Existing Annotations Review

GO Term	Evidence	Action	Reason
GO:0005053 peroxisome matrix targeting signal-2 binding	IBA GO_REF:0000033	ACCEPT	Summary: IBA annotation for PTS2 binding. This is the defining molecular function of PEX7 across eukaryotes -- it is the PTS2 receptor. Multiple experimental studies in human confirm direct binding of PEX7 to PTS2 signals via its WD40 groove (PMID:9090381, PMID:11931631, PMID:22057399, PMID:25538232). The IBA annotation is well-supported by phylogenetic inference and experimental data. Reason: PTS2 binding is the core, defining molecular function of PEX7. This is supported by extensive experimental evidence from multiple groups. Supporting Evidence: PMID:9090381 PEX7, a candidate gene for RCDP identified in yeast, encodes the receptor for peroxisomal matrix proteins with the type-2 peroxisome targeting signal (PTS2). PMID:11931631 Specific binding of human Pex7p to PTS2 could be demonstrated only when Pex7p was formed in vitro by a coupled transcription/translation system or synthesized in vivo in Chinese hamster ovary K1 cells PMID:22057399 Three-dimensional structural modeling of the PTS2 receptor PEX7 reveals a groove with an evolutionarily conserved charge distribution complementary to PTS2 signals.
GO:0016558 protein import into peroxisome matrix	IBA GO_REF:0000033	ACCEPT	Summary: IBA annotation for the biological process of peroxisomal matrix protein import. PEX7 is an essential component of the PTS2-dependent import pathway, acting as the cargo receptor. Loss of PEX7 leads to failure of PTS2 protein import (PMID:9090381, PMID:9090383, PMID:9090382). Reason: Protein import into peroxisome matrix is the core biological process in which PEX7 functions. This is the central role of PEX7 as the PTS2 receptor. Supporting Evidence: PMID:9090381 expression of either corrects the PTS2-import defect characteristic of RCDP cells PMID:9090383 expression of human PEX7 in RCDP cells rescues PTS2 targeting
GO:0005829 cytosol	IBA GO_REF:0000033	ACCEPT	Summary: IBA annotation for cytosolic localization. PEX7 is a cycling receptor that shuttles between the cytosol and the peroxisomal matrix. Multiple studies confirm its cytosolic localization (PMID:11931631, PMID:25538232). Reason: Cytosol is a well-established localization for PEX7 as a soluble receptor that binds cargo in the cytosol before transport to peroxisomes. Supporting Evidence: PMID:11931631 Pex7p-GFP was located both in the lumen of peroxisomes and in the cytosol. PMID:25538232 PEX7 variants harboring a mutation in the cargo-binding groove are solely cytosolic.
GO:0005782 peroxisomal matrix	IBA GO_REF:0000033	ACCEPT	Summary: IBA annotation for peroxisomal matrix localization. PEX7 translocates into the peroxisomal matrix as part of the import cycle, together with PTS2-cargo and PEX5L (PMID:11931631, PMID:25538232). Reason: Peroxisomal matrix localization is well established for PEX7 as a cycling receptor. It enters the matrix with cargo and is then recycled back to the cytosol. Supporting Evidence: PMID:11931631 Pex7p-GFP was located both in the lumen of peroxisomes and in the cytosol.
GO:0005053 peroxisome matrix targeting signal-2 binding	IEA GO_REF:0000002	ACCEPT	Summary: IEA annotation from InterPro mapping. PEX7 contains WD40 domains (InterPro IPR044536, PEX7 family) that are correctly mapped to PTS2 binding. This is consistent with all experimental evidence. Reason: The InterPro-based mapping is correct. PEX7 is indeed the PTS2 receptor. This IEA annotation is concordant with the IBA and IDA annotations for the same term.
GO:0005782 peroxisomal matrix	IEA GO_REF:0000044	ACCEPT	Summary: IEA annotation from UniProt subcellular location mapping. UniProt records PEX7 as localized to the peroxisome matrix, consistent with experimental data. Reason: Correct mapping from UniProt subcellular location. Concordant with IBA and IDA evidence.
GO:0005829 cytosol	IEA GO_REF:0000120	ACCEPT	Summary: IEA annotation from combined automated methods. Cytosol localization is well established experimentally for PEX7. Reason: Correct automated annotation. Concordant with IBA and IDA evidence for cytosolic localization.
GO:0015031 protein transport	IEA GO_REF:0000043	ACCEPT	Summary: IEA annotation from UniProt keyword mapping to the broad term "protein transport." PEX7 is involved in transport of proteins into peroxisomes. This is a broad parent term of the more specific "protein import into peroxisome matrix" (GO:0016558). Reason: While this is a broad term, it is not incorrect. The more specific term GO:0016558 is already annotated via IBA and IDA. It is acceptable for an IEA to be broader than what is captured by IBA or literature.
GO:0016558 protein import into peroxisome matrix	IEA GO_REF:0000120	ACCEPT	Summary: IEA annotation from combined automated methods for peroxisomal matrix protein import. This is the core biological process of PEX7. Reason: Correct automated annotation, concordant with IBA and IDA evidence.
GO:0005515 protein binding	IPI PMID:28514442 Architecture of the human interactome defines protein commun...	REMOVE	Summary: IPI protein binding annotation from a large-scale interactome study (BioPlex). This is a high-throughput study that detected interactions with PEX7 but the generic "protein binding" term is uninformative. Reason: "Protein binding" is an uninformative term per curation guidelines. High-throughput interactome studies detect many interactions, but for a well-characterized protein like PEX7, the specific binding functions (PTS2 binding, PEX5L interaction) are already captured by more informative terms.
GO:0005515 protein binding	IPI PMID:32814053 Interactome Mapping Provides a Network of Neurodegenerative ...	REMOVE	Summary: IPI protein binding from a neurodegenerative disease interactome mapping study. This is a high-throughput study and the generic protein binding term is uninformative for PEX7. Reason: "Protein binding" is uninformative. PEX7's specific binding activities are captured by GO:0005053 (PTS2 binding) and other more specific terms.
GO:0005515 protein binding	IPI PMID:33961781 Dual proteome-scale networks reveal cell-specific remodeling...	REMOVE	Summary: IPI protein binding from the BioPlex 3.0 dual proteome-scale interactome study. High-throughput detection of protein interactions with PEX7. The generic term is uninformative. Reason: "Protein binding" is uninformative per curation guidelines. PEX7's specific binding functions are already well-annotated.
GO:0005515 protein binding	IPI PMID:40739340 PEX39 facilitates the peroxisomal import of PTS2-containing ...	REMOVE	Summary: IPI protein binding from a recent study identifying PEX39 as a facilitator of PTS2 import. This study identified PEX7 as interacting with PEX39 in the context of PTS2-dependent protein import. While the specific interaction is biologically meaningful, the generic "protein binding" term is uninformative. Reason: "Protein binding" is uninformative. The PEX7-PEX39 interaction is biologically interesting but should be annotated with a more specific term if warranted.
GO:0005053 peroxisome matrix targeting signal-2 binding	IDA PMID:22057399 Structural requirements for interaction of peroxisomal targe...	ACCEPT	Summary: IDA annotation for PTS2 binding from Kunze et al. (2011). This study used mammalian two-hybrid assays to demonstrate the direct interaction between PEX7 and PTS2-carrying cargo proteins, and identified the structural basis: a conserved groove on PEX7 with charge complementarity to the PTS2 amphipathic helix. Charge-inverting mutations E113R and E200R in PEX7 abolished PTS2 binding. Reason: Strong direct experimental evidence for PTS2 binding by PEX7, with structural and mutational validation. Supporting Evidence: PMID:22057399 Three-dimensional structural modeling of the PTS2 receptor PEX7 reveals a groove with an evolutionarily conserved charge distribution complementary to PTS2 signals. Mammalian two-hybrid assays and cross-complementation of a mutation in PTS2 by a compensatory mutation in PEX7 confirm the interaction site.
GO:0005053 peroxisome matrix targeting signal-2 binding	IDA PMID:25538232 Mechanistic insights into PTS2-mediated peroxisomal protein ...	ACCEPT	Summary: IDA annotation for PTS2 binding from Kunze et al. (2015). This study demonstrated that PEX7-PTS2 interaction is drastically stabilized (about 20-fold) by the co-receptor PEX5L, forming a trimeric complex. Mutations in the PTS2-binding groove (E113R, E200R) abolished cargo binding, while E287R affected PEX5L interaction. Reason: Direct experimental evidence for PTS2 binding, with detailed mechanistic insights into the trimeric complex formation. Supporting Evidence: PMID:25538232 the interaction strength between cargo and PEX7 is drastically increased in the presence of the co-receptor PEX5L PMID:25538232 cargo binding is a prerequisite for the interaction between PEX7 and PEX5L
GO:0005515 protein binding	IPI PMID:11546814 Domain mapping of human PEX5 reveals functional and structur...	MODIFY	Summary: IPI protein binding from Dodt et al. (2001). This study mapped the regions of PEX5L involved in PEX7 interaction (amino acids 191-222 of PEX5L are sufficient for PEX7 interaction). The PEX5L-PEX7 interaction is biologically critical for PTS2-dependent import. However, "protein binding" is an uninformative term. Reason: The underlying biology is the PEX7-PEX5L co-receptor interaction, which is essential for PTS2 import. However, "protein binding" is too general. A more informative term should capture the specific peroxin-peroxin interaction. Proposed replacements: peroxisome matrix targeting signal-2 binding Supporting Evidence: PMID:11546814 PEX5L physically interacts with PEX7, the import receptor for PTS2-containing proteins. In this report we map the regions of human PEX5L involved in PTS2 protein import, PEX7 interaction
GO:0005515 protein binding	IPI PMID:25538232 Mechanistic insights into PTS2-mediated peroxisomal protein ...	REMOVE	Summary: IPI protein binding from Kunze et al. (2015). This study demonstrated PEX7 interactions with PEX5L and cargo proteins, forming a trimeric complex. The generic "protein binding" is uninformative for this well-characterized functional interaction. Reason: "Protein binding" is uninformative. The specific interactions (PTS2 binding and PEX5L co-receptor interaction) are already captured by GO:0005053 annotations from this same paper.
GO:0005782 peroxisomal matrix	IDA PMID:11546814 Domain mapping of human PEX5 reveals functional and structur...	ACCEPT	Summary: IDA annotation for peroxisomal matrix localization from Dodt et al. (2001). The study showed PEX7 localization at peroxisomes via PEX5L-mediated docking and translocation. Reason: Experimental evidence supports PEX7 translocation into the peroxisomal matrix as part of the import cycle. Supporting Evidence: PMID:11546814 amino acids 1-214 are sufficient for targeting to peroxisomes
GO:0005782 peroxisomal matrix	IDA PMID:25538232 Mechanistic insights into PTS2-mediated peroxisomal protein ...	ACCEPT	Summary: IDA annotation for peroxisomal matrix localization from Kunze et al. (2015). This study showed that peroxisomal targeting of PEX7 depends on cargo binding and can be stimulated by overexpression of cargo protein. Reason: Direct experimental evidence showing cargo-dependent peroxisomal targeting of PEX7. Supporting Evidence: PMID:25538232 the peroxisomal transfer of PEX7 depends on cargo binding and that ectopic overexpression of cargo protein stimulates this process
GO:0005829 cytosol	IDA PMID:25538232 Mechanistic insights into PTS2-mediated peroxisomal protein ...	ACCEPT	Summary: IDA annotation for cytosol localization from Kunze et al. (2015). Cytosolic PEX7 was directly observed, especially for cargo-binding mutants that remain exclusively cytosolic. Reason: Direct experimental evidence. PEX7 mutants that cannot bind cargo (E113R, E200R) are exclusively cytosolic, confirming cytosol as a genuine localization for PEX7. Supporting Evidence: PMID:25538232 PEX7 variants harboring a mutation in the cargo-binding groove are solely cytosolic
GO:0016558 protein import into peroxisome matrix	IDA PMID:11546814 Domain mapping of human PEX5 reveals functional and structur...	ACCEPT	Summary: IDA annotation for peroxisomal matrix protein import from Dodt et al. (2001). This study demonstrated the essential role of PEX5L in PTS2 protein import and mapped the PEX7-interacting region of PEX5L. Reason: Direct experimental evidence that PEX7, in concert with PEX5L, mediates PTS2-dependent protein import into the peroxisomal matrix. Supporting Evidence: PMID:11546814 amino acids 1-230 of PEX5L are required for PTS2 protein import
GO:0016558 protein import into peroxisome matrix	IDA PMID:22057399 Structural requirements for interaction of peroxisomal targe...	ACCEPT	Summary: IDA annotation for peroxisomal protein import from Kunze et al. (2011). This study demonstrated that PEX7 mutations (E113R) destroy the ability to complement PEX7 deficiency in RCDP1 fibroblasts, confirming PEX7's role in PTS2-dependent import. Reason: Complementation of RCDP1 fibroblasts and mutational analysis directly demonstrate PEX7's role in peroxisomal import. Supporting Evidence: PMID:22057399 the mutation E113R in myc-hPEX7 destroyed its ability to complement PEX7 deficiency in RCDP1 fibroblasts
GO:0016558 protein import into peroxisome matrix	IDA PMID:25538232 Mechanistic insights into PTS2-mediated peroxisomal protein ...	ACCEPT	Summary: IDA annotation for peroxisomal protein import from Kunze et al. (2015). This study provided detailed mechanistic insight into the sequential assembly of the PEX7-cargo-PEX5L trimeric complex required for import. Reason: Detailed mechanistic evidence for PEX7's role in peroxisomal protein import through the trimeric complex. Supporting Evidence: PMID:25538232 the sequential formation of a highly stable trimeric complex involving cargo protein, PEX7 and PEX5L stabilizes cargo binding and is a prerequisite for PTS2-mediated peroxisomal import
