999recombinanthumanperoxisomal pages 5-7
skowyra2024towardssolvingthe pages 3-4
khalilian2025spectrumofgenetic pages 3-4
gopalswamy2023distinctconformationaland pages 1-3
khalilian2025spectrumofgenetic pages 1-2
khalilian2025spectrumofgenetic pages 4-6
ghosh2024molecularcharacterizationof pages 28-31
https://doi.org/10.1371/journal.pbio.3002567
https://doi.org/10.1016/j.tcb.2023.08.005
https://doi.org/10.1515/hsz-2022-0177
https://doi.org/10.1186/s12920-025-02126-3
https://doi.org/10.1007/s00418-023-02259-5
https://doi.org/10.1242/jcs.259775
https://doi.org/10.1016/j.tcb.2023.08.005,
https://doi.org/10.1515/hsz-2022-0177,
https://doi.org/10.1371/journal.pbio.3002567,
https://doi.org/10.1242/jcs.259775,
https://doi.org/10.1007/s00418-023-02259-5,
https://doi.org/10.1186/s12920-025-02126-3,
https://doi.org/10.53846/goediss-10355,

📄 View Raw YAML

id: P50542
gene_symbol: PEX5
product_type: PROTEIN
status: INITIALIZED
taxon:
  id: NCBITaxon:9606
  label: Homo sapiens
description: PEX5 is the peroxisomal targeting signal 1 (PTS1) receptor, a soluble cycling receptor that recognizes C-terminal
  PTS1 tripeptide motifs (-SKL and variants) on peroxisomal matrix proteins in the cytosol. PEX5 contains an N-terminal intrinsically
  disordered region with eight PEX14-binding WxxxF/Y motifs and a C-terminal TPR domain that binds PTS1 cargo. After cargo
  binding, PEX5 docks at the peroxisomal membrane via PEX13/PEX14, delivers cargo into the matrix, and is recycled to the
  cytosol through mono-ubiquitination at Cys11 by the PEX2/PEX10/PEX12 RING complex and extraction by the PEX1/PEX6 AAA ATPase.
  The long isoform (PEX5L) additionally co-receptors PEX7 for PTS2 cargo import. PEX5 also participates in pexophagy signaling
  through ATM-mediated phosphorylation and ubiquitination. Mutations cause peroxisome biogenesis disorders (Zellweger spectrum).
alternative_products:
- name: 1 (PEX5L {ECO:0000303|PubMed:11546814})
  id: P50542-1
- name: 2 (PEX5S {ECO:0000303|PubMed:11546814})
  id: P50542-2
  sequence_note: VSP_021880
- name: '3'
  id: P50542-3
  sequence_note: VSP_024106
- name: '4'
  id: P50542-4
  sequence_note: VSP_043639
existing_annotations:
- term:
    id: GO:0005052
    label: peroxisome matrix targeting signal-1 binding
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  review:
    summary: PTS1 binding is the core molecular function of PEX5. The IBA annotation is phylogenetically well-supported and
      consistent with extensive experimental data showing PEX5 recognizes C-terminal PTS1 tripeptide motifs via its TPR domain
      (PMID:21976670, PMID:10514471, PMID:12456682).
    action: ACCEPT
    reason: PTS1 binding is the primary molecular function of PEX5, deeply conserved from yeast to human, and supported by
      IBA phylogenetic inference as well as numerous IDA/IPI annotations.
    supported_by:
    - reference_id: PMID:21976670
      supporting_text: PEX5 protein binds monomeric catalase blocking its tetramerization and releases it upon binding the
        N-terminal domain of PEX14
    - reference_id: PMID:10514471
      supporting_text: HsPMP20 bound directly to the human peroxisomal targeting signal 1 receptor, HsPEX5
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  review:
    summary: PEX5 is predominantly cytosolic, cycling between the cytosol and the peroxisomal membrane. The IBA annotation
      is consistent with experimental localization data (PMID:16314507, PMID:11336669).
    action: ACCEPT
    reason: PEX5 is a predominantly cytosolic receptor that transiently associates with the peroxisomal membrane during the
      import cycle. Cytosol localization is well established by IBA and multiple experimental studies.
    supported_by:
    - reference_id: PMID:11336669
      supporting_text: human Pex5p does not just bind cargo and deliver it to the peroxisome membrane, but participates in
        multiple rounds of entry into the peroxisome matrix and export to the cytosol
    - reference_id: PMID:16314507
      supporting_text: 'Shuttling mechanism of peroxisome targeting signal type 1 receptor Pex5: ATP-independent import and
        ATP-dependent export'
- term:
    id: GO:0005778
    label: peroxisomal membrane
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  review:
    summary: PEX5 transiently localizes to the peroxisomal membrane during the import cycle, docking via PEX13/PEX14. The
      IBA annotation is consistent with the cycling receptor model supported by extensive experimental data (PMID:16314507,
      PMID:11336669).
    action: ACCEPT
    reason: Peroxisomal membrane localization is integral to PEX5 function as a cycling receptor. IBA annotation is phylogenetically
      well-supported.
    supported_by:
    - reference_id: PMID:16314507
      supporting_text: Pex5 was in two distinct, 500- and 800-kDa complexes comprising different sets of peroxins, such as
        Pex14 and Pex2
- term:
    id: GO:0016560
    label: protein import into peroxisome matrix, docking
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  review:
    summary: Docking of PEX5 at the peroxisomal membrane via PEX13/PEX14 is a core step in the PTS1 import pathway. The IBA
      annotation is consistent with the well-characterized docking mechanism (PMID:21976670, PMID:19197237).
    action: ACCEPT
    reason: Docking is a defined sub-step of the PEX5 import cycle, phylogenetically conserved and well-supported experimentally.
    supported_by:
    - reference_id: PMID:21976670
      supporting_text: PEX5 protein binds monomeric catalase blocking its tetramerization and releases it upon binding the
        N-terminal domain of PEX14
- term:
    id: GO:0005782
    label: peroxisomal matrix
  evidence_type: IEA
  original_reference_id: GO_REF:0000044
  review:
    summary: PEX5 transiently enters the peroxisomal matrix during the import cycle. This IEA annotation from UniProt subcellular
      location mapping is consistent with the established cycling mechanism (PMID:11336669).
    action: ACCEPT
    reason: IEA annotation is consistent with the well-established cycling mechanism where PEX5 enters the peroxisomal matrix
      to deliver cargo before being recycled.
    supported_by:
    - reference_id: PMID:11336669
      supporting_text: human Pex5p does not just bind cargo and deliver it to the peroxisome membrane, but participates in
        multiple rounds of entry into the peroxisome matrix and export to the cytosol
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: IEA
  original_reference_id: GO_REF:0000044
  review:
    summary: Cytosol localization of PEX5 is well established. This IEA annotation is broader than the IBA annotation for
      the same term but consistent.
    action: ACCEPT
    reason: Redundant with IBA annotation for the same term, but not incorrect. IEA from UniProt subcellular location mapping
      is consistent with experimental data.
- term:
    id: GO:0015031
    label: protein transport
  evidence_type: IEA
  original_reference_id: GO_REF:0000043
  review:
    summary: PEX5 mediates protein transport to peroxisomes. This IEA annotation from UniProt keyword mapping is very general.
      The more specific term GO:0016558 (protein import into peroxisome matrix) is already annotated with multiple experimental
      evidence codes.
    action: ACCEPT
    reason: While very general, this IEA annotation is not incorrect. More specific terms are annotated separately with experimental
      evidence. The IEA-derived broader term does not conflict.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:10562279
  review:
    summary: PMID:10562279 demonstrates PEX5 interaction with PEX12 and PEX10 in the peroxisomal import pathway. Protein binding
      is uninformative; the actual function is involvement in the RING complex interaction during cargo translocation.
    action: MODIFY
    reason: Protein binding is too vague. PEX5 interacts with PEX12 as part of the ubiquitin ligase complex interaction during
      the import cycle. A more specific MF term should capture this.
    proposed_replacement_terms:
    - id: GO:0005052
      label: peroxisome matrix targeting signal-1 binding
    supported_by:
    - reference_id: PMID:10562279
      supporting_text: PEX12 interacts with PEX5 and PEX10 and acts downstream of receptor docking in peroxisomal matrix protein
        import
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:12096124
  review:
    summary: PMID:12096124 used a non-transcription-based bacterial two-hybrid to analyze peroxin interactions including PEX5.
      Protein binding is uninformative for the actual function.
    action: MARK_AS_OVER_ANNOTATED
    reason: Protein binding is too vague for a protein whose core function is defined by specific binding activities (PTS1
      binding, PEX14 interaction). The peroxin-peroxin interactions are better captured by process and more specific MF terms.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:19197237
  review:
    summary: PMID:19197237 provides structural basis for competitive interactions of PEX14 with PEX5 and PEX19. This describes
      the key PEX5-PEX14 docking interaction.
    action: MARK_AS_OVER_ANNOTATED
    reason: Protein binding is too vague. The PEX5-PEX14 interaction is better captured by GO:0016560 (protein import into
      peroxisome matrix, docking) which is already annotated.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:21044950
  review:
    summary: PMID:21044950 is a genome-wide YFP fluorescence complementation screen for telomere signaling regulators. The
      relevance to PEX5 core function is unclear.
    action: MARK_AS_OVER_ANNOTATED
    reason: High-throughput screen result. Protein binding is uninformative and the telomere signaling context is unlikely
      to represent a core PEX5 function.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:21525035
  review:
    summary: PMID:21525035 shows PEX14 is required for microtubule-based peroxisome motility. PEX5 may interact with PEX14
      in this context but the primary annotation is about PEX14.
    action: MARK_AS_OVER_ANNOTATED
    reason: Protein binding is too vague. The PEX5-PEX14 interaction is better captured by docking and import terms already
      annotated.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:25416956
  review:
    summary: PMID:25416956 is a proteome-scale map of the human interactome network. High-throughput interaction data.
    action: MARK_AS_OVER_ANNOTATED
    reason: Protein binding from a high-throughput interactome screen is uninformative for PEX5 whose specific binding functions
      are well characterized.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:22529745
  isoform: P50542-1
  review:
    summary: PMID:22529745 examines molecular requirements for peroxisomal targeting of AGT as a determinant in primary hyperoxaluria
      type 1. PEX5L interaction with AGT is part of its PTS1 receptor function.
    action: MARK_AS_OVER_ANNOTATED
    reason: Protein binding is too vague. The interaction with AGT represents PEX5 performing its core PTS1 receptor function
      (cargo recognition), already captured by GO:0005052.
- term:
    id: GO:0016558
    label: protein import into peroxisome matrix
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  review:
    summary: IEA annotation for protein import into peroxisome matrix via Ensembl Compara ortholog transfer. Consistent with
      the well-established core function of PEX5.
    action: ACCEPT
    reason: Correct IEA annotation consistent with the core function of PEX5 as PTS1 receptor mediating peroxisomal matrix
      protein import.
- term:
    id: GO:0005794
    label: Golgi apparatus
  evidence_type: IDA
  original_reference_id: GO_REF:0000052
  review:
    summary: Golgi apparatus localization from immunofluorescence data curation. PEX5 is not known to function at the Golgi.
      This may reflect antibody cross-reactivity or misidentification in high-throughput immunofluorescence studies.
    action: REMOVE
    reason: PEX5 is a cytosolic/peroxisomal cycling receptor with no known Golgi function. This localization is not supported
      by the extensive literature on PEX5 subcellular distribution and is likely an artifact.
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: IDA
  original_reference_id: GO_REF:0000052
  review:
    summary: Cytosol localization from immunofluorescence data curation. Consistent with the well-established predominantly
      cytosolic localization of PEX5.
    action: ACCEPT
    reason: Cytosol localization is well established for PEX5 as a cycling receptor.
- term:
    id: GO:0140597
    label: protein carrier chaperone
  evidence_type: IDA
  original_reference_id: PMID:28765278
  review:
    summary: PMID:28765278 demonstrates that PEX5 enters a large cavity-forming protein assembly (the translocon) to release
      its cargo. This supports protein carrier activity as PEX5 physically carries folded cargo into the peroxisome.
    action: ACCEPT
    reason: Protein carrier activity accurately describes PEX5 function as it physically escorts folded PTS1 cargo from cytosol
      into the peroxisomal matrix translocon.
    supported_by:
    - reference_id: PMID:28765278
      supporting_text: the peroxisomal matrix protein translocon is a large cavity-forming protein assembly into which PEX5
        protein enters to release its cargo
- term:
    id: GO:0016562
    label: protein import into peroxisome matrix, receptor recycling
  evidence_type: IDA
  original_reference_id: PMID:29884772
  review:
    summary: PMID:29884772 shows monoubiquitinated PEX5 interacts with PEX1/PEX6 AAA ATPases and is unfolded during dislocation
      into the cytosol. This directly demonstrates receptor recycling.
    action: ACCEPT
    reason: Receptor recycling is a core step in the PEX5 import cycle, directly demonstrated by this study.
    supported_by:
    - reference_id: PMID:29884772
      supporting_text: Peroxisomal monoubiquitinated PEX5 interacts with the AAA ATPases PEX1 and PEX6 and is unfolded during
        its dislocation into the cytosol
- term:
    id: GO:0000425
    label: pexophagy
  evidence_type: IDA
  original_reference_id: PMID:26344566
  review:
    summary: PMID:26344566 shows ATM functions at the peroxisome to induce pexophagy in response to ROS. PEX5 is phosphorylated
      by ATM and ubiquitinated to recruit autophagy adaptors. PEX5 participates in pexophagy but this is not its primary evolved
      function.
    action: KEEP_AS_NON_CORE
    reason: PEX5 serves as a substrate for ATM-mediated pexophagy signaling, but pexophagy is a secondary quality control
      process rather than the core evolved function of PEX5 as a PTS1 import receptor.
    supported_by:
    - reference_id: PMID:26344566
      supporting_text: ATM functions at the peroxisome to induce pexophagy in response to ROS
- term:
    id: GO:0005052
    label: peroxisome matrix targeting signal-1 binding
  evidence_type: IDA
  original_reference_id: PMID:26344566
  review:
    summary: PMID:26344566 also demonstrates PTS1 binding by PEX5 in the context of pexophagy studies. PTS1 binding is the
      core molecular function of PEX5.
    action: ACCEPT
    reason: PTS1 binding is the core molecular function of PEX5, demonstrated here in the pexophagy context.
- term:
    id: GO:0005782
    label: peroxisomal matrix
  evidence_type: IC
  original_reference_id: PMID:24662292
  isoform: P50542-1
  review:
    summary: Peroxisomal matrix localization by IC (inferred by curator) from PMID:24662292 which studies ubiquitination modes
      regulating PTS1 receptor Pex5p and PTS1 protein import. PEX5 transiently enters the matrix.
    action: ACCEPT
    reason: PEX5 enters the peroxisomal matrix during the import cycle. IC from the ubiquitination study is consistent.
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: IDA
  original_reference_id: PMID:25538232
  isoform: P50542-1
  review:
    summary: PMID:25538232 provides mechanistic insights into PTS2-mediated peroxisomal protein import and localizes PEX5L
      to the cytosol.
    action: ACCEPT
    reason: Cytosol localization of PEX5L is well established and consistent with its role as a cycling receptor.
- term:
    id: GO:0016558
    label: protein import into peroxisome matrix
  evidence_type: IDA
  original_reference_id: PMID:26344566
  review:
    summary: PMID:26344566 demonstrates PEX5-mediated protein import into the peroxisome matrix in the context of pexophagy/ROS
      studies.
    action: ACCEPT
    reason: Protein import into peroxisome matrix is the core biological process function of PEX5.
- term:
    id: GO:0016558
    label: protein import into peroxisome matrix
  evidence_type: IDA
  original_reference_id: PMID:25538232
  isoform: P50542-1
  review:
    summary: PMID:25538232 demonstrates PEX5L-mediated peroxisomal matrix protein import via PTS2 pathway with PEX7 as co-receptor.
    action: ACCEPT
    reason: Core function of PEX5L isoform in PTS2-mediated import.
- term:
    id: GO:0044721
    label: protein import into peroxisome matrix, substrate release
  evidence_type: IC
  original_reference_id: PMID:25538232
  isoform: P50542-1
  review:
    summary: Substrate release is a defined sub-step of the PEX5 import cycle, inferred by curator from PTS2 import mechanistic
      data.
    action: ACCEPT
    reason: Substrate release is a necessary step in the PEX5 cycling mechanism.
- term:
    id: GO:0140597
    label: protein carrier chaperone
  evidence_type: IDA
  original_reference_id: PMID:26344566
  review:
    summary: Protein carrier activity demonstrated in context of PMID:26344566 pexophagy studies. PEX5 carries PTS1 cargo.
    action: ACCEPT
    reason: Protein carrier activity is a core molecular function of PEX5.
- term:
    id: GO:0140597
    label: protein carrier chaperone
  evidence_type: IDA
  original_reference_id: PMID:25538232
  isoform: P50542-1
  review:
    summary: Protein carrier activity of PEX5L isoform in PTS2-mediated import.
    action: ACCEPT
    reason: Core molecular function of PEX5L as a carrier for PTS2 cargo via PEX7.
- term:
    id: GO:0034614
    label: cellular response to reactive oxygen species
  evidence_type: IDA
  original_reference_id: PMID:26344566
  review:
    summary: PMID:26344566 shows PEX5 is involved in cellular response to ROS at peroxisomes, linking ROS to ATM-mediated
      pexophagy signaling. This is a secondary/downstream role.
    action: KEEP_AS_NON_CORE
    reason: PEX5 serves as a substrate in the ROS-ATM-pexophagy signaling axis, but this is not its primary evolved function.
      It is a consequence of PEX5 being at the peroxisomal membrane where it can be phosphorylated by ATM in response to ROS.
    supported_by:
    - reference_id: PMID:26344566
      supporting_text: ATM functions at the peroxisome to induce pexophagy in response to ROS
- term:
    id: GO:0044721
    label: protein import into peroxisome matrix, substrate release
  evidence_type: IDA
  original_reference_id: PMID:26344566
  review:
    summary: Substrate release demonstrated by PMID:26344566. PEX5 releases cargo into the peroxisomal matrix.
    action: ACCEPT
    reason: Substrate release is a defined sub-step of the PEX5 import cycle.
- term:
    id: GO:0016562
    label: protein import into peroxisome matrix, receptor recycling
  evidence_type: IDA
  original_reference_id: PMID:22371489
  review:
    summary: PMID:22371489 identifies USP9X as a deubiquitinase acting on ubiquitin-PEX5 thioester conjugate, supporting receptor
      recycling.
    action: ACCEPT
    reason: Receptor recycling is a core step in the PEX5 import cycle. USP9X deubiquitination enables PEX5 recycling.
    supported_by:
    - reference_id: PMID:22371489
      supporting_text: Identification of ubiquitin-specific protease 9X (USP9X) as a deubiquitinase acting on ubiquitin-peroxin
        5 (PEX5) thioester conjugate
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:25538232
  review:
    summary: PMID:25538232 demonstrates that PEX5L drastically increases the interaction strength between cargo protein and
      receptor PEX7 in PTS2-mediated import.
    action: MARK_AS_OVER_ANNOTATED
    reason: Protein binding is too vague. The PEX5L-PEX7 co-receptor interaction is better captured by GO:0016558 (protein
      import into peroxisome matrix) annotations already present.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:11546814
  isoform: P50542-1
  review:
    summary: PMID:11546814 maps PEX5 domains showing functional and structural similarities to yeast Pex18p/Pex21p. Demonstrates
      PEX5L isoform interaction with PEX7.
    action: MARK_AS_OVER_ANNOTATED
    reason: Protein binding is too vague. The PEX5-PEX7 interaction for PTS2 import is better captured by process terms already
      annotated. A more specific MF term would be preferred.
- term:
    id: GO:0005782
    label: peroxisomal matrix
  evidence_type: IDA
  original_reference_id: PMID:11546814
  isoform: P50542-1
  review:
    summary: PMID:11546814 maps PEX5 domains and localizes PEX5L to peroxisomal matrix. Consistent with the cycling receptor
      model.
    action: ACCEPT
    reason: Peroxisomal matrix localization of PEX5 is consistent with its cycling through the matrix during cargo delivery.
    supported_by:
    - reference_id: PMID:11546814
      supporting_text: Domain mapping of human PEX5 reveals functional and structural similarities to Saccharomyces cerevisiae
        Pex18p and Pex21p
- term:
    id: GO:0016558
    label: protein import into peroxisome matrix
  evidence_type: IDA