GO:0005515 protein binding	IPI PMID:30204880 A newly isolated Pex7-binding, atypical PTS2 protein P7BP2 i...	REMOVE	Summary: IPI protein binding from Niwa et al. (2018). This study identified VWA8 (P7BP2) as a novel PEX7-binding protein with an atypical PTS2. The interaction is between PEX7 and VWA8's PTS2, making this essentially a PTS2-binding interaction. Reason: "Protein binding" is uninformative. The PEX7-VWA8 interaction is mediated via PTS2 recognition, which is already captured by GO:0005053 annotations. The interaction demonstrates a new PTS2 cargo, not a new binding activity. Supporting Evidence: PMID:30204880 The binding to Pex7p and peroxisomal localization of P7BP2 depends on the cleavable PTS2 in the N-terminal region
GO:0005778 peroxisomal membrane	TAS Reactome:R-HSA-9033485	ACCEPT	Summary: TAS annotation for peroxisomal membrane from Reactome. This reaction describes PEX2:PEX10:PEX12 monoubiquitination of PEX5L at the peroxisomal membrane. PEX7 is transiently associated with the peroxisomal membrane during the import cycle when it docks at the PEX13-PEX14 complex as part of the PEX5L-PEX7-cargo trimeric complex. Reason: PEX7 transiently associates with the peroxisomal membrane during the import cycle as part of the docking and translocation process. While not a permanent membrane resident, this transient association is biologically meaningful.
GO:0005778 peroxisomal membrane	TAS Reactome:R-HSA-9033499	ACCEPT	Summary: TAS annotation for peroxisomal membrane from Reactome. This reaction describes PEX1:PEX6:PEX26 dissociating PEX5L and PEX7 from the peroxisomal membrane for recycling. Reason: PEX7 is present at the peroxisomal membrane during the recycling step of the import cycle, which is well established.
GO:0005778 peroxisomal membrane	TAS Reactome:R-HSA-9033514	ACCEPT	Summary: TAS annotation for peroxisomal membrane from Reactome. This reaction describes translocation of PEX5L:PEX7 cargo from cytosol to peroxisomal matrix, during which PEX7 passes through the membrane. Reason: PEX7 transits through the peroxisomal membrane during cargo translocation. Transient membrane association is biologically accurate.
GO:0005778 peroxisomal membrane	TAS Reactome:R-HSA-9033516	ACCEPT	Summary: TAS annotation for peroxisomal membrane from Reactome. Describes PEX2:PEX10:PEX12:Ub:PEX5L:PEX7:PEX13:PEX14 binding to PEX1:PEX6:PEX26 complex at the membrane. Reason: PEX7 is part of the membrane-associated complex during the import and recycling cycle.
GO:0005778 peroxisomal membrane	TAS Reactome:R-HSA-9033527	ACCEPT	Summary: TAS annotation for peroxisomal membrane from Reactome. Describes PEX2:PEX10:PEX12 binding PEX5L within the membrane-associated complex containing PEX7. Reason: Part of the well-established membrane-associated import machinery complex involving PEX7.
GO:0005829 cytosol	TAS Reactome:R-HSA-9033232	ACCEPT	Summary: TAS annotation for cytosol from Reactome. This reaction describes PEX7 binding cargo proteins containing PTS2 in the cytosol. Reason: PEX7 binds PTS2-cargo in the cytosol before transport to peroxisomes. This is the initial step of the import cycle.
GO:0005829 cytosol	TAS Reactome:R-HSA-9033499	ACCEPT	Summary: TAS annotation for cytosol from Reactome. Describes PEX7 recycling from peroxisomal membrane back to cytosol. Reason: PEX7 is recycled to the cytosol after cargo delivery. Well established.
GO:0005829 cytosol	TAS Reactome:R-HSA-9033514	ACCEPT	Summary: TAS annotation for cytosol from Reactome. Cargo translocation from cytosol to matrix involves PEX7 starting in the cytosol. Reason: PEX7 starts in the cytosol as part of the translocation process. Concordant with other evidence.
GO:0005829 cytosol	TAS Reactome:R-NUL-9033857	ACCEPT	Summary: TAS annotation for cytosol from Reactome (non-human species reaction). Describes Pex14 binding PEX5L:PEX7:Acaa1a in the cytosol (mouse reaction used to infer human). Reason: Cytosolic localization of PEX7 is well established and conserved.
GO:0005829 cytosol	TAS Reactome:R-NUL-9033896	ACCEPT	Summary: TAS annotation for cytosol from Reactome (non-human species reaction). Describes PEX5L binding PEX7:Acaa1a in cytosol (mouse reaction). Reason: Cytosolic localization of PEX7 is well established and conserved.
GO:0005053 peroxisome matrix targeting signal-2 binding	IDA PMID:9090383 Rhizomelic chondrodysplasia punctata is caused by deficiency...	ACCEPT	Summary: IDA annotation for PTS2 binding from Purdue et al. (1997). One of the original papers identifying human PEX7 as the PTS2 receptor. Showed that PEX7 expression in RCDP cells rescues PTS2 targeting and restores DHAP-AT activity. The authors concluded "these results imply that several peroxisomal proteins are targeted by PTS2 signals." Reason: Foundational paper demonstrating PEX7 is the human PTS2 receptor. Supporting Evidence: PMID:9090383 expression of human PEX7 in RCDP cells rescues PTS2 targeting and restores some activity of dihydroxyacetone phosphate acyltransferase (DHAP-AT)
GO:0005053 peroxisome matrix targeting signal-2 binding	IDA PMID:11931631 Functional studies on human Pex7p: subcellular localization ...	ACCEPT	Summary: IDA annotation for PTS2 binding from Ghys et al. (2002). This study demonstrated specific binding of human PEX7 to PTS2 using multiple approaches, and showed that only monomeric PEX7 binds PTS2. The interaction is reduced by cysteine alkylation and impaired by N-terminal truncation. Reason: Direct demonstration of PEX7-PTS2 binding with characterization of binding requirements. Supporting Evidence: PMID:11931631 Specific binding of human Pex7p to PTS2 could be demonstrated only when Pex7p was formed in vitro by a coupled transcription/translation system or synthesized in vivo in Chinese hamster ovary K1 cells PMID:11931631 only monomeric Pex7p binds to PTS2. The interaction is reduced upon cysteine alkylation and is impaired upon truncation of the N-terminus of Pex7p.
GO:0005782 peroxisomal matrix	IDA PMID:11931631 Functional studies on human Pex7p: subcellular localization ...	ACCEPT	Summary: IDA annotation for peroxisomal matrix localization from Ghys et al. (2002). GFP-tagged PEX7 was directly observed in the peroxisomal lumen. Reason: Direct visualization of PEX7-GFP in the peroxisomal lumen. Supporting Evidence: PMID:11931631 Pex7p-GFP was located both in the lumen of peroxisomes and in the cytosol.
GO:0005829 cytosol	IDA PMID:11931631 Functional studies on human Pex7p: subcellular localization ...	ACCEPT	Summary: IDA annotation for cytosol localization from Ghys et al. (2002). GFP-tagged PEX7 was observed in both peroxisomes and cytosol. Reason: Direct visualization of PEX7-GFP in the cytosol. Supporting Evidence: PMID:11931631 Pex7p-GFP was located both in the lumen of peroxisomes and in the cytosol.
GO:0019899 enzyme binding	IPI PMID:11931631 Functional studies on human Pex7p: subcellular localization ...	MODIFY	Summary: IPI annotation for enzyme binding from Ghys et al. (2002). This reflects PEX7 binding to PTS2-carrying enzymes (thiolase, PHYH, AGPS). However, this binding is specifically mediated through the PTS2 signal on these enzymes, making GO:0005053 (PTS2 binding) the more appropriate and informative term. Reason: "Enzyme binding" is technically not wrong since PEX7 does bind enzymes (thiolase, PHYH, AGPS), but it mischaracterizes the nature of the interaction. PEX7 binds these proteins specifically through their PTS2 signals, not through enzyme-specific features. The more informative and accurate term is GO:0005053 (PTS2 binding). Proposed replacements: peroxisome matrix targeting signal-2 binding Supporting Evidence: PMID:11931631 Pex7p is a WD40-containing protein involved in peroxisomal import of proteins containing an N-terminal peroxisome-targeting signal (PTS2)
GO:0042803 protein homodimerization activity	IDA PMID:11931631 Functional studies on human Pex7p: subcellular localization ...	MARK AS OVER ANNOTATED	Summary: IDA annotation for protein homodimerization from Ghys et al. (2002). This is problematic. The same paper explicitly states that "only monomeric Pex7p binds to PTS2," and that interaction of Pex7p with other peroxins "could not be demonstrated in bacterial or yeast two-hybrid screens, or in pull-down binding assays." While some homodimerization may have been detected, the paper emphasizes that the functionally active form is the monomer. This annotation likely represents an over-annotation of an observation that is not functionally relevant. Reason: While some PEX7 homodimerization may be detected, the same paper (PMID:11931631) states that only monomeric PEX7 binds PTS2, indicating that homodimerization is not functionally important for PEX7's known biological roles. This likely represents an over-annotation. Supporting Evidence: PMID:11931631 only monomeric Pex7p binds to PTS2
GO:0007031 peroxisome organization	IMP PMID:10022913 Identification and characterization of the human orthologue ...	MARK AS OVER ANNOTATED	Summary: IMP annotation for peroxisome organization from Will et al. (1999). This paper is primarily about HsPex14p, not PEX7. The annotation likely derives from the observation that PEX7 mutations (in RCDP patient cells) affect peroxisomal protein import and consequently peroxisome organization. However, PEX7 loss specifically disrupts PTS2-dependent protein import, not peroxisome organization broadly. Peroxisomes are still present and functional for PTS1-dependent import in RCDP cells. Reason: PEX7 mutations cause specific PTS2 import deficiency, not global peroxisome organization defects. RCDP cells still have peroxisomes with normal PTS1 import. "Peroxisome organization" is too broad and implies a more general role than what PEX7 performs. The core process is "protein import into peroxisome matrix" (GO:0016558). Supporting Evidence: PMID:9090382 RCDP cells from CG11 cannot import a PTS2 reporter protein PMID:9090383 the peroxisomal targeting and proteolytic removal of the amino-terminal type 2 peroxisomal targeting sequence (PTS2) of thiolase are defective, whereas the biogenesis of proteins targeted by carboxyterminal type 1 peroxisomal targeting sequences (PTS1) is unimpaired
GO:0005777 peroxisome	IDA PMID:9090382 Rhizomelic chondrodysplasia punctata is a peroxisomal protei...	ACCEPT	Summary: IDA annotation for peroxisome localization from Motley et al. (1997). This is one of the three simultaneous papers identifying human PEX7 as the PTS2 receptor. The broader term "peroxisome" (GO:0005777) is acceptable as a parent term, though more specific terms (peroxisomal matrix, peroxisomal membrane) are also annotated. Reason: Peroxisome localization is established. While more specific CC terms (peroxisomal matrix, peroxisomal membrane) exist, this broader term is acceptable as it was annotated from one of the foundational papers. Supporting Evidence: PMID:9090382 expression of PEX7 in RCDP fibroblasts from CG11 rescues the PTS2 protein import deficiency
GO:0008611 ether lipid biosynthetic process	IMP PMID:12522768 Identification of PEX7 as the second gene involved in Refsum...	KEEP AS NON CORE	Summary: IMP annotation for ether lipid biosynthesis from van den Brink et al. (2003). PEX7 mutations cause deficiency of plasmalogen synthesis due to failure to import AGPS (alkyldihydroxyacetonephosphate synthase), a PTS2-carrying enzyme involved in plasmalogen/ether lipid synthesis. The connection to ether lipid biosynthesis is indirect -- PEX7 imports the enzyme, not directly catalyzes the pathway. Reason: PEX7 is not directly involved in ether lipid biosynthesis. The effect on ether lipid synthesis is an indirect consequence of failing to import the PTS2-carrying enzyme AGPS into peroxisomes. This is a downstream phenotypic consequence, not a core function of PEX7. Supporting Evidence: PMID:12522768 Biochemical analyses of the patients with RD revealed defects not only in phytanic acid alpha-oxidation but also in plasmalogen synthesis and peroxisomal thiolase.
GO:0008611 ether lipid biosynthetic process	IMP PMID:9090383 Rhizomelic chondrodysplasia punctata is caused by deficiency...	KEEP AS NON CORE	Summary: IMP annotation for ether lipid biosynthesis from Purdue et al. (1997). PEX7 expression in RCDP cells restores DHAP-AT activity (involved in plasmalogen/ether lipid synthesis) by enabling import of AGPS. The ether lipid deficiency is a downstream consequence of PTS2 import failure. Reason: Ether lipid biosynthesis is a downstream consequence of PEX7's role in PTS2 import, not a direct function. PEX7 imports AGPS which is needed for ether lipid synthesis, but PEX7 does not directly participate in the biosynthetic pathway. Supporting Evidence: PMID:9090383 expression of human PEX7 in RCDP cells rescues PTS2 targeting and restores some activity of dihydroxyacetone phosphate acyltransferase (DHAP-AT), a peroxisomal enzyme of plasmalogen biosynthesis
GO:0005053 peroxisome matrix targeting signal-2 binding	IDA PMID:9090381 Human PEX7 encodes the peroxisomal PTS2 receptor and is resp...	ACCEPT	Summary: IDA annotation for PTS2 binding from Braverman et al. (1997). One of the original papers identifying human PEX7 as the PTS2 receptor. Demonstrated that PEX7 expression corrects the PTS2-import defect in RCDP cells, and identified RCDP-causing mutations in PEX7. Reason: Foundational experimental evidence establishing PEX7 as the human PTS2 receptor. Supporting Evidence: PMID:9090381 PEX7, a candidate gene for RCDP identified in yeast, encodes the receptor for peroxisomal matrix proteins with the type-2 peroxisome targeting signal (PTS2).
GO:0016558 protein import into peroxisome matrix	IMP PMID:12522768 Identification of PEX7 as the second gene involved in Refsum...	ACCEPT	Summary: IMP annotation for peroxisomal protein import from van den Brink et al. (2003). PEX7 mutations in Refsum disease patients cause defects in PTS2-dependent protein import (thiolase, PHYH, AGPS import failures). Reason: Mutations in PEX7 in human patients cause PTS2-dependent import deficiency, confirming PEX7's role in peroxisomal protein import. Supporting Evidence: PMID:12522768 mutations in the PEX7 gene may result in a broad clinical spectrum ranging from severe rhizomelic chondrodysplasia punctata to relatively mild RD
GO:0016558 protein import into peroxisome matrix	IDA PMID:9090381 Human PEX7 encodes the peroxisomal PTS2 receptor and is resp...	ACCEPT	Summary: IDA annotation for peroxisomal protein import from Braverman et al. (1997). Expression of PEX7 corrects the PTS2-import defect in RCDP cells, directly demonstrating PEX7's role in peroxisomal import. Reason: Direct experimental evidence: PEX7 expression corrects PTS2 import defect in RCDP cells. Supporting Evidence: PMID:9090381 expression of either corrects the PTS2-import defect characteristic of RCDP cells

References

GO_REF:0000002

Gene Ontology annotation through association of InterPro records with GO terms

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:0000120

Combined Automated Annotation using Multiple IEA Methods

PMID:10022913

Identification and characterization of the human orthologue of yeast Pex14p.

Characterized HsPex14p as a peroxisomal membrane protein that binds PEX5 (PTS1 receptor). Notably, interaction of HsPex14p with the PTS2-receptor (PEX7) was not observed, distinguishing the human system from yeast.

PMID:11546814

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

Mapped PEX5L regions for PTS2 import (aa 1-230), PEX7 interaction (aa 191-222), and peroxisomal targeting (aa 1-214). Identified a 21-amino acid motif shared with yeast Pex18p/Pex21p. Demonstrated PEX5L as the essential co-receptor for PEX7 in mammalian PTS2 import.

PMID:11931631

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

Demonstrated specific PEX7-PTS2 binding, showed only monomeric PEX7 binds PTS2, confirmed dual localization (cytosol and peroxisomal matrix) using GFP-tagged PEX7. PEX7-GFP restored PTS2 import in RCDP fibroblasts.

PMID:12522768

Identification of PEX7 as the second gene involved in Refsum disease.

Identified PEX7 mutations as a cause of Refsum disease (mild PBD), showing that PEX7 mutations produce a clinical spectrum from severe RCDP to mild Refsum disease. Biochemical defects include phytanic acid oxidation, plasmalogen synthesis, and thiolase import.

PMID:22057399

Structural requirements for interaction of peroxisomal targeting signal 2 and its receptor PEX7.

Identified the PTS2 as an amphipathic helix binding to a conserved groove on PEX7. Glu-113 and Glu-200 in PEX7 are critical for PTS2 binding. E113R abolished PEX7 function in complementation of RCDP cells. Identified KChIP4 as a novel peroxisomal protein.

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.

PEX5L increases PEX7-cargo interaction about 20-fold. Cargo binding is prerequisite for PEX7-PEX5L interaction. E287R mutation in PEX7 specifically disrupts PEX5L interaction while retaining some cargo binding. Sequential assembly of trimeric complex prevents futile PEX7 cycling.

PMID:28514442

Architecture of the human interactome defines protein communities and disease networks.

High-throughput interactome study (BioPlex). Detected protein interactions with PEX7 in an unbiased manner.

PMID:30204880

A newly isolated Pex7-binding, atypical PTS2 protein P7BP2 is a novel dynein-type AAA+ protein.

Identified VWA8 as a novel PEX7-binding protein with an atypical PTS2. VWA8 is transported to peroxisomes via PEX5L-PEX7 pathway. Demonstrates that PEX7 recognizes atypical PTS2 variants.

PMID:32814053

Interactome Mapping Provides a Network of Neurodegenerative Disease Proteins and Uncovers Widespread Protein Aggregation in Affected Brains.

High-throughput interactome study detecting protein interactions in the context of neurodegenerative disease networks.

PMID:33961781

Dual proteome-scale networks reveal cell-specific remodeling of the human interactome.

BioPlex 3.0 high-throughput interactome study detecting protein-protein interactions across cell types.

PMID:40739340

PEX39 facilitates the peroxisomal import of PTS2-containing proteins.