  original_reference_id: PMID:11546814
  isoform: P50542-1
  review:
    summary: PMID:11546814 demonstrates PEX5L-mediated peroxisomal matrix protein import. Core function.
    action: ACCEPT
    reason: Core biological process function of PEX5.
- term:
    id: GO:0140597
    label: protein carrier chaperone
  evidence_type: IDA
  original_reference_id: PMID:11546814
  isoform: P50542-1
  review:
    summary: PMID:11546814 demonstrates PEX5L protein carrier activity in peroxisomal import.
    action: ACCEPT
    reason: Core molecular function of PEX5 as a protein carrier.
- term:
    id: GO:0005052
    label: peroxisome matrix targeting signal-1 binding
  evidence_type: IDA
  original_reference_id: PMID:21976670
  review:
    summary: PMID:21976670 shows PEX5 binds monomeric catalase (a PTS1 cargo) and blocks its tetramerization, releasing it
      upon PEX14 binding. Directly demonstrates PTS1 binding.
    action: ACCEPT
    reason: Core molecular function. PTS1 binding is the primary cargo recognition mechanism of PEX5.
    supported_by:
    - reference_id: PMID:21976670
      supporting_text: PEX5 protein binds monomeric catalase blocking its tetramerization and releases it upon binding the
        N-terminal domain of PEX14
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:24235149
  review:
    summary: PMID:24235149 identifies a novel PEX14 protein-interacting site on PEX5 critical for matrix protein import.
    action: MARK_AS_OVER_ANNOTATED
    reason: Protein binding is too vague. The PEX5-PEX14 interaction is the docking step, already captured by GO:0016560.
- term:
    id: GO:0005782
    label: peroxisomal matrix
  evidence_type: IDA
  original_reference_id: PMID:16314507
  review:
    summary: PMID:16314507 uses cell-free systems to demonstrate PEX5 import into and export from peroxisomes. Directly supports
      peroxisomal matrix localization.
    action: ACCEPT
    reason: Directly demonstrated by cell-free translocation assays.
    supported_by:
    - reference_id: PMID:16314507
      supporting_text: ATP was not required for (35)S-Pex5 import but was indispensable for export
- term:
    id: GO:0005782
    label: peroxisomal matrix
  evidence_type: IMP
  original_reference_id: PMID:33389129
  review:
    summary: PMID:33389129 identifies a PEX5 missense allele responsible for defective PTS2 cargo import. IMP evidence supports
      PEX5 role in peroxisomal matrix localization via mutant phenotype.
    action: ACCEPT
    reason: Mutant phenotype analysis demonstrates PEX5 role in peroxisomal matrix protein delivery.
    supported_by:
    - reference_id: PMID:33389129
      supporting_text: A missense allele of PEX5 is responsible for the defective import of PTS2 cargo proteins into peroxisomes
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: IDA
  original_reference_id: PMID:16314507
  review:
    summary: PMID:16314507 demonstrates PEX5 cytosolic localization via cell-free translocation assays showing ATP-dependent
      export to cytosol.
    action: ACCEPT
    reason: Cytosol localization directly demonstrated by the shuttling mechanism study.
- term:
    id: GO:0016558
    label: protein import into peroxisome matrix
  evidence_type: IDA
  original_reference_id: PMID:16314507
  review:
    summary: PMID:16314507 directly demonstrates PEX5-mediated protein import into peroxisome matrix using cell-free systems.
    action: ACCEPT
    reason: Core biological process function of PEX5, directly demonstrated.
    supported_by:
    - reference_id: PMID:16314507
      supporting_text: ATP was not required for (35)S-Pex5 import but was indispensable for export
- term:
    id: GO:0016558
    label: protein import into peroxisome matrix
  evidence_type: IDA
  original_reference_id: PMID:21976670
  review:
    summary: PMID:21976670 demonstrates PEX5-mediated peroxisomal import in context of catalase tetramerization study.
    action: ACCEPT
    reason: Core function of PEX5.
- term:
    id: GO:0016558
    label: protein import into peroxisome matrix
  evidence_type: IDA
  original_reference_id: PMID:24235149
  review:
    summary: PMID:24235149 identifies a novel PEX14-interacting site on PEX5 critical for matrix protein import.
    action: ACCEPT
    reason: Core biological process function of PEX5.
- term:
    id: GO:0016558
    label: protein import into peroxisome matrix
  evidence_type: IMP
  original_reference_id: PMID:33389129
  review:
    summary: PMID:33389129 demonstrates that a PEX5 missense allele causes defective PTS2 cargo protein import.
    action: ACCEPT
    reason: Mutant phenotype directly links PEX5 to peroxisomal matrix protein import.
    supported_by:
    - reference_id: PMID:33389129
      supporting_text: A missense allele of PEX5 is responsible for the defective import of PTS2 cargo proteins into peroxisomes
- term:
    id: GO:0016562
    label: protein import into peroxisome matrix, receptor recycling
  evidence_type: IDA
  original_reference_id: PMID:11336669
  review:
    summary: PMID:11336669 demonstrates PEX5 is translocated into the peroxisomal matrix and recycled to the cytosol, directly
      showing receptor recycling.
    action: ACCEPT
    reason: Receptor recycling is a core step in the PEX5 cycling mechanism. This landmark paper directly demonstrates the
      shuttling/recycling mechanism.
    supported_by:
    - reference_id: PMID:11336669
      supporting_text: human Pex5p does not just bind cargo and deliver it to the peroxisome membrane, but participates in
        multiple rounds of entry into the peroxisome matrix and export to the cytosol
- term:
    id: GO:0044721
    label: protein import into peroxisome matrix, substrate release
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  review:
    summary: ISS annotation for substrate release from orthologs. Substrate release is a well-established step in the PEX5
      import cycle.
    action: ACCEPT
    reason: Substrate release is a conserved step in the cycling mechanism.
- term:
    id: GO:0140597
    label: protein carrier chaperone
  evidence_type: IDA
  original_reference_id: PMID:16314507
  review:
    summary: PMID:16314507 demonstrates PEX5 protein carrier activity in cell-free translocation systems.
    action: ACCEPT
    reason: Core molecular function of PEX5 as a protein carrier.
- term:
    id: GO:0140597
    label: protein carrier chaperone
  evidence_type: IDA
  original_reference_id: PMID:21976670
  review:
    summary: PMID:21976670 demonstrates PEX5 carrier activity for catalase.
    action: ACCEPT
    reason: Core molecular function of PEX5.
- term:
    id: GO:0140597
    label: protein carrier chaperone
  evidence_type: IDA
  original_reference_id: PMID:24235149
  review:
    summary: PMID:24235149 supports PEX5 protein carrier activity via PEX14 interaction site critical for import.
    action: ACCEPT
    reason: Core molecular function of PEX5.
- term:
    id: GO:0140597
    label: protein carrier chaperone
  evidence_type: IMP
  original_reference_id: PMID:33389129
  review:
    summary: PMID:33389129 mutant phenotype supports PEX5 protein carrier activity for PTS2 cargo proteins.
    action: ACCEPT
    reason: Core molecular function of PEX5 demonstrated by mutant phenotype.
- term:
    id: GO:0005052
    label: peroxisome matrix targeting signal-1 binding
  evidence_type: IDA
  original_reference_id: PMID:17157249
  review:
    summary: PMID:17157249 demonstrates recognition of a functional PTS1 target by the dynamic import receptor PEX5.
    action: ACCEPT
    reason: Core molecular function. PTS1 binding demonstrated experimentally.
- term:
    id: GO:0005782
    label: peroxisomal matrix
  evidence_type: IDA
  original_reference_id: PMID:24662292
  review:
    summary: PMID:24662292 studies distinct modes of PEX5 ubiquitination regulating PTS1 import, supporting peroxisomal matrix
      localization.
    action: ACCEPT
    reason: Peroxisomal matrix localization consistent with PEX5 cycling mechanism.
- term:
    id: GO:0016558
    label: protein import into peroxisome matrix
  evidence_type: IDA
  original_reference_id: PMID:17157249
  review:
    summary: PMID:17157249 demonstrates PEX5-mediated peroxisomal matrix protein import.
    action: ACCEPT
    reason: Core biological process function of PEX5.
- term:
    id: GO:0016558
    label: protein import into peroxisome matrix
  evidence_type: IDA
  original_reference_id: PMID:24662292
  review:
    summary: PMID:24662292 demonstrates PEX5-mediated peroxisomal import in context of ubiquitination studies.
    action: ACCEPT
    reason: Core biological process function of PEX5.
- term:
    id: GO:0140597
    label: protein carrier chaperone
  evidence_type: IDA
  original_reference_id: PMID:17157249
  review:
    summary: PMID:17157249 supports PEX5 protein carrier activity.
    action: ACCEPT
    reason: Core molecular function of PEX5.
- term:
    id: GO:0140597
    label: protein carrier chaperone
  evidence_type: IDA
  original_reference_id: PMID:24662292
  review:
    summary: PMID:24662292 supports PEX5 protein carrier activity in context of ubiquitination regulation.
    action: ACCEPT
    reason: Core molecular function of PEX5.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:12488033
  review:
    summary: PMID:12488033 characterizes PEX14 membrane topology and PEX14-PEX14 interaction, with PEX5 as an interacting
      partner.
    action: MARK_AS_OVER_ANNOTATED
    reason: Protein binding is too vague. PEX5-PEX14 docking interaction is captured by more specific terms.
- term:
    id: GO:0031333
    label: negative regulation of protein-containing complex assembly
  evidence_type: IDA
  original_reference_id: PMID:21976670
  review:
    summary: PMID:21976670 shows PEX5 binds monomeric catalase and blocks its tetramerization. This negative regulation of
      complex assembly is a mechanistic consequence of PEX5 binding monomeric PTS1 cargo to prevent premature oligomerization
      before import.
    action: KEEP_AS_NON_CORE
    reason: This is a mechanistic consequence of PEX5 binding monomeric catalase for import, not an independent function.
      The anti-tetramerization effect ensures catalase is imported as a monomer. It is a secondary effect of the primary PTS1
      cargo binding function.
    supported_by:
    - reference_id: PMID:21976670
      supporting_text: PEX5 protein binds monomeric catalase blocking its tetramerization and releases it upon binding the
        N-terminal domain of PEX14
- term:
    id: GO:0033328
    label: peroxisome membrane targeting sequence binding
  evidence_type: IPI
  original_reference_id: PMID:21976670
  review:
    summary: PMID:21976670 shows PEX5 binds the peroxisome membrane targeting sequence in the context of PEX14 interaction.