Identified PEX39 as a novel peroxin that facilitates PTS2-dependent protein import. PEX39 interacts with PEX7 and the PTS2 import machinery.

PMID:9090381

Human PEX7 encodes the peroxisomal PTS2 receptor and is responsible for rhizomelic chondrodysplasia punctata.

Foundational paper identifying human PEX7 as the PTS2 receptor. Expression corrects PTS2 import defect in RCDP cells. Identified RCDP-causing mutations (L292ter, A218V, G217R).

PMID:9090382

Rhizomelic chondrodysplasia punctata is a peroxisomal protein targeting disease caused by a non-functional PTS2 receptor.

Cloned human PEX7, demonstrated PTS2-specific import deficiency in RCDP (PTS1 import unaffected). Expression rescues PTS2 import in RCDP fibroblasts. Identified mutations in PEX7 in RCDP CG11 patients.

PMID:9090383

Rhizomelic chondrodysplasia punctata is caused by deficiency of human PEX7, a homologue of the yeast PTS2 receptor.

Identified human PEX7 as the yeast Pex7p orthologue. Expression in RCDP cells rescues PTS2 targeting and DHAP-AT activity. Multiple peroxisomal proteins use PTS2 signals recognized by PEX7.

Reactome:R-HSA-9033232

PEX7 binds cargo proteins containing PTS2

Reactome:R-HSA-9033485

PEX2:PEX10:PEX12 monoubiquitinates PEX5L at cysteine-11

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-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-NUL-9033857

Pex14 binds PEX5L (in PEX5L:PEX7:Acaa1a)

Reactome:R-NUL-9033896

PEX5L binds PEX7:Acaa1a

Deep Research

Falcon

(PEX7-deep-research-falcon.md)

Research Report: Human **PEX7** (UniProt **O00628**) — Functional Annotation (PTS2 Receptor/Peroxin-7) Falcon Edison Scientific Literature 32 citations 2026-03-05T00:35:32.439790

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 PEX7 (UniProt O00628) — Functional Annotation (PTS2 Receptor/Peroxin-7)

0) Target verification (gene/protein identity)

The evidence base used here is consistent with the UniProt-provided identity: human PEX7 encodes the peroxisomal targeting signal 2 (PTS2) receptor (peroxin-7), a WD40-repeat β-propeller protein required for the PTS2 peroxisomal matrix protein import pathway. Multiple sources explicitly define PEX7/Pex7 as the receptor for PTS2-containing matrix proteins, note its WD40 seven-bladed propeller architecture, and describe its requirement for the human co-receptor PEX5L. (rudowitz2023importandquality pages 2-3, ghosh2023dynamicsofthe pages 1-2, ghosh2024molecularcharacterizationof pages 19-22)

Topic	Summary Statement	Evidence	Source
Identity & Structure	Human PEX7 (UniProt O00628) is the cytosolic receptor for peroxisomal matrix proteins carrying a Type 2 targeting signal (PTS2). It belongs to the WD40 repeat family, forming a seven-bladed $\beta$-propeller structure essential for ligand binding.	(lipinski2025earlystagesof pages 16-19, ghosh2024molecularcharacterizationof pages 19-22, rudowitz2023importandquality pages 2-3)	Rudowitz et al., 2023; Lipiński, 2025; Ghosh, 2024
Targeting Signal	Recognizes the N-terminal PTS2 nonapeptide motif with the consensus `[R/K][L/I/V/Q]X2[L/I/V/H/Q][L/S/G/A/K]X[H/Q][L/A/F]`. Binding triggers conformational changes facilitating import.	(lipinski2025earlystagesof pages 16-19, rudowitz2023importandquality pages 2-3)	Rudowitz et al., 2023; Lipiński, 2025
Co-receptor Mechanism	PEX7 cannot drive import alone; in humans, it requires the long isoform of PEX5 (PEX5L) as a co-receptor. PEX5L contains a specific 37-residue epitope (approx. residues 191–222) that binds PEX7, forming a stable cargo-receptor complex.	(ghosh2024molecularcharacterizationof pages 19-22, rudowitz2023importandquality pages 2-3, ghosh2023dynamicsofthe pages 1-2, lipinski2025earlystagesofa pages 16-19)	Ghosh et al., 2023; Rudowitz et al., 2023; Ghosh, 2024
Docking & Translocation	The PEX7-PEX5L-cargo complex docks at the peroxisomal membrane via interactions with PEX13 and PEX14. PEX5L integration into the membrane is linked to the formation of a dynamic, gated translocation pore (diameter ~0.6 nm resting to ~9 nm active).	(rudowitz2023importandquality pages 2-3, ghosh2023dynamicsofthe pages 1-2, ghosh2023dynamicsofthe pages 5-7, ghosh2024molecularcharacterizationof pages 25-28)	Ghosh et al., 2023; Rudowitz et al., 2023; Ghosh, 2024
Key Cargos	Canonical cargos include AGPS (plasmalogen biosynthesis), PHYH (phytanic acid oxidation), and ACAA1 (fatty acid beta-oxidation). Pathogenic PEX7 variants cause deficiency in these enzymes.	(braverman2020rhizomelicchondrodysplasiapunctata pages 19-22, gerami2023antenatalultrasonographicdiagnosis pages 1-2, braverman2020rhizomelicchondrodysplasiapunctata pages 13-15)	Braverman et al., 2020; Gerami et al., 2023
Recent Novel Cargo (2024)	HMG-CoA Reductase (HMGCR): Under low sterol/statin conditions, a truncated soluble fragment of HMGCR is imported into peroxisomes via a PEX7/PTS2-dependent mechanism to support cholesterol synthesis.	(braverman2020rhizomelicchondrodysplasiapunctata pages 19-22, wang2024peroxisomallocalizationof pages 2-3, wang2024peroxisomallocalizationof pages 1-2)	Wang et al., 2024
Disease Association	Biallelic PEX7 mutations cause Rhizomelic Chondrodysplasia Punctata Type 1 (RCDP1). Classic features: rhizomelia, punctate calcifications, cataracts, severe intellectual disability, and early mortality.	(braverman2020rhizomelicchondrodysplasiapunctata pages 1-3, braverman2020rhizomelicchondrodysplasiapunctata pages 3-8, braverman2020rhizomelicchondrodysplasiapunctata pages 8-10)	Braverman et al., 2020; Gerami et al., 2023
Biochemical Hallmarks	RCDP1 is characterized by profound plasmalogen deficiency in erythrocytes (severity correlates with levels) and elevated plasma phytanic acid. VLCFA levels are typically normal.	(braverman2020rhizomelicchondrodysplasiapunctata pages 1-3, braverman2020rhizomelicchondrodysplasiapunctata pages 19-22, braverman2020rhizomelicchondrodysplasiapunctata pages 13-15)	Braverman et al., 2020
Quantitative Data	In differentiated THP-1 cells and primary macrophages, ~65-68% of truncated HMGCR localizes to peroxisomes under lipid depletion; this localization is abolished in PEX7-deficient RCDP1 fibroblasts.	(wang2024peroxisomallocalizationof pages 2-3, wang2024peroxisomallocalizationof media c7ce012e)	Wang et al., 2024

Table: This table summarizes the primary function, molecular mechanisms, cargo specificity, and disease relevance of human PEX7, integrating established knowledge with recent findings from 2023-2024 literature regarding its role in cholesterol metabolism.

1) Key concepts and definitions (current understanding)

1.1 Peroxisomal matrix protein import and targeting signals

Peroxisomal matrix proteins are synthesized in the cytosol and imported post-translationally, often in a folded state, using targeting signals and cycling receptors. (ghosh2023dynamicsofthe pages 1-2)

PTS1 vs PTS2
- PTS1: a targeting signal recognized by PEX5/PEX5L (the principal PTS1 receptor). (ghosh2023dynamicsofthe pages 1-2)
- PTS2: an N-terminal nonapeptide signal recognized by PEX7. A consensus motif for PTS2 has been described (e.g., [R/K][L/I/V/Q]X2[L/I/V/H/Q][L/S/G/A/K]X[H/Q][L/A/F]). (rudowitz2023importandquality pages 2-3)

1.2 What PEX7 does (primary molecular function)

Primary function: PEX7 is the cytosolic receptor that binds PTS2-containing peroxisomal matrix proteins, enabling their delivery to the peroxisome for import into the matrix. (rudowitz2023importandquality pages 2-3, ghosh2023dynamicsofthe pages 1-2)

PEX7 is not an enzyme; it is a cargo-recognition and trafficking factor (a “peroxin”) whose substrate specificity is defined by recognition of the PTS2 targeting motif on cargo proteins. (rudowitz2023importandquality pages 2-3)

1.3 Structural/biophysical concepts relevant to PEX7

PEX7 is described as a WD40-repeat protein forming a seven-bladed β-propeller, consistent with a scaffolding/ligand-binding role. (rudowitz2023importandquality pages 2-3)

1.4 Co-receptor requirement in humans: PEX5L

A key mechanistic point is that PEX7 cannot drive import alone and requires a co-receptor. In humans, the long isoform PEX5L is the PTS2 co-receptor, so PTS1 and PTS2 pathways converge downstream at PEX5/PEX5L-mediated steps. (rudowitz2023importandquality pages 2-3, ghosh2023dynamicsofthe pages 1-2)

2) Mechanism, pathway placement, and subcellular localization

2.1 Where PEX7 acts

PEX7 is a cytosolic receptor that binds PTS2 cargos in the cytosol and participates in their targeting to the peroxisomal membrane import machinery. (rudowitz2023importandquality pages 2-3, ghosh2023dynamicsofthe pages 1-2)

2.2 Core import cycle for PEX7-dependent cargo (current model)

A consolidated import cycle supported by recent review/primary literature is:
1. Cargo recognition in cytosol: PEX7 binds PTS2-bearing cargo, together with its co-receptor PEX5L in humans. (rudowitz2023importandquality pages 2-3, ghosh2023dynamicsofthe pages 1-2)
2. Docking at the peroxisomal membrane: receptor–cargo complexes dock via interactions with PEX13/PEX14 (docking complex). (ghosh2023dynamicsofthe pages 1-2, rudowitz2023importandquality pages 2-3)
3. Translocation through a dynamic pore: PEX5/PEX5L becomes part of an import complex; a transient, gated pore can form to allow translocation of folded proteins. (ghosh2023dynamicsofthe pages 1-2, ghosh2023dynamicsofthe pages 5-7)
4. Cargo release: cargo is released into the matrix (mechanistic details remain actively studied). (ghosh2023dynamicsofthe pages 1-2)
5. Receptor recycling: receptor components are ubiquitinated and extracted back to the cytosol by AAA ATPases (PEX1/PEX6/PEX26), enabling repeated rounds of import. (ghosh2023dynamicsofthe pages 1-2)