      However, PEX5 is the PTS1 receptor, not a PMP targeting sequence receptor. The annotation may reflect PEX5 interaction
      with PEX14 N-terminal domain.
    action: UNDECIDED
    reason: PEX5 recognizes PTS1 signals, not peroxisome membrane targeting sequences (mPTS). PEX19 is the mPTS receptor.
      This annotation may be a mis-annotation or may refer to PEX5 binding a specific motif on PEX14 that overlaps with mPTS-like
      sequences. Needs clarification.
- term:
    id: GO:0005778
    label: peroxisomal membrane
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-9664855
  review:
    summary: Reactome TAS annotation for peroxisomal membrane localization. PEX5 transiently associates with the peroxisomal
      membrane during the import cycle via docking with PEX13/PEX14. Multiple Reactome reactions represent different steps
      of the import and recycling cycle at the membrane.
    action: ACCEPT
    reason: Peroxisomal membrane localization is correct for PEX5 as a cycling receptor. Reactome models different steps of
      the cycle (docking, ubiquitination, cargo release, recycling, pexophagy) that all involve PEX5 at the peroxisomal membrane.
- term:
    id: GO:0005778
    label: peroxisomal membrane
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-9664862
  review:
    summary: Reactome TAS annotation for peroxisomal membrane localization. PEX5 transiently associates with the peroxisomal
      membrane during the import cycle via docking with PEX13/PEX14. Multiple Reactome reactions represent different steps
      of the import and recycling cycle at the membrane.
    action: ACCEPT
    reason: Peroxisomal membrane localization is correct for PEX5 as a cycling receptor. Reactome models different steps of
      the cycle (docking, ubiquitination, cargo release, recycling, pexophagy) that all involve PEX5 at the peroxisomal membrane.
- term:
    id: GO:0005778
    label: peroxisomal membrane
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-9664879
  review:
    summary: Reactome TAS annotation for peroxisomal membrane localization. PEX5 transiently associates with the peroxisomal
      membrane during the import cycle via docking with PEX13/PEX14. Multiple Reactome reactions represent different steps
      of the import and recycling cycle at the membrane.
    action: ACCEPT
    reason: Peroxisomal membrane localization is correct for PEX5 as a cycling receptor. Reactome models different steps of
      the cycle (docking, ubiquitination, cargo release, recycling, pexophagy) that all involve PEX5 at the peroxisomal membrane.
- term:
    id: GO:0005778
    label: peroxisomal membrane
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-9664880
  review:
    summary: Reactome TAS annotation for peroxisomal membrane localization. PEX5 transiently associates with the peroxisomal
      membrane during the import cycle via docking with PEX13/PEX14. Multiple Reactome reactions represent different steps
      of the import and recycling cycle at the membrane.
    action: ACCEPT
    reason: Peroxisomal membrane localization is correct for PEX5 as a cycling receptor. Reactome models different steps of
      the cycle (docking, ubiquitination, cargo release, recycling, pexophagy) that all involve PEX5 at the peroxisomal membrane.
- term:
    id: GO:0005778
    label: peroxisomal membrane
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-9664881
  review:
    summary: Reactome TAS annotation for peroxisomal membrane localization. PEX5 transiently associates with the peroxisomal
      membrane during the import cycle via docking with PEX13/PEX14. Multiple Reactome reactions represent different steps
      of the import and recycling cycle at the membrane.
    action: ACCEPT
    reason: Peroxisomal membrane localization is correct for PEX5 as a cycling receptor. Reactome models different steps of
      the cycle (docking, ubiquitination, cargo release, recycling, pexophagy) that all involve PEX5 at the peroxisomal membrane.
- term:
    id: GO:0005778
    label: peroxisomal membrane
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-9664883
  review:
    summary: Reactome TAS annotation for peroxisomal membrane localization. PEX5 transiently associates with the peroxisomal
      membrane during the import cycle via docking with PEX13/PEX14. Multiple Reactome reactions represent different steps
      of the import and recycling cycle at the membrane.
    action: ACCEPT
    reason: Peroxisomal membrane localization is correct for PEX5 as a cycling receptor. Reactome models different steps of
      the cycle (docking, ubiquitination, cargo release, recycling, pexophagy) that all involve PEX5 at the peroxisomal membrane.
- term:
    id: GO:0005778
    label: peroxisomal membrane
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-9664888
  review:
    summary: Reactome TAS annotation for peroxisomal membrane localization. PEX5 transiently associates with the peroxisomal
      membrane during the import cycle via docking with PEX13/PEX14. Multiple Reactome reactions represent different steps
      of the import and recycling cycle at the membrane.
    action: ACCEPT
    reason: Peroxisomal membrane localization is correct for PEX5 as a cycling receptor. Reactome models different steps of
      the cycle (docking, ubiquitination, cargo release, recycling, pexophagy) that all involve PEX5 at the peroxisomal membrane.
- term:
    id: GO:0005778
    label: peroxisomal membrane
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-9664892
  review:
    summary: Reactome TAS annotation for peroxisomal membrane localization. PEX5 transiently associates with the peroxisomal
      membrane during the import cycle via docking with PEX13/PEX14. Multiple Reactome reactions represent different steps
      of the import and recycling cycle at the membrane.
    action: ACCEPT
    reason: Peroxisomal membrane localization is correct for PEX5 as a cycling receptor. Reactome models different steps of
      the cycle (docking, ubiquitination, cargo release, recycling, pexophagy) that all involve PEX5 at the peroxisomal membrane.
- term:
    id: GO:0005778
    label: peroxisomal membrane
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-9674127
  review:
    summary: Reactome TAS annotation for peroxisomal membrane localization. PEX5 transiently associates with the peroxisomal
      membrane during the import cycle via docking with PEX13/PEX14. Multiple Reactome reactions represent different steps
      of the import and recycling cycle at the membrane.
    action: ACCEPT
    reason: Peroxisomal membrane localization is correct for PEX5 as a cycling receptor. Reactome models different steps of
      the cycle (docking, ubiquitination, cargo release, recycling, pexophagy) that all involve PEX5 at the peroxisomal membrane.
- term:
    id: GO:0005778
    label: peroxisomal membrane
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-9674131
  review:
    summary: Reactome TAS annotation for peroxisomal membrane localization. PEX5 transiently associates with the peroxisomal
      membrane during the import cycle via docking with PEX13/PEX14. Multiple Reactome reactions represent different steps
      of the import and recycling cycle at the membrane.
    action: ACCEPT
    reason: Peroxisomal membrane localization is correct for PEX5 as a cycling receptor. Reactome models different steps of
      the cycle (docking, ubiquitination, cargo release, recycling, pexophagy) that all involve PEX5 at the peroxisomal membrane.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:10514471
  review:
    summary: PMID:10514471 characterizes PMP20 (PRDX5) as a PTS1 cargo that binds PEX5 via its C-terminal SQL tripeptide.
      This demonstrates PEX5 PTS1 receptor function rather than generic protein binding.
    action: MARK_AS_OVER_ANNOTATED
    reason: Protein binding is too vague. This interaction reflects PEX5 recognizing PMP20 as a PTS1 cargo, which is the core
      PTS1 receptor function already captured by GO:0005052.
    supported_by:
    - reference_id: PMID:10514471
      supporting_text: HsPMP20 bound directly to the human peroxisomal targeting signal 1 receptor, HsPEX5. Mutagenesis analysis
        showed that the C-terminal tripeptide sequence, SQL, of HsPMP20 is necessary for its binding to HsPEX5
- term:
    id: GO:0005778
    label: peroxisomal membrane
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-8953917
  review:
    summary: Reactome TAS annotation for peroxisomal membrane localization. PEX5 transiently associates with the peroxisomal
      membrane during the import cycle via docking with PEX13/PEX14. Multiple Reactome reactions represent different steps
      of the import and recycling cycle at the membrane.
    action: ACCEPT
    reason: Peroxisomal membrane localization is correct for PEX5 as a cycling receptor. Reactome models different steps of
      the cycle (docking, ubiquitination, cargo release, recycling, pexophagy) that all involve PEX5 at the peroxisomal membrane.
- term:
    id: GO:0005778
    label: peroxisomal membrane
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-8953946
  review:
    summary: Reactome TAS annotation for peroxisomal membrane localization. PEX5 transiently associates with the peroxisomal
      membrane during the import cycle via docking with PEX13/PEX14. Multiple Reactome reactions represent different steps
      of the import and recycling cycle at the membrane.
    action: ACCEPT
    reason: Peroxisomal membrane localization is correct for PEX5 as a cycling receptor. Reactome models different steps of
      the cycle (docking, ubiquitination, cargo release, recycling, pexophagy) that all involve PEX5 at the peroxisomal membrane.
- term:
    id: GO:0005778
    label: peroxisomal membrane
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-9033235
  review:
    summary: Reactome TAS annotation for peroxisomal membrane localization. PEX5 transiently associates with the peroxisomal
      membrane during the import cycle via docking with PEX13/PEX14. Multiple Reactome reactions represent different steps
      of the import and recycling cycle at the membrane.
    action: ACCEPT
    reason: Peroxisomal membrane localization is correct for PEX5 as a cycling receptor. Reactome models different steps of
      the cycle (docking, ubiquitination, cargo release, recycling, pexophagy) that all involve PEX5 at the peroxisomal membrane.
- term:
    id: GO:0005778
    label: peroxisomal membrane
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-9033485
  review:
    summary: Reactome TAS annotation for peroxisomal membrane localization. PEX5 transiently associates with the peroxisomal
      membrane during the import cycle via docking with PEX13/PEX14. Multiple Reactome reactions represent different steps