2.3 Experimental evidence for a receptor-associated pore (relevant to PEX7 pathway convergence)

A 2023 study reconstituted purified human PEX5L-containing complexes into planar lipid membranes and observed water-filled pores with dynamic conductance states and cargo/receptor-complex sensitivity, supporting a model in which receptor complexes can constitute a translocation pore. Because human PTS2 import requires PEX5L as co-receptor for PEX7, these data are relevant to the PEX7-dependent pathway downstream convergence and mechanistic understanding of import. (ghosh2023dynamicsofthe pages 1-2, ghosh2023dynamicsofthe pages 5-7)

3) Key cargos and biological processes supported by PEX7

3.1 Canonical PTS2 enzyme cargos (human disease-relevant)

A clinical genetics review on PEX7-RCDP states that PEX7 (PTS2 receptor) imports multiple PTS2-targeted enzymes, including:
- AGPS (alkylglycerone phosphate synthase; required for plasmalogen/ether lipid synthesis),
- PHYH (phytanoyl-CoA 2-hydroxylase; required for phytanic acid oxidation), and
- ACAA1 (peroxisomal 3-ketoacyl-CoA thiolase; peroxisomal fatty acid metabolism). (braverman2020rhizomelicchondrodysplasiapunctata pages 19-22)

These cargos connect PEX7 function to two hallmark peroxisomal metabolic outputs: ether lipid (plasmalogen) biosynthesis and α-oxidation of phytanic acid. (braverman2020rhizomelicchondrodysplasiapunctata pages 19-22)

4) Human disease relevance: PEX7 and RCDP1 (Rhizomelic Chondrodysplasia Punctata type 1)

4.1 Definition and clinical phenotype

PEX7-related rhizomelic chondrodysplasia punctata (RCDP1) is an autosomal recessive peroxisome biogenesis disorder caused by biallelic pathogenic variants in PEX7. (braverman2020rhizomelicchondrodysplasiapunctata pages 1-3, braverman2020rhizomelicchondrodysplasiapunctata pages 19-22)

Classic (severe) RCDP1 is characterized by rhizomelia (proximal limb shortening), chondrodysplasia punctata (epiphyseal stippling), vertebral coronal clefts, and cataracts often present at birth or early infancy, with profound growth and neurodevelopmental impairment and frequent seizures. (braverman2020rhizomelicchondrodysplasiapunctata pages 1-3, braverman2020rhizomelicchondrodysplasiapunctata pages 8-10)

4.2 Biochemical hallmarks and mechanistic interpretation

A key biochemical signature is marked deficiency of plasmalogens in red blood cells with severity correlation, and elevated plasma phytanic acid (especially after dietary exposure), while very-long-chain fatty acids (VLCFA) are typically normal, consistent with selective loss of specific PTS2 enzyme activities rather than global peroxisome absence. (braverman2020rhizomelicchondrodysplasiapunctata pages 1-3)

Mechanistically, disease is attributed to disrupted PTS2 import causing deficient activity of specific PTS2 enzymes (including AGPS and PHYH), while PTS1 import can remain intact. (braverman2020rhizomelicchondrodysplasiapunctata pages 19-22)

4.3 Prognosis and survival statistics

Cohort survival data summarized in the PEX7-RCDP review indicate severe outcomes in classic disease. One series reported survival of ~90% at 1 year, declining to ~55% by 5 years and ~20% by 12 years; another series reported 80% to age 5, 45% to age 12, and 35% to adulthood, with deaths commonly due to respiratory complications. (braverman2020rhizomelicchondrodysplasiapunctata pages 3-8)

4.4 Epidemiology and prevalence statistics

The same review describes RCDP1 as very rare (reported as <1:100,000, with an estimate of 0.5 per 100,000 births) and notes approximately ~190 living affected individuals in the U.S. (braverman2020rhizomelicchondrodysplasiapunctata pages 10-13)

4.5 Genotype–phenotype correlations and notable alleles

Genotype–phenotype correlations summarized include:
- p.Leu292Ter: commonly associated with classic (severe) disease when homozygous; described as a common founder allele. (braverman2020rhizomelicchondrodysplasiapunctata pages 10-13, braverman2020rhizomelicchondrodysplasiapunctata pages 22-23)
- p.His285Arg: described as a frequent hypomorphic allele associated with milder phenotypes and suggested as a Dutch founder variant. (braverman2020rhizomelicchondrodysplasiapunctata pages 10-13)

The review also emphasizes that “leaky” alleles (including some 5′UTR/intronic and frameshift contexts permitting reinitiation) can be associated with milder/nonclassic RCDP or adult Refsum disease-like phenotypes. (braverman2020rhizomelicchondrodysplasiapunctata pages 22-23)

4.6 Diagnostics and real-world implementation

Clinical and laboratory testing
- Diagnosis is established by suggestive clinical/radiographic features plus biallelic pathogenic variants in PEX7. (braverman2020rhizomelicchondrodysplasiapunctata pages 3-8)
- Molecular diagnostic yield: sequence analysis of coding and flanking intronic regions identified ~97% of pathogenic variants in a cohort of 133 individuals. (braverman2020rhizomelicchondrodysplasiapunctata pages 3-8)
- Biochemical testing includes RBC plasmalogen quantification (e.g., by GC-MS; LC-MS/MS approaches are also discussed as diagnostically useful). (braverman2020rhizomelicchondrodysplasiapunctata pages 1-3, braverman2020rhizomelicchondrodysplasiapunctata pages 3-8)

Prenatal diagnosis
A 2023 ultrasound case report highlights prenatal detection (rhizomelia + epiphyseal stippling) followed by invasive testing and PEX7 molecular confirmation; it also states that RCDP type 1 comprises >90% of reported RCDP cases. (gerami2023antenatalultrasonographicdiagnosis pages 1-2)

5) Recent developments and latest research (prioritizing 2023–2024)

5.1 2023: Updated mechanistic view of PTS2 import and pore dynamics

A 2023 review synthesizes updated understanding of PTS2 recognition by PEX7, its WD40 propeller structure, the requirement for a co-receptor (PEX5L in humans), and docking interactions with peroxisomal membrane components such as PEX13/PEX14. (rudowitz2023importandquality pages 2-3)
A 2023 primary study provides experimental evidence that purified PEX5L-containing complexes can form dynamic pores in reconstituted membranes, supporting a receptor-associated translocon model relevant to both PTS1 and PTS2 pathways (given PEX5L’s co-receptor role for PEX7). (ghosh2023dynamicsofthe pages 1-2, ghosh2023dynamicsofthe pages 5-7)

5.2 2024: Expansion of PEX7-dependent cargo space to cholesterol metabolism (HMGCR)

A 2024 study reports a new PEX7-dependent phenomenon: under sterol-depleted and statin-treated conditions, a truncated soluble catalytic domain of HMG-CoA reductase (HMGCR) shows dual localization to ER and peroxisomes, and peroxisomal localization depends on PEX7-mediated PTS2 import. Peroxisomal HMGCR localization was absent in fibroblasts from RCDP1 patients lacking functional PEX7, and a PTS2-like motif was shown functional in a reporter context. (wang2024peroxisomallocalizationof pages 1-2)

Quantitative data (Table 1): the study quantified peroxisomal HMGCR fractions in cell types under treatment; for example, differentiated THP-1 cells and primary macrophages showed high peroxisomal localization fractions (up to ~68% and 65%, respectively). (wang2024peroxisomallocalizationof media c7ce012e)

6) Current applications and real-world implementations

6.1 Clinical genetics and metabolic diagnostics

PEX7 is implemented clinically as a diagnostic gene in peroxisome biogenesis disorder workups, particularly for RCDP1, supported by established biochemical tests (RBC plasmalogens; phytanic acid) and confirmatory sequencing. (braverman2020rhizomelicchondrodysplasiapunctata pages 1-3, braverman2020rhizomelicchondrodysplasiapunctata pages 3-8)

6.2 Prenatal imaging + molecular confirmation

Prenatal ultrasound patterns (rhizomelia and stippled epiphyses) are used in practice to trigger confirmatory molecular testing (including PEX7) and counseling for autosomal recessive recurrence risk. (gerami2023antenatalultrasonographicdiagnosis pages 1-2)

6.3 Translational implications of the HMGCR finding

The 2024 evidence that HMGCR fragments can be PEX7/PTS2-imported under cholesterol depletion suggests peroxisomal import pathways may contribute to context-dependent redistribution of metabolic enzymes during sterol stress, with potential implications for understanding statin responses and peroxisome–ER metabolic coordination. This remains an emerging area rather than established clinical practice. (wang2024peroxisomallocalizationof pages 1-2, wang2024peroxisomallocalizationof media c7ce012e)

7) Expert opinions and authoritative synthesis

Two authoritative, mechanistically focused sources (a 2023 Journal of Cell Science review and a 2023 Biological Chemistry primary study) support a contemporary view that peroxisomal import can proceed through dynamic, receptor-associated translocation machinery and that PEX7-mediated PTS2 import requires PEX5L in humans, emphasizing convergence of PTS1/PTS2 systems at shared downstream steps. (rudowitz2023importandquality pages 2-3, ghosh2023dynamicsofthe pages 1-2)

On the clinical side, a comprehensive RCDP1 review synthesizes genotype–phenotype, prognosis, and biochemical hallmarks, emphasizing that PEX7 mutations specifically disrupt import of PTS2 enzymes (AGPS/PHYH/ACAA1) and that RBC plasmalogen levels are a key biomarker tied to clinical severity. (braverman2020rhizomelicchondrodysplasiapunctata pages 1-3, braverman2020rhizomelicchondrodysplasiapunctata pages 19-22)

8) Key statistics and data points (from cited studies)

Survival (classic PEX7-RCDP): ~90% at 1 year, ~55% at 5 years, ~20% at 12 years in one series; another series 80% to age 5, 45% to age 12, 35% to adulthood; many deaths due to respiratory complications. (braverman2020rhizomelicchondrodysplasiapunctata pages 3-8)
Molecular diagnostic yield: ~97% pathogenic variant detection by sequence analysis in a cohort of 133 individuals. (braverman2020rhizomelicchondrodysplasiapunctata pages 3-8)
Prevalence estimates: <1:100,000; ~0.5 per 100,000 births; ~190 living affected individuals in the U.S. (braverman2020rhizomelicchondrodysplasiapunctata pages 10-13)
HMGCR peroxisomal localization (2024): high peroxisomal fractions in specific treated cell types (e.g., up to ~68% in differentiated THP-1; ~65% in primary macrophages). (wang2024peroxisomallocalizationof media c7ce012e)

9) Source details (URLs and publication dates where available)

Rudowitz M, Erdmann R. Import and quality control of peroxisomal proteins. Journal of Cell Science (Aug 2023). https://doi.org/10.1242/jcs.260999 (rudowitz2023importandquality pages 2-3)
Ghosh M, Denkert N, Reuter M, et al. Dynamics of the translocation pore of the human peroxisomal protein import machinery. Biological Chemistry (Aug 2023). https://doi.org/10.1515/hsz-2022-0170 (ghosh2023dynamicsofthe pages 1-2)
Wang J, Kunze M, Villoria-González A, Weinhofer I, Berger J. Peroxisomal Localization of a Truncated HMG-CoA Reductase under Low Cholesterol Conditions. Biomolecules (Feb 2024). https://doi.org/10.3390/biom14020244 (wang2024peroxisomallocalizationof pages 1-2)
Gerami R, Barkhordari S. Antenatal ultrasonographic diagnosis of rhizomelic chondrodysplasia punctata. Journal of Ultrasound (Oct 2023). https://doi.org/10.1007/s40477-022-00737-5 (gerami2023antenatalultrasonographicdiagnosis pages 1-2)

10) Summary for functional annotation

Human PEX7 (O00628) is a WD40 β-propeller cytosolic receptor that recognizes N-terminal PTS2 signals on a restricted set of peroxisomal matrix proteins and, with the PEX5L co-receptor, docks at the PEX13/PEX14 import machinery to enable translocation into the peroxisome matrix and subsequent receptor recycling by ubiquitination/AAA ATPases. (rudowitz2023importandquality pages 2-3, ghosh2023dynamicsofthe pages 1-2)

Clinically, biallelic loss-of-function variants cause RCDP1, with characteristic skeletal, ocular, neurologic phenotype, plasmalogen deficiency, and poor survival in classic disease; severity correlates with plasmalogen levels and specific alleles. (braverman2020rhizomelicchondrodysplasiapunctata pages 1-3, braverman2020rhizomelicchondrodysplasiapunctata pages 3-8)

Recent research (2023–2024) advances mechanistic understanding of the dynamic import pore and broadens the landscape of potential PEX7-dependent peroxisomal cargo under metabolic stress (HMGCR fragment import under sterol depletion/statin exposure). (ghosh2023dynamicsofthe pages 1-2, wang2024peroxisomallocalizationof pages 1-2)

References

(rudowitz2023importandquality pages 2-3): Markus Rudowitz and Ralf Erdmann. Import and quality control of peroxisomal proteins. Journal of cell science, Aug 2023. URL: https://doi.org/10.1242/jcs.260999, doi:10.1242/jcs.260999. This article has 16 citations and is from a domain leading peer-reviewed journal.
(ghosh2023dynamicsofthe pages 1-2): Mausumi Ghosh, Niels Denkert, Maren Reuter, Jessica Klümper, Katharina Reglinski, Rebecca Peschel, Wolfgang Schliebs, Ralf Erdmann, and Michael Meinecke. Dynamics of the translocation pore of the human peroxisomal protein import machinery. Biological Chemistry, 404:169-178, Aug 2023. URL: https://doi.org/10.1515/hsz-2022-0170, doi:10.1515/hsz-2022-0170. This article has 10 citations and is from a peer-reviewed journal.
(ghosh2024molecularcharacterizationof pages 19-22): 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.
(lipinski2025earlystagesof pages 16-19): O Lipiński. Early stages of peroxisomal protein import. Unknown journal, 2025.
(lipinski2025earlystagesofa pages 16-19): O Lipiński. Early stages of peroxisomal protein import. Unknown journal, 2025.
(ghosh2023dynamicsofthe pages 5-7): Mausumi Ghosh, Niels Denkert, Maren Reuter, Jessica Klümper, Katharina Reglinski, Rebecca Peschel, Wolfgang Schliebs, Ralf Erdmann, and Michael Meinecke. Dynamics of the translocation pore of the human peroxisomal protein import machinery. Biological Chemistry, 404:169-178, Aug 2023. URL: https://doi.org/10.1515/hsz-2022-0170, doi:10.1515/hsz-2022-0170. This article has 10 citations and is from a peer-reviewed journal.
(ghosh2024molecularcharacterizationof pages 25-28): 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.
(braverman2020rhizomelicchondrodysplasiapunctata pages 19-22): NE Braverman, SJ Steinberg, and W Fallatah. Rhizomelic chondrodysplasia punctata type 1. Unknown journal, 2020.
(gerami2023antenatalultrasonographicdiagnosis pages 1-2): Reza Gerami and Shoresh Barkhordari. Antenatal ultrasonographic diagnosis of rhizomelic chondrodysplasia punctata. Journal of Ultrasound, 26:539-542, Oct 2023. URL: https://doi.org/10.1007/s40477-022-00737-5, doi:10.1007/s40477-022-00737-5. This article has 6 citations.
(braverman2020rhizomelicchondrodysplasiapunctata pages 13-15): NE Braverman, SJ Steinberg, and W Fallatah. Rhizomelic chondrodysplasia punctata type 1. Unknown journal, 2020.
(wang2024peroxisomallocalizationof pages 2-3): Jianqiu Wang, Markus Kunze, Andrea Villoria-González, Isabelle Weinhofer, and Johannes Berger. Peroxisomal localization of a truncated hmg-coa reductase under low cholesterol conditions. Feb 2024. URL: https://doi.org/10.3390/biom14020244, doi:10.3390/biom14020244. This article has 7 citations.
(wang2024peroxisomallocalizationof pages 1-2): Jianqiu Wang, Markus Kunze, Andrea Villoria-González, Isabelle Weinhofer, and Johannes Berger. Peroxisomal localization of a truncated hmg-coa reductase under low cholesterol conditions. Feb 2024. URL: https://doi.org/10.3390/biom14020244, doi:10.3390/biom14020244. This article has 7 citations.
(braverman2020rhizomelicchondrodysplasiapunctata pages 1-3): NE Braverman, SJ Steinberg, and W Fallatah. Rhizomelic chondrodysplasia punctata type 1. Unknown journal, 2020.
(braverman2020rhizomelicchondrodysplasiapunctata pages 3-8): NE Braverman, SJ Steinberg, and W Fallatah. Rhizomelic chondrodysplasia punctata type 1. Unknown journal, 2020.
(braverman2020rhizomelicchondrodysplasiapunctata pages 8-10): NE Braverman, SJ Steinberg, and W Fallatah. Rhizomelic chondrodysplasia punctata type 1. Unknown journal, 2020.
(wang2024peroxisomallocalizationof media c7ce012e): Jianqiu Wang, Markus Kunze, Andrea Villoria-González, Isabelle Weinhofer, and Johannes Berger. Peroxisomal localization of a truncated hmg-coa reductase under low cholesterol conditions. Feb 2024. URL: https://doi.org/10.3390/biom14020244, doi:10.3390/biom14020244. This article has 7 citations.
(braverman2020rhizomelicchondrodysplasiapunctata pages 10-13): NE Braverman, SJ Steinberg, and W Fallatah. Rhizomelic chondrodysplasia punctata type 1. Unknown journal, 2020.
(braverman2020rhizomelicchondrodysplasiapunctata pages 22-23): NE Braverman, SJ Steinberg, and W Fallatah. Rhizomelic chondrodysplasia punctata type 1. Unknown journal, 2020.

Citations

ghosh2023dynamicsofthe pages 1-2
rudowitz2023importandquality pages 2-3
braverman2020rhizomelicchondrodysplasiapunctata pages 19-22
braverman2020rhizomelicchondrodysplasiapunctata pages 1-3
braverman2020rhizomelicchondrodysplasiapunctata pages 3-8
braverman2020rhizomelicchondrodysplasiapunctata pages 10-13
braverman2020rhizomelicchondrodysplasiapunctata pages 22-23
gerami2023antenatalultrasonographicdiagnosis pages 1-2
wang2024peroxisomallocalizationof pages 1-2
ghosh2024molecularcharacterizationof pages 19-22
lipinski2025earlystagesof pages 16-19
lipinski2025earlystagesofa pages 16-19
ghosh2023dynamicsofthe pages 5-7
ghosh2024molecularcharacterizationof pages 25-28
braverman2020rhizomelicchondrodysplasiapunctata pages 13-15
wang2024peroxisomallocalizationof pages 2-3
braverman2020rhizomelicchondrodysplasiapunctata pages 8-10
R/K
L/I/V/Q
L/I/V/H/Q
L/S/G/A/K
H/Q
L/A/F
https://doi.org/10.1242/jcs.260999
https://doi.org/10.1515/hsz-2022-0170
https://doi.org/10.3390/biom14020244
https://doi.org/10.1007/s40477-022-00737-5
https://doi.org/10.1242/jcs.260999,
https://doi.org/10.1515/hsz-2022-0170,
https://doi.org/10.53846/goediss-10355,
https://doi.org/10.1007/s40477-022-00737-5,
https://doi.org/10.3390/biom14020244,

📄 View Raw YAML

id: O00628
gene_symbol: PEX7
product_type: PROTEIN
status: IN_PROGRESS
taxon:
  id: NCBITaxon:9606
  label: Homo sapiens
description: >-
  PEX7 (peroxin 7) encodes the peroxisomal targeting signal 2 (PTS2) receptor,
  a WD40 repeat-containing protein that forms a seven-bladed beta-propeller
  structure. PEX7 specifically recognizes the N-terminal PTS2 nonapeptide on a
  small subset of peroxisomal matrix proteins (thiolase/ACAA1,
  phytanoyl-CoA hydroxylase/PHYH, and alkyldihydroxyacetonephosphate
  synthase/AGPS in mammals). PEX7 binds PTS2-carrying cargo in the cytosol,
  then forms a trimeric complex with the co-receptor PEX5L (the long isoform
  of PEX5), which mediates docking at the peroxisomal membrane via the
  PEX13-PEX14 complex. The trimeric complex translocates cargo into the
  peroxisomal matrix, after which PEX7 and PEX5L are recycled to the cytosol.
  Mutations in PEX7 cause rhizomelic chondrodysplasia punctata type 1 (RCDP1)
  and mild variants resembling Refsum disease. The protein is deeply conserved
  from yeast (Pex7p) to human.
alternative_products:
- name: '1'
  id: O00628-1
- name: '2'
  id: O00628-2
  sequence_note: VSP_056393
existing_annotations:
# --- IBA annotations (phylogenetic) ---
- term:
    id: GO:0005053
    label: peroxisome matrix targeting signal-2 binding
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  review:
    summary: >-
      IBA annotation for PTS2 binding. This is the defining molecular function
      of PEX7 across eukaryotes -- it is the PTS2 receptor. Multiple
      experimental studies in human confirm direct binding of PEX7 to PTS2
      signals via its WD40 groove (PMID:9090381, PMID:11931631, PMID:22057399,
      PMID:25538232). The IBA annotation is well-supported by phylogenetic
      inference and experimental data.
    action: ACCEPT
    reason: >-
      PTS2 binding is the core, defining molecular function of PEX7. This is
      supported by extensive experimental evidence from multiple groups.
    supported_by:
      - reference_id: PMID:9090381
        supporting_text: "PEX7, a candidate gene for RCDP identified in yeast, encodes the receptor for peroxisomal matrix proteins with the type-2 peroxisome targeting signal (PTS2)."
      - reference_id: PMID:11931631
        supporting_text: "Specific binding of human Pex7p to PTS2 could be demonstrated only when Pex7p was formed in vitro by a coupled transcription/translation system or synthesized in vivo in Chinese hamster ovary K1 cells"
      - reference_id: PMID:22057399
        supporting_text: "Three-dimensional structural modeling of the PTS2 receptor PEX7 reveals a groove with an evolutionarily conserved charge distribution complementary to PTS2 signals."