      of the import and recycling cycle at the membrane.
    action: ACCEPT
    reason: Peroxisomal membrane localization is correct for PEX5 as a cycling receptor. Reactome models different steps of
      the cycle (docking, ubiquitination, cargo release, recycling, pexophagy) that all involve PEX5 at the peroxisomal membrane.
- term:
    id: GO:0005778
    label: peroxisomal membrane
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-9033499
  review:
    summary: Reactome TAS annotation for peroxisomal membrane localization. PEX5 transiently associates with the peroxisomal
      membrane during the import cycle via docking with PEX13/PEX14. Multiple Reactome reactions represent different steps
      of the import and recycling cycle at the membrane.
    action: ACCEPT
    reason: Peroxisomal membrane localization is correct for PEX5 as a cycling receptor. Reactome models different steps of
      the cycle (docking, ubiquitination, cargo release, recycling, pexophagy) that all involve PEX5 at the peroxisomal membrane.
- term:
    id: GO:0005778
    label: peroxisomal membrane
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-9033514
  review:
    summary: Reactome TAS annotation for peroxisomal membrane localization. PEX5 transiently associates with the peroxisomal
      membrane during the import cycle via docking with PEX13/PEX14. Multiple Reactome reactions represent different steps
      of the import and recycling cycle at the membrane.
    action: ACCEPT
    reason: Peroxisomal membrane localization is correct for PEX5 as a cycling receptor. Reactome models different steps of
      the cycle (docking, ubiquitination, cargo release, recycling, pexophagy) that all involve PEX5 at the peroxisomal membrane.
- term:
    id: GO:0005778
    label: peroxisomal membrane
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-9033516
  review:
    summary: Reactome TAS annotation for peroxisomal membrane localization. PEX5 transiently associates with the peroxisomal
      membrane during the import cycle via docking with PEX13/PEX14. Multiple Reactome reactions represent different steps
      of the import and recycling cycle at the membrane.
    action: ACCEPT
    reason: Peroxisomal membrane localization is correct for PEX5 as a cycling receptor. Reactome models different steps of
      the cycle (docking, ubiquitination, cargo release, recycling, pexophagy) that all involve PEX5 at the peroxisomal membrane.
- term:
    id: GO:0005778
    label: peroxisomal membrane
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-9033527
  review:
    summary: Reactome TAS annotation for peroxisomal membrane localization. PEX5 transiently associates with the peroxisomal
      membrane during the import cycle via docking with PEX13/PEX14. Multiple Reactome reactions represent different steps
      of the import and recycling cycle at the membrane.
    action: ACCEPT
    reason: Peroxisomal membrane localization is correct for PEX5 as a cycling receptor. Reactome models different steps of
      the cycle (docking, ubiquitination, cargo release, recycling, pexophagy) that all involve PEX5 at the peroxisomal membrane.
- term:
    id: GO:0005778
    label: peroxisomal membrane
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-9033533
  review:
    summary: Reactome TAS annotation for peroxisomal membrane localization. PEX5 transiently associates with the peroxisomal
      membrane during the import cycle via docking with PEX13/PEX14. Multiple Reactome reactions represent different steps
      of the import and recycling cycle at the membrane.
    action: ACCEPT
    reason: Peroxisomal membrane localization is correct for PEX5 as a cycling receptor. Reactome models different steps of
      the cycle (docking, ubiquitination, cargo release, recycling, pexophagy) that all involve PEX5 at the peroxisomal membrane.
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-9033491
  review:
    summary: Reactome TAS annotation for cytosol localization. PEX5 is predominantly cytosolic and returns to the cytosol
      after each import cycle.
    action: ACCEPT
    reason: Cytosol localization is correct for PEX5 as a predominantly cytosolic cycling receptor.
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-9033499
  review:
    summary: Reactome TAS annotation for cytosol localization. PEX5 is predominantly cytosolic and returns to the cytosol
      after each import cycle.
    action: ACCEPT
    reason: Cytosol localization is correct for PEX5 as a predominantly cytosolic cycling receptor.
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-9033509
  review:
    summary: Reactome TAS annotation for cytosol localization. PEX5 is predominantly cytosolic and returns to the cytosol
      after each import cycle.
    action: ACCEPT
    reason: Cytosol localization is correct for PEX5 as a predominantly cytosolic cycling receptor.
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-9033235
  review:
    summary: Reactome TAS annotation for cytosol localization. PEX5 is predominantly cytosolic and returns to the cytosol
      after each import cycle.
    action: ACCEPT
    reason: Cytosol localization is correct for PEX5 as a predominantly cytosolic cycling receptor.
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-9033236
  review:
    summary: Reactome TAS annotation for cytosol localization. PEX5 is predominantly cytosolic and returns to the cytosol
      after each import cycle.
    action: ACCEPT
    reason: Cytosol localization is correct for PEX5 as a predominantly cytosolic cycling receptor.
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-9033514
  review:
    summary: Reactome TAS annotation for cytosol localization. PEX5 is predominantly cytosolic and returns to the cytosol
      after each import cycle.
    action: ACCEPT
    reason: Cytosol localization is correct for PEX5 as a predominantly cytosolic cycling receptor.
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-9664850
  review:
    summary: Reactome TAS annotation for cytosol localization. PEX5 is predominantly cytosolic and returns to the cytosol
      after each import cycle.
    action: ACCEPT
    reason: Cytosol localization is correct for PEX5 as a predominantly cytosolic cycling receptor.
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-9664883
  review:
    summary: Reactome TAS annotation for cytosol localization. PEX5 is predominantly cytosolic and returns to the cytosol
      after each import cycle.
    action: ACCEPT
    reason: Cytosol localization is correct for PEX5 as a predominantly cytosolic cycling receptor.
- term:
    id: GO:0005052
    label: peroxisome matrix targeting signal-1 binding
  evidence_type: IDA
  original_reference_id: PMID:11463335
  review:
    summary: PMID:11463335 identifies PEX5p-related novel PTS1-binding proteins and demonstrates PEX5 PTS1 binding in comparative
      assays.
    action: ACCEPT
    reason: Core molecular function of PEX5 demonstrated in comparative binding assays.
    supported_by:
    - reference_id: PMID:11463335
      supporting_text: Identification of PEX5p-related novel peroxisome-targeting signal 1 (PTS1)-binding proteins in mammals
- term:
    id: GO:0016558
    label: protein import into peroxisome matrix
  evidence_type: IMP
  original_reference_id: PMID:11463335
  review:
    summary: PMID:11463335 demonstrates PEX5 role in peroxisomal matrix protein import via mutant phenotype.
    action: ACCEPT
    reason: Core biological process function.
- term:
    id: GO:0032991
    label: protein-containing complex
  evidence_type: IDA
  original_reference_id: PMID:19584060
  review:
    summary: PMID:19584060 provides SAXS solution structure of PEX5-PEX14-PTS1 protein complexes. PEX5 forms defined complexes
      with PEX14 and PTS1 cargo.
    action: ACCEPT
    reason: PEX5 forms specific protein complexes with PEX14 and cargo as part of the import mechanism. The annotation to
      protein-containing complex is accurate.
- term:
    id: GO:0016560
    label: protein import into peroxisome matrix, docking
  evidence_type: IDA
  original_reference_id: PMID:21976670
  review:
    summary: PMID:21976670 shows PEX5 docking at peroxisomal membrane via PEX14 interaction (releasing catalase upon PEX14
      NTD binding).
    action: ACCEPT
    reason: Docking is a core step in the PEX5 import cycle.
    supported_by:
    - reference_id: PMID:21976670
      supporting_text: PEX5 protein binds monomeric catalase blocking its tetramerization and releases it upon binding the
        N-terminal domain of PEX14
- term:
    id: GO:0005052
    label: peroxisome matrix targeting signal-1 binding
  evidence_type: IPI
  original_reference_id: PMID:21375735
  review:
    summary: PMID:21375735 demonstrates that PTS1 in sterol carrier protein 2 is autonomous and essential for PEX5 receptor
      recognition.
    action: ACCEPT
    reason: Core molecular function. PTS1 binding demonstrated via IPI with SCP2 cargo.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:19584060
  review:
    summary: PMID:19584060 provides solution structure of PEX5-PEX14-PTS1 complexes by SAXS.
    action: MARK_AS_OVER_ANNOTATED
    reason: Protein binding is too vague. Structural characterization of the PEX5-PEX14 complex supports docking (GO:0016560)
      already annotated.
- term:
    id: GO:0005777
    label: peroxisome
  evidence_type: IDA
  original_reference_id: PMID:21375735
  review:
    summary: PMID:21375735 localizes PEX5 to peroxisomes. This is broader than peroxisomal membrane (GO:0005778) or matrix
      (GO:0005782).
    action: ACCEPT
    reason: PEX5 localizes to peroxisomes (both membrane and transiently matrix). The peroxisome annotation is accurate if
      less specific than the membrane/matrix annotations.
- term:
    id: GO:0006625
    label: protein targeting to peroxisome
  evidence_type: IDA
  original_reference_id: PMID:21375735
  isoform: P50542-1
  review:
    summary: PMID:21375735 demonstrates PEX5L-mediated protein targeting to peroxisome with SCP2 as cargo.
    action: ACCEPT
    reason: Core biological process function of PEX5. Protein targeting to peroxisome is the primary role.
- term:
    id: GO:0045046
    label: protein import into peroxisome membrane
  evidence_type: IMP
  original_reference_id: PMID:14709540
  review:
    summary: PMID:14709540 is about PEX19 as chaperone/import receptor for peroxisomal membrane proteins. PEX5 siRNA served
      as a control in this study demonstrating selective PMP import defects. The annotation of PEX5 to protein import into
      peroxisome membrane is likely incorrect - PEX5 imports matrix proteins, not membrane proteins.
    action: REMOVE
    reason: PEX5 is the PTS1 receptor for matrix protein import, not membrane protein import. PEX19 is the membrane protein