- term:
    id: GO:0016558
    label: protein import into peroxisome matrix
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  review:
    summary: >-
      IBA annotation for the biological process of peroxisomal matrix protein
      import. PEX7 is an essential component of the PTS2-dependent import
      pathway, acting as the cargo receptor. Loss of PEX7 leads to failure of
      PTS2 protein import (PMID:9090381, PMID:9090383, PMID:9090382).
    action: ACCEPT
    reason: >-
      Protein import into peroxisome matrix is the core biological process in
      which PEX7 functions. This is the central role of PEX7 as the PTS2
      receptor.
    supported_by:
      - reference_id: PMID:9090381
        supporting_text: "expression of either corrects the PTS2-import defect characteristic of RCDP cells"
      - reference_id: PMID:9090383
        supporting_text: "expression of human PEX7 in RCDP cells rescues PTS2 targeting"

- term:
    id: GO:0005829
    label: cytosol
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  review:
    summary: >-
      IBA annotation for cytosolic localization. PEX7 is a cycling receptor
      that shuttles between the cytosol and the peroxisomal matrix. Multiple
      studies confirm its cytosolic localization (PMID:11931631, PMID:25538232).
    action: ACCEPT
    reason: >-
      Cytosol is a well-established localization for PEX7 as a soluble
      receptor that binds cargo in the cytosol before transport to peroxisomes.
    supported_by:
      - reference_id: PMID:11931631
        supporting_text: "Pex7p-GFP was located both in the lumen of peroxisomes and in the cytosol."
      - reference_id: PMID:25538232
        supporting_text: "PEX7 variants harboring a mutation in the cargo-binding groove are solely cytosolic."

- term:
    id: GO:0005782
    label: peroxisomal matrix
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  review:
    summary: >-
      IBA annotation for peroxisomal matrix localization. PEX7 translocates
      into the peroxisomal matrix as part of the import cycle, together with
      PTS2-cargo and PEX5L (PMID:11931631, PMID:25538232).
    action: ACCEPT
    reason: >-
      Peroxisomal matrix localization is well established for PEX7 as a
      cycling receptor. It enters the matrix with cargo and is then recycled
      back to the cytosol.
    supported_by:
      - reference_id: PMID:11931631
        supporting_text: "Pex7p-GFP was located both in the lumen of peroxisomes and in the cytosol."

# --- IEA annotations (electronic) ---
- term:
    id: GO:0005053
    label: peroxisome matrix targeting signal-2 binding
  evidence_type: IEA
  original_reference_id: GO_REF:0000002
  review:
    summary: >-
      IEA annotation from InterPro mapping. PEX7 contains WD40 domains
      (InterPro IPR044536, PEX7 family) that are correctly mapped to PTS2
      binding. This is consistent with all experimental evidence.
    action: ACCEPT
    reason: >-
      The InterPro-based mapping is correct. PEX7 is indeed the PTS2 receptor.
      This IEA annotation is concordant with the IBA and IDA annotations for
      the same term.

- term:
    id: GO:0005782
    label: peroxisomal matrix
  evidence_type: IEA
  original_reference_id: GO_REF:0000044
  review:
    summary: >-
      IEA annotation from UniProt subcellular location mapping. UniProt records
      PEX7 as localized to the peroxisome matrix, consistent with experimental
      data.
    action: ACCEPT
    reason: >-
      Correct mapping from UniProt subcellular location. Concordant with IBA
      and IDA evidence.

- term:
    id: GO:0005829
    label: cytosol
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  review:
    summary: >-
      IEA annotation from combined automated methods. Cytosol localization is
      well established experimentally for PEX7.
    action: ACCEPT
    reason: >-
      Correct automated annotation. Concordant with IBA and IDA evidence for
      cytosolic localization.

- term:
    id: GO:0015031
    label: protein transport
  evidence_type: IEA
  original_reference_id: GO_REF:0000043
  review:
    summary: >-
      IEA annotation from UniProt keyword mapping to the broad term
      "protein transport." PEX7 is involved in transport of proteins into
      peroxisomes. This is a broad parent term of the more specific
      "protein import into peroxisome matrix" (GO:0016558).
    action: ACCEPT
    reason: >-
      While this is a broad term, it is not incorrect. The more specific term
      GO:0016558 is already annotated via IBA and IDA. It is acceptable for an
      IEA to be broader than what is captured by IBA or literature.

- term:
    id: GO:0016558
    label: protein import into peroxisome matrix
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  review:
    summary: >-
      IEA annotation from combined automated methods for peroxisomal matrix
      protein import. This is the core biological process of PEX7.
    action: ACCEPT
    reason: >-
      Correct automated annotation, concordant with IBA and IDA evidence.

# --- IPI protein binding annotations ---
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:28514442
  review:
    summary: >-
      IPI protein binding annotation from a large-scale interactome study
      (BioPlex). This is a high-throughput study that detected interactions
      with PEX7 but the generic "protein binding" term is uninformative.
    action: REMOVE
    reason: >-
      "Protein binding" is an uninformative term per curation guidelines.
      High-throughput interactome studies detect many interactions, but for a
      well-characterized protein like PEX7, the specific binding functions
      (PTS2 binding, PEX5L interaction) are already captured by more
      informative terms.

- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:32814053
  review:
    summary: >-
      IPI protein binding from a neurodegenerative disease interactome mapping
      study. This is a high-throughput study and the generic protein binding
      term is uninformative for PEX7.
    action: REMOVE
    reason: >-
      "Protein binding" is uninformative. PEX7's specific binding activities
      are captured by GO:0005053 (PTS2 binding) and other more specific terms.

- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:33961781
  review:
    summary: >-
      IPI protein binding from the BioPlex 3.0 dual proteome-scale interactome
      study. High-throughput detection of protein interactions with PEX7. The
      generic term is uninformative.
    action: REMOVE
    reason: >-
      "Protein binding" is uninformative per curation guidelines. PEX7's
      specific binding functions are already well-annotated.

- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:40739340
  review:
    summary: >-
      IPI protein binding from a recent study identifying PEX39 as a
      facilitator of PTS2 import. This study identified PEX7 as interacting
      with PEX39 in the context of PTS2-dependent protein import. While the
      specific interaction is biologically meaningful, the generic "protein
      binding" term is uninformative.
    action: REMOVE
    reason: >-
      "Protein binding" is uninformative. The PEX7-PEX39 interaction is
      biologically interesting but should be annotated with a more specific
      term if warranted.

- term:
    id: GO:0005053
    label: peroxisome matrix targeting signal-2 binding
  evidence_type: IDA
  original_reference_id: PMID:22057399
  review:
    summary: >-
      IDA annotation for PTS2 binding from Kunze et al. (2011). This study
      used mammalian two-hybrid assays to demonstrate the direct interaction
      between PEX7 and PTS2-carrying cargo proteins, and identified the
      structural basis: a conserved groove on PEX7 with charge complementarity
      to the PTS2 amphipathic helix. Charge-inverting mutations E113R and
      E200R in PEX7 abolished PTS2 binding.
    action: ACCEPT
    reason: >-
      Strong direct experimental evidence for PTS2 binding by PEX7, with
      structural and mutational validation.
    supported_by:
      - reference_id: PMID:22057399
        supporting_text: "Three-dimensional structural modeling of the PTS2 receptor PEX7 reveals a groove with an evolutionarily conserved charge distribution complementary to PTS2 signals. Mammalian two-hybrid assays and cross-complementation of a mutation in PTS2 by a compensatory mutation in PEX7 confirm the interaction site."

- term:
    id: GO:0005053
    label: peroxisome matrix targeting signal-2 binding
  evidence_type: IDA
  original_reference_id: PMID:25538232
  review:
    summary: >-
      IDA annotation for PTS2 binding from Kunze et al. (2015). This study
      demonstrated that PEX7-PTS2 interaction is drastically stabilized
      (about 20-fold) by the co-receptor PEX5L, forming a trimeric complex.
      Mutations in the PTS2-binding groove (E113R, E200R) abolished cargo
      binding, while E287R affected PEX5L interaction.
    action: ACCEPT
    reason: >-
      Direct experimental evidence for PTS2 binding, with detailed
      mechanistic insights into the trimeric complex formation.
    supported_by:
      - reference_id: PMID:25538232
        supporting_text: "the interaction strength between cargo and PEX7 is drastically increased in the presence of the co-receptor PEX5L"
      - reference_id: PMID:25538232
        supporting_text: "cargo binding is a prerequisite for the interaction between PEX7 and PEX5L"

- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:11546814
  review:
    summary: >-
      IPI protein binding from Dodt et al. (2001). This study mapped the
      regions of PEX5L involved in PEX7 interaction (amino acids 191-222
      of PEX5L are sufficient for PEX7 interaction). The PEX5L-PEX7
      interaction is biologically critical for PTS2-dependent import.
      However, "protein binding" is an uninformative term.
    action: MODIFY
    reason: >-
      The underlying biology is the PEX7-PEX5L co-receptor interaction, which
      is essential for PTS2 import. However, "protein binding" is too
      general. A more informative term should capture the specific
      peroxin-peroxin interaction.
    proposed_replacement_terms:
      - id: GO:0005053
        label: peroxisome matrix targeting signal-2 binding
    supported_by:
      - reference_id: PMID:11546814
        supporting_text: "PEX5L physically interacts with PEX7, the import receptor for PTS2-containing proteins. In this report we map the regions of human PEX5L involved in PTS2 protein import, PEX7 interaction"
    additional_reference_ids:
      - PMID:25538232

- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:25538232
  review:
    summary: >-
      IPI protein binding from Kunze et al. (2015). This study demonstrated
      PEX7 interactions with PEX5L and cargo proteins, forming a trimeric
      complex. The generic "protein binding" is uninformative for this
      well-characterized functional interaction.
    action: REMOVE
    reason: >-
      "Protein binding" is uninformative. The specific interactions (PTS2
      binding and PEX5L co-receptor interaction) are already captured by
      GO:0005053 annotations from this same paper.

# --- IDA subcellular location annotations ---
- term:
    id: GO:0005782
    label: peroxisomal matrix
  evidence_type: IDA
  original_reference_id: PMID:11546814
  review:
    summary: >-
      IDA annotation for peroxisomal matrix localization from Dodt et al.
      (2001). The study showed PEX7 localization at peroxisomes via
      PEX5L-mediated docking and translocation.
    action: ACCEPT
    reason: >-
      Experimental evidence supports PEX7 translocation into the peroxisomal
      matrix as part of the import cycle.
    supported_by:
      - reference_id: PMID:11546814
        supporting_text: "amino acids 1-214 are sufficient for targeting to peroxisomes"

- term:
    id: GO:0005782
    label: peroxisomal matrix
  evidence_type: IDA
  original_reference_id: PMID:25538232
  review:
    summary: >-
      IDA annotation for peroxisomal matrix localization from Kunze et al.
      (2015). This study showed that peroxisomal targeting of PEX7 depends
      on cargo binding and can be stimulated by overexpression of cargo
      protein.
    action: ACCEPT
    reason: >-
      Direct experimental evidence showing cargo-dependent peroxisomal
      targeting of PEX7.
    supported_by:
      - reference_id: PMID:25538232
        supporting_text: "the peroxisomal transfer of PEX7 depends on cargo binding and that ectopic overexpression of cargo protein stimulates this process"

- term:
    id: GO:0005829
    label: cytosol
  evidence_type: IDA
  original_reference_id: PMID:25538232
  review:
    summary: >-
      IDA annotation for cytosol localization from Kunze et al. (2015).
      Cytosolic PEX7 was directly observed, especially for cargo-binding
      mutants that remain exclusively cytosolic.
    action: ACCEPT
    reason: >-
      Direct experimental evidence. PEX7 mutants that cannot bind cargo
      (E113R, E200R) are exclusively cytosolic, confirming cytosol as a
      genuine localization for PEX7.
    supported_by:
      - reference_id: PMID:25538232
        supporting_text: "PEX7 variants harboring a mutation in the cargo-binding groove are solely cytosolic"

# --- IDA annotations for biological process ---
- term:
    id: GO:0016558
    label: protein import into peroxisome matrix
  evidence_type: IDA
  original_reference_id: PMID:11546814
  review:
    summary: >-
      IDA annotation for peroxisomal matrix protein import from Dodt et al.
      (2001). This study demonstrated the essential role of PEX5L in
      PTS2 protein import and mapped the PEX7-interacting region of PEX5L.
    action: ACCEPT
    reason: >-
      Direct experimental evidence that PEX7, in concert with PEX5L,
      mediates PTS2-dependent protein import into the peroxisomal matrix.
    supported_by:
      - reference_id: PMID:11546814
        supporting_text: "amino acids 1-230 of PEX5L are required for PTS2 protein import"

- term:
    id: GO:0016558
    label: protein import into peroxisome matrix
  evidence_type: IDA
  original_reference_id: PMID:22057399
  review:
    summary: >-
      IDA annotation for peroxisomal protein import from Kunze et al. (2011).
      This study demonstrated that PEX7 mutations (E113R) destroy the ability
      to complement PEX7 deficiency in RCDP1 fibroblasts, confirming PEX7's
      role in PTS2-dependent import.
    action: ACCEPT
    reason: >-
      Complementation of RCDP1 fibroblasts and mutational analysis directly
      demonstrate PEX7's role in peroxisomal import.
    supported_by:
      - reference_id: PMID:22057399
        supporting_text: "the mutation E113R in myc-hPEX7 destroyed its ability to complement PEX7 deficiency in RCDP1 fibroblasts"

- term:
    id: GO:0016558
    label: protein import into peroxisome matrix
  evidence_type: IDA
  original_reference_id: PMID:25538232
  review:
    summary: >-
      IDA annotation for peroxisomal protein import from Kunze et al. (2015).
      This study provided detailed mechanistic insight into the sequential
      assembly of the PEX7-cargo-PEX5L trimeric complex required for import.
    action: ACCEPT
    reason: >-
      Detailed mechanistic evidence for PEX7's role in peroxisomal protein
      import through the trimeric complex.
    supported_by:
      - reference_id: PMID:25538232
        supporting_text: "the sequential formation of a highly stable trimeric complex involving cargo protein, PEX7 and PEX5L stabilizes cargo binding and is a prerequisite for PTS2-mediated peroxisomal import"

# --- IPI protein binding from PMID:30204880 ---
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:30204880
  review:
    summary: >-
      IPI protein binding from Niwa et al. (2018). This study identified
      VWA8 (P7BP2) as a novel PEX7-binding protein with an atypical PTS2.
      The interaction is between PEX7 and VWA8's PTS2, making this
      essentially a PTS2-binding interaction.
    action: REMOVE
    reason: >-
      "Protein binding" is uninformative. The PEX7-VWA8 interaction is
      mediated via PTS2 recognition, which is already captured by GO:0005053
      annotations. The interaction demonstrates a new PTS2 cargo, not a new
      binding activity.
    supported_by:
      - reference_id: PMID:30204880
        supporting_text: "The binding to Pex7p and peroxisomal localization of P7BP2 depends on the cleavable PTS2 in the N-terminal region"

# --- TAS Reactome annotations for peroxisomal membrane ---
- term:
    id: GO:0005778
    label: peroxisomal membrane
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-9033485
  review:
    summary: >-
      TAS annotation for peroxisomal membrane from Reactome. This reaction
      describes PEX2:PEX10:PEX12 monoubiquitination of PEX5L at the
      peroxisomal membrane. PEX7 is transiently associated with the
      peroxisomal membrane during the import cycle when it docks at the
      PEX13-PEX14 complex as part of the PEX5L-PEX7-cargo trimeric complex.
    action: ACCEPT
    reason: >-
      PEX7 transiently associates with the peroxisomal membrane during the
      import cycle as part of the docking and translocation process.
      While not a permanent membrane resident, this transient association
      is biologically meaningful.

- term:
    id: GO:0005778
    label: peroxisomal membrane
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-9033499
  review:
    summary: >-
      TAS annotation for peroxisomal membrane from Reactome. This reaction
      describes PEX1:PEX6:PEX26 dissociating PEX5L and PEX7 from the
      peroxisomal membrane for recycling.
    action: ACCEPT
    reason: >-
      PEX7 is present at the peroxisomal membrane during the recycling step
      of the import cycle, which is well established.

- term:
    id: GO:0005778
    label: peroxisomal membrane
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-9033514
  review:
    summary: >-
      TAS annotation for peroxisomal membrane from Reactome. This reaction
      describes translocation of PEX5L:PEX7 cargo from cytosol to
      peroxisomal matrix, during which PEX7 passes through the membrane.
    action: ACCEPT
    reason: >-
      PEX7 transits through the peroxisomal membrane during cargo
      translocation. Transient membrane association is biologically accurate.

- term:
    id: GO:0005778
    label: peroxisomal membrane
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-9033516
  review:
    summary: >-
      TAS annotation for peroxisomal membrane from Reactome. Describes
      PEX2:PEX10:PEX12:Ub:PEX5L:PEX7:PEX13:PEX14 binding to
      PEX1:PEX6:PEX26 complex at the membrane.
    action: ACCEPT
    reason: >-
      PEX7 is part of the membrane-associated complex during the import
      and recycling cycle.

- term:
    id: GO:0005778
    label: peroxisomal membrane
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-9033527
  review:
    summary: >-
      TAS annotation for peroxisomal membrane from Reactome. Describes
      PEX2:PEX10:PEX12 binding PEX5L within the membrane-associated complex
      containing PEX7.
    action: ACCEPT
    reason: >-
      Part of the well-established membrane-associated import machinery
      complex involving PEX7.

# --- TAS Reactome annotations for cytosol ---
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-9033232
  review:
    summary: >-
      TAS annotation for cytosol from Reactome. This reaction describes
      PEX7 binding cargo proteins containing PTS2 in the cytosol.
    action: ACCEPT
    reason: >-
      PEX7 binds PTS2-cargo in the cytosol before transport to peroxisomes.
      This is the initial step of the import cycle.

- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-9033499
  review:
    summary: >-
      TAS annotation for cytosol from Reactome. Describes PEX7 recycling
      from peroxisomal membrane back to cytosol.
    action: ACCEPT
    reason: >-
      PEX7 is recycled to the cytosol after cargo delivery. Well established.

- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-9033514
  review:
    summary: >-
      TAS annotation for cytosol from Reactome. Cargo translocation from
      cytosol to matrix involves PEX7 starting in the cytosol.
    action: ACCEPT
    reason: >-
      PEX7 starts in the cytosol as part of the translocation process.
      Concordant with other evidence.

- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-NUL-9033857
  review:
    summary: >-
      TAS annotation for cytosol from Reactome (non-human species reaction).
      Describes Pex14 binding PEX5L:PEX7:Acaa1a in the cytosol (mouse
      reaction used to infer human).
    action: ACCEPT
    reason: >-
      Cytosolic localization of PEX7 is well established and conserved.

- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-NUL-9033896
  review:
    summary: >-
      TAS annotation for cytosol from Reactome (non-human species reaction).
      Describes PEX5L binding PEX7:Acaa1a in cytosol (mouse reaction).
    action: ACCEPT
    reason: >-
      Cytosolic localization of PEX7 is well established and conserved.

# --- IDA annotations from older papers ---
- term:
    id: GO:0005053
    label: peroxisome matrix targeting signal-2 binding
  evidence_type: IDA
  original_reference_id: PMID:9090383
  review:
    summary: >-
      IDA annotation for PTS2 binding from Purdue et al. (1997). One of the
      original papers identifying human PEX7 as the PTS2 receptor. Showed
      that PEX7 expression in RCDP cells rescues PTS2 targeting and restores
      DHAP-AT activity. The authors concluded "these results imply that
      several peroxisomal proteins are targeted by PTS2 signals."
    action: ACCEPT
    reason: >-
      Foundational paper demonstrating PEX7 is the human PTS2 receptor.
    supported_by:
      - reference_id: PMID:9090383
        supporting_text: "expression of human PEX7 in RCDP cells rescues PTS2 targeting and restores some activity of dihydroxyacetone phosphate acyltransferase (DHAP-AT)"

- term:
    id: GO:0005053
    label: peroxisome matrix targeting signal-2 binding
  evidence_type: IDA
  original_reference_id: PMID:11931631
  review:
    summary: >-
      IDA annotation for PTS2 binding from Ghys et al. (2002). This study
      demonstrated specific binding of human PEX7 to PTS2 using multiple
      approaches