      import receptor. In PMID:14709540, PEX5 siRNA was used as a control showing selective matrix protein import deficiency,
      which is the opposite phenotype from PEX19 siRNA. Annotating PEX5 to membrane protein import is incorrect.
    supported_by:
    - reference_id: PMID:14709540
      supporting_text: inhibition of PEX5 induced a selective deficit in peroxisomal matrix protein import... Inhibition of
        PEX19 induced the converse phenotype, a selective defect in PMP import
- term:
    id: GO:0000268
    label: peroxisome targeting sequence binding
  evidence_type: IDA
  original_reference_id: PMID:18346465
  review:
    summary: PMID:18346465 compares PTS1- and Rab8b-binding properties of PEX5 and PEX5Rp/TRIP8b. PEX5 binds peroxisome targeting
      sequences. GO:0000268 (peroxisome targeting sequence binding) is a parent term that encompasses both PTS1 and PTS2 signal
      binding.
    action: ACCEPT
    reason: PEX5 binds peroxisome targeting sequences (primarily PTS1). This is a correct broader annotation consistent with
      the more specific GO:0005052.
    supported_by:
    - reference_id: PMID:18346465
      supporting_text: the TPR domains of Pex5p and Pex5Rp/TRIP8b have distinct but overlapping substrate specificities
- term:
    id: GO:0016558
    label: protein import into peroxisome matrix
  evidence_type: IGI
  original_reference_id: PMID:18346465
  review:
    summary: PMID:18346465 provides genetic interaction evidence for PEX5 role in peroxisomal matrix protein import via comparison
      with TRIP8b/PEX5Rp.
    action: ACCEPT
    reason: Core biological process function of PEX5.
- term:
    id: GO:0031267
    label: small GTPase binding
  evidence_type: IPI
  original_reference_id: PMID:18346465
  review:
    summary: PMID:18346465 shows PEX5 binds Rab8b small GTPase. However, this binding was compared to TRIP8b and the biological
      significance for PEX5 is unclear. PEX5 is not known to function as a Rab8b effector.
    action: MARK_AS_OVER_ANNOTATED
    reason: Small GTPase binding by PEX5 may be a non-physiological interaction or a minor binding activity. PEX5 is not known
      to function as a Rab8b effector. TRIP8b is the primary Rab8b-binding TPR protein.
    supported_by:
    - reference_id: PMID:18346465
      supporting_text: the TPR domains of Pex5p and Pex5Rp/TRIP8b have distinct but overlapping substrate specificities
- term:
    id: GO:0019899
    label: enzyme binding
  evidence_type: IPI
  original_reference_id: PMID:11060344
  review:
    summary: PMID:11060344 shows in vitro interaction between recombinant racemase (AMACR) and PEX5. AMACR is a PTS1 cargo
      (C-terminal -KASL), so this interaction reflects PTS1 receptor function.
    action: MODIFY
    reason: Enzyme binding is too generic. The interaction with AMACR reflects PEX5 PTS1 receptor function recognizing the
      KASL targeting signal. Better captured by GO:0005052 (PTS1 binding).
    proposed_replacement_terms:
    - id: GO:0005052
      label: peroxisome matrix targeting signal-1 binding
    supported_by:
    - reference_id: PMID:11060344
      supporting_text: the in vitro interaction between recombinant racemase and recombinant human PTS1 receptor (Pex5p)...
        we concluded that ASL is a new PTS1 variant
- term:
    id: GO:0019899
    label: enzyme binding
  evidence_type: IPI
  original_reference_id: PMID:11669066
  review:
    summary: PMID:11669066 identifies a novel human peroxisomal 2,4-dienoyl-CoA reductase via PEX5 interaction using phage
      display. This likely reflects PTS1 cargo recognition.
    action: MODIFY
    reason: Enzyme binding is too generic. The interaction likely reflects PTS1 receptor cargo recognition function, better
      captured by GO:0005052.
    proposed_replacement_terms:
    - id: GO:0005052
      label: peroxisome matrix targeting signal-1 binding
- term:
    id: GO:0005778
    label: peroxisomal membrane
  evidence_type: HDA
  original_reference_id: PMID:21525035
  review:
    summary: PMID:21525035 provides high-throughput direct assay evidence for PEX5 at the peroxisomal membrane. Consistent
      with PEX5 membrane association during import.
    action: ACCEPT
    reason: Peroxisomal membrane localization is correct for PEX5 as a cycling receptor.
- term:
    id: GO:0016558
    label: protein import into peroxisome matrix
  evidence_type: IGI
  original_reference_id: PMID:11931631
  isoform: P50542-1
  review:
    summary: PMID:11931631 provides functional studies on human PEX7 including subcellular localization and interaction with
      PTS2-containing proteins and peroxins including PEX5L. IGI evidence for PEX5L role in peroxisomal matrix protein import.
    action: ACCEPT
    reason: Core function of PEX5L in PTS2-mediated import via PEX7 co-receptor function.
- term:
    id: GO:0016558
    label: protein import into peroxisome matrix
  evidence_type: NAS
  original_reference_id: PMID:10514471
  review:
    summary: PMID:10514471 reports PMP20/PRDX5 is imported into peroxisomal matrix via PEX5. NAS evidence supports PEX5 role
      in import.
    action: ACCEPT
    reason: Core biological process function of PEX5. NAS evidence from a relevant cargo study.
    supported_by:
    - reference_id: PMID:10514471
      supporting_text: these results indicate that HsPMP20 is imported into the peroxisomal matrix via PEX5p
- term:
    id: GO:0005052
    label: peroxisome matrix targeting signal-1 binding
  evidence_type: IDA
  original_reference_id: PMID:10514471
  review:
    summary: PMID:10514471 directly demonstrates PTS1 binding between PEX5 and PMP20 via C-terminal SQL tripeptide.
    action: ACCEPT
    reason: Core molecular function. PTS1 binding directly demonstrated.
    supported_by:
    - reference_id: PMID:10514471
      supporting_text: HsPMP20 bound directly to the human peroxisomal targeting signal 1 receptor, HsPEX5. Mutagenesis analysis
        showed that the C-terminal tripeptide sequence, SQL, of HsPMP20 is necessary for its binding to HsPEX5
- term:
    id: GO:0005737
    label: cytoplasm
  evidence_type: IDA
  original_reference_id: PMID:10514471
  review:
    summary: PMID:10514471 localizes PEX5 to the cytoplasm. This is broader than cytosol (GO:0005829) which is already annotated.
    action: ACCEPT
    reason: Cytoplasm localization is correct and broader than the more specific cytosol term. Both are valid.
- term:
    id: GO:0016020
    label: membrane
  evidence_type: IDA
  original_reference_id: PMID:10514471
  review:
    summary: PMID:10514471 reports PEX5 association with a particulate (membrane) fraction. The generic membrane term is very
      broad.
    action: MARK_AS_OVER_ANNOTATED
    reason: The generic membrane term (GO:0016020) is too broad and uninformative when more specific localizations (peroxisomal
      membrane GO:0005778) are already annotated.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:9820813
  review:
    summary: PMID:9820813 shows that the C-terminal tripeptide SNL of D-aspartate oxidase is a functional PTS1 signal that
      binds PEX5. This is a PTS1 cargo recognition interaction.
    action: MARK_AS_OVER_ANNOTATED
    reason: Protein binding is too vague. This interaction reflects PTS1 receptor function (GO:0005052) already annotated.
    supported_by:
    - reference_id: PMID:9820813
      supporting_text: C-terminal tripeptide Ser-Asn-Leu (SNL) of human D-aspartate oxidase is a functional peroxisome-targeting
        signal
- term:
    id: GO:0005777
    label: peroxisome
  evidence_type: IDA
  original_reference_id: PMID:11829486
  review:
    summary: PMID:11829486 characterizes mouse Pex13 and localizes it to peroxisomes, with PEX5 as an interacting partner
      localized to peroxisomes.
    action: ACCEPT
    reason: Peroxisome localization is correct for PEX5.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:8858165
  isoform: P50542-1
  review:
    summary: PMID:8858165 shows Pex13p is an SH3 protein of the peroxisome membrane and a docking factor for PEX5. This is
      the PEX5-PEX13 docking interaction.
    action: MARK_AS_OVER_ANNOTATED
    reason: Protein binding is too vague. The PEX5-PEX13 interaction is part of the docking mechanism, captured by GO:0016560.
    supported_by:
    - reference_id: PMID:8858165
      supporting_text: Pex13p is an SH3 protein of the peroxisome membrane and a docking factor for the predominantly cytoplasmic
        PTs1 receptor
- term:
    id: GO:0005052
    label: peroxisome matrix targeting signal-1 binding
  evidence_type: IDA
  original_reference_id: PMID:12456682
  isoform: P50542-1
  review:
    summary: PMID:12456682 shows PEX5 binds PTS1 independently of Hsp70 and PEX12. Directly demonstrates PTS1 binding.
    action: ACCEPT
    reason: Core molecular function.
    supported_by:
    - reference_id: PMID:12456682
      supporting_text: PEX5 binds the PTS1 independently of Hsp70 and the peroxin PEX12
- term:
    id: GO:0051262
    label: protein tetramerization
  evidence_type: IDA
  original_reference_id: PMID:12456682
  isoform: P50542-1
  review:
    summary: PMID:12456682 reports PEX5 tetramerization. This is a structural observation about PEX5 oligomerization state.
    action: KEEP_AS_NON_CORE
    reason: Protein tetramerization is a structural property of PEX5 observed in vitro but not its primary functional role.
      The biological significance of PEX5 tetramerization for import function is not clearly established.
- term:
    id: GO:0005052
    label: peroxisome matrix targeting signal-1 binding
  evidence_type: IMP
  original_reference_id: PMID:9668159
  isoform: P50542-1
  review:
    summary: PMID:9668159 shows PEX5L isoform is required for PTS2 protein import, with PTS1 binding demonstrated by mutant
      complementation. IMP evidence supports PTS1 binding.
    action: ACCEPT
    reason: Core molecular function demonstrated by mutant phenotype analysis.
    supported_by:
    - reference_id: PMID:9668159
      supporting_text: Transfection of PBD005 cells with PEX5S cDNA restores PTS1 but not PTS2 import; transfection with PXR5L
        cDNA restores both PTS1 and PTS2 protein import
- term:
    id: GO:0006625
    label: protein targeting to peroxisome
  evidence_type: IMP
  original_reference_id: PMID:9668159
  isoform: P50542-1
  review:
    summary: PMID:9668159 demonstrates PEX5L is required for protein targeting to peroxisome (both PTS1 and PTS2 pathways).
    action: ACCEPT
    reason: Core biological process function of PEX5.
    supported_by:
    - reference_id: PMID:9668159
      supporting_text: the long isoform of the Pex5 protein is required for peroxisomal import of PTS2 proteins
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:9653144
  review:
    summary: PMID:9653144 identifies PEX14 as a human PTS1 receptor docking protein directly required for peroxisomal protein
      import. This is the PEX5-PEX14 docking interaction.
    action: MARK_AS_OVER_ANNOTATED
    reason: Protein binding is too vague. The PEX5-PEX14 docking interaction is captured by GO:0016560.
    supported_by:
    - reference_id: PMID:9653144
      supporting_text: Identification of a human PTS1 receptor docking protein directly required for peroxisomal protein import
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:15911627
  review:
    summary: PMID:15911627 shows peroxisomal import of AGT requires ancillary targeting information remote from its C terminus.
      Demonstrates PEX5 interaction with AGT cargo.
    action: MARK_AS_OVER_ANNOTATED
    reason: Protein binding is too vague. PEX5-AGT interaction represents PTS1 receptor cargo recognition function, captured
      by GO:0005052.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:10837480
  review:
    summary: PMID:10837480 shows PEX12 ring finger domain interacts with PEX5 and PEX10. This is part of the ubiquitination
      machinery interaction during receptor recycling.
    action: MARK_AS_OVER_ANNOTATED
    reason: Protein binding is too vague. PEX5-PEX12 interaction is part of the receptor recycling/ubiquitination mechanism,
      captured by GO:0016562.
    supported_by:
    - reference_id: PMID:10837480
      supporting_text: ring finger domain is essential for Pex12p function and interacts with the peroxisome-targeting signal
        type 1-receptor Pex5p and a ring peroxin, Pex10p
references:
- id: GO_REF:0000024
  title: Manual transfer of experimentally-verified manual GO annotation data to orthologs by curator judgment of sequence
    similarity
  findings: []
- id: GO_REF:0000033
  title: Annotation inferences using phylogenetic trees
  findings: []
- id: GO_REF:0000043
  title: Gene Ontology annotation based on UniProtKB/Swiss-Prot keyword mapping
  findings: []
- id: GO_REF:0000044
  title: Gene Ontology annotation based on UniProtKB/Swiss-Prot Subcellular Location vocabulary mapping, accompanied by conservative
    changes to GO terms applied by UniProt
  findings: []
- id: GO_REF:0000052
  title: Gene Ontology annotation based on curation of immunofluorescence data
  findings: []
- id: GO_REF:0000107
  title: Automatic transfer of experimentally verified manual GO annotation data to orthologs using Ensembl Compara
  findings: []
- id: PMID:10514471
  title: Characterization of human and murine PMP20 peroxisomal proteins that exhibit antioxidant activity in vitro.
  findings: []
- id: PMID:10562279
  title: PEX12 interacts with PEX5 and PEX10 and acts downstream of receptor docking in peroxisomal matrix protein import.
  findings: []
- id: PMID:10837480
  title: 'Molecular anatomy of the peroxin Pex12p: ring finger domain is essential for Pex12p function and interacts with
    the peroxisome-targeting signal type 1-receptor Pex5p and a ring peroxin, Pex10p.'
  findings: []
- id: PMID:11060344
  title: Mitochondrial and peroxisomal targeting of 2-methylacyl-CoA racemase in humans.
  findings: []
- id: PMID:11336669
  title: The human peroxisomal targeting signal receptor, Pex5p, is translocated into the peroxisomal matrix and recycled
    to the cytosol.
  findings: []
- id: PMID:11463335
  title: Identification of PEX5p-related novel peroxisome-targeting signal 1 (PTS1)-binding proteins in mammals.
  findings: []
- id: PMID:11546814
  title: Domain mapping of human PEX5 reveals functional and structural similarities to Saccharomyces cerevisiae Pex18p and
    Pex21p.
  findings: []
- id: PMID:11669066
  title: Identification of a novel human peroxisomal 2,4-dienoyl-CoA reductase related protein using the M13 phage protein
    VI phage display technology.
  findings: []
- id: PMID: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.'
  findings: []
- id: PMID:11931631
  title: 'Functional studies on human Pex7p: subcellular localization and interaction with proteins containing a peroxisome-targeting
    signal type 2 and other peroxins.'
  findings: []
- id: PMID:12096124
  title: Analysis of mammalian peroxin interactions using a non-transcription-based bacterial two-hybrid assay.
  findings: []
- id: PMID:12456682
  title: PEX5 binds the PTS1 independently of Hsp70 and the peroxin PEX12.
  findings: []
- id: PMID:12488033
  title: 'Mammalian Pex14p: membrane topology and characterisation of the Pex14p-Pex14p interaction.'
  findings: []
- id: PMID:14709540
  title: PEX19 is a predominantly cytosolic chaperone and import receptor for class 1 peroxisomal membrane proteins.
  findings: []
- id: PMID:15911627
  title: Peroxisomal import of human alanine:glyoxylate aminotransferase requires ancillary targeting information remote from
    its C terminus.
  findings: []
- id: PMID:16314507
  title: 'Shuttling mechanism of peroxisome targeting signal type 1 receptor Pex5: ATP-independent import and ATP-dependent
    export.'
  findings: []
- id: PMID:17157249
  title: Recognition of a functional peroxisome type 1 target by the dynamic import receptor pex5p.
  findings: []
- id: PMID:18346465
  title: Comparison of the PTS1- and Rab8b-binding properties of Pex5p and Pex5Rp/TRIP8b.
  findings: []
- id: PMID:19197237
  title: Structural basis for competitive interactions of Pex14 with the import receptors Pex5 and Pex19.
  findings: []
- id: PMID:19584060
  title: Solution structure of human Pex5.Pex14.PTS1 protein complexes obtained by small angle X-ray scattering.
  findings: []
- id: PMID:21044950
  title: Genome-wide YFP fluorescence complementation screen identifies new regulators for telomere signaling in human cells.
  findings: []
- id: PMID:21375735
  title: The Peroxisomal Targeting Signal 1 in sterol carrier protein 2 is autonomous and essential for receptor recognition.
  findings: []
- id: PMID:21525035
  title: PEX14 is required for microtubule-based peroxisome motility in human cells.
  findings: []
- id: PMID:21976670
  title: PEX5 protein binds monomeric catalase blocking its tetramerization and releases it upon binding the N-terminal domain
    of PEX14.
  findings: []
- id: PMID:22371489
  title: Identification of ubiquitin-specific protease 9X (USP9X) as a deubiquitinase acting on ubiquitin-peroxin 5 (PEX5)
    thioester conjugate.
  findings: []
- id: PMID:22529745
  title: Molecular requirements for peroxisomal targeting of alanine-glyoxylate aminotransferase as an essential determinant
    in primary hyperoxaluria type 1.
  findings: []
- id: PMID:24235149
  title: A novel Pex14 protein-interacting site of human Pex5 is critical for matrix protein import into peroxisomes.
  findings: []
- id: PMID:24662292
  title: Distinct modes of ubiquitination of peroxisome-targeting signal type 1 (PTS1) receptor Pex5p regulate PTS1 protein
    import.
  findings: []
- id: PMID:25416956
  title: A proteome-scale map of the human interactome network.
  findings: []
- id: PMID: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.'
  findings: []
- id: PMID:26344566
  title: ATM functions at the peroxisome to induce pexophagy in response to ROS.
  findings: []
- id: PMID:28765278
  title: The peroxisomal matrix protein translocon is a large cavity-forming protein assembly into which PEX5 protein enters
    to release its cargo.
  findings: []
- id: PMID:29884772
  title: Peroxisomal monoubiquitinated PEX5 interacts with the AAA ATPases PEX1 and PEX6 and is unfolded during its dislocation
    into the cytosol.
  findings: []
- id: PMID:33389129
  title: A missense allele of PEX5 is responsible for the defective import of PTS2 cargo proteins into peroxisomes.
  findings: []
- id: PMID:8858165
  title: Pex13p is an SH3 protein of the peroxisome membrane and a docking factor for the predominantly cytoplasmic PTs1 receptor.
  findings: []
- id: PMID:9653144
  title: Identification of a human PTS1 receptor docking protein directly required for peroxisomal protein import.
  findings: []
- id: PMID:9668159
  title: An isoform of pex5p, the human PTS1 receptor, is required for the import of PTS2 proteins into peroxisomes.
  findings: []
- id: PMID:9820813
  title: C-terminal tripeptide Ser-Asn-Leu (SNL) of human D-aspartate oxidase is a functional peroxisome-targeting signal.
  findings: []
- id: Reactome:R-HSA-8953917
  title: PEX2:PEX10:PEX12 binds PEX5S,L (in PEX5S:PEX13:PEX14) and Ub:UBE2D1,2,3
  findings: []
- id: Reactome:R-HSA-8953946
  title: PEX2:PEX10:PEX12 monoubiquitinates PEX5S,L at cysteine-11
  findings: []
- id: Reactome:R-HSA-9033235
  title: Cargo of PEX5S,L translocates from the cytosol to the peroxisomal matrix
  findings: []
- id: Reactome:R-HSA-9033236
  title: PEX5S,L:Cargo binds PEX13:PEX14:PEX2:PEX10:PEX12 (Docking and Translocation Module)
  findings: []
- id: Reactome:R-HSA-9033485
  title: PEX2:PEX10:PEX12 monoubiquitinates PEX5L at cysteine-11
  findings: []
- id: Reactome:R-HSA-9033491
  title: USP9X hydrolyzes Ub:PEX5L yielding PEX5L and Ubiquitin
  findings: []
- id: Reactome:R-HSA-9033499
  title: PEX1:PEX6:PEX26:ZFAND6 dissociates Ub:PEX5L and PEX7 from PEX14:PEX13:PEX2:PEX10:PEX12 and translocates PEX5L and
    PEX7 from the peroxisomal membrane to the cytosol
  findings: []
- id: Reactome:R-HSA-9033509
  title: USP9X binds Ub:PEX5L
  findings: []
- id: Reactome:R-HSA-9033514
  title: Cargo of PEX5L:PEX7 translocates from the cytosol to the peroxisomal matrix
  findings: []
- id: Reactome:R-HSA-9033516
  title: PEX2:PEX10:PEX12:Ub:PEX5L:PEX7:PEX13:PEX14 binds PEX1:PEX6:PEX26 and ZFAND6
  findings: []
- id: Reactome:R-HSA-9033527
  title: PEX2:PEX10:PEX12 binds PEX5L (in PEX5L:PEX7:PEX13:PEX14:PEX2:PEX10:PEX12) and Ub:UBE2D1,2,3
  findings: []
- id: Reactome:R-HSA-9033533
  title: PEX2:PEX10:PEX12:Ub:PEX5S,L:PEX13:PEX14 binds PEX1:PEX6:PEX26 and ZFAND6
  findings: []
- id: Reactome:R-HSA-9664850
  title: ATM binds PEX5
  findings: []
- id: Reactome:R-HSA-9664855
  title: MAP1LC3B binds ATM dimer:Ub-p-PEX5:SQSTM1
  findings: []
- id: Reactome:R-HSA-9664862
  title: ATM dimer:PEX5 phosphorylates PEX5
  findings: []
- id: Reactome:R-HSA-9664879
  title: ATM:PEX5 binds ATM
  findings: []
- id: Reactome:R-HSA-9664880
  title: MAP1LC3B binds ATM dimer:Ub-p-PEX5:SQSTM1:NBR1
  findings: []
- id: Reactome:R-HSA-9664881
  title: NBR1 binds ATM:Ub-p-PEX5:SQSTM1
  findings: []
- id: Reactome:R-HSA-9664883
  title: ATM:PEX5 translocates from cytosol to peroxisomal membrane
  findings: []
- id: Reactome:R-HSA-9664888
  title: ATM dimer:p-PEX5 ubiquitinates to form ATM dimer:Ub-p-PEX5
  findings: []
- id: Reactome:R-HSA-9664892
  title: SQSTM1 binds ATM dimer:Ub-p-PEX5
  findings: []
- id: Reactome:R-HSA-9674127
  title: USP30 deubiquitinates ATM dimer:Ub-p-PEX5
  findings: []
- id: Reactome:R-HSA-9674131
  title: USP30 binds ATM dimer:Ub-p-PEX5
  findings: []

PEX5

Gene Description

Existing Annotations Review

References

Deep Research

Falcon

Research Report: Human PEX5 (UniProt P50542) — Functional Annotation and Current Understanding

0. Target verification (critical identity check)

1. Key concepts and definitions (current understanding)

1.1 Peroxisomal targeting signals and receptors

1.2 PEX5 as a cycling receptor: “importomer” model and ATP usage

1.3 Domain architecture and motifs (definition-level)

2. Mechanism of action: molecular function, pathway placement, localization

2.1 Cargo recognition and delivery

2.2 Docking/translocation at the peroxisomal membrane

2.3 Recycling (receptor export module) and ubiquitin switch

3. Recent developments (prioritizing 2023–2024)

3.1 2024: Why Cys11 is used—reversible noncanonical cysteine ubiquitination

3.2 2024: Import mechanism frameworks and “mystery-solving” synthesis (expert analysis)

3.3 2023: Quantitative, motif-resolved PEX5–PEX14 interaction landscape

4. Current applications and real-world implementations

4.1 Clinical genetics and diagnostic sequencing for peroxisome biogenesis disorders

4.2 Peroxisome quality control and pexophagy as translational context

5. Expert opinions and authoritative analysis (interpretive synthesis)

5.1 Mechanistic “state of the field” (2024 reviews)

5.2 Why the 2024 cysteine-ubiquitination work is influential

6. Relevant statistics and quantitative data (recent studies emphasized)

6.1 Quantitative interaction strengths

6.2 Physical parameters of the selective phase model

6.3 Cell/organellar turnover metric relevant to pathway perturbation

6.4 Recent clinical case-series statistic for PEX5

7. Human disease relevance (PEX5-specific)

7.1 Example pathogenic PEX5 variant and phenotype

7.2 Mechanistic link between molecular defect and phenotype

8. Summary table (functional annotation snapshot)

9. Key sources (with URLs and publication dates)

Citations

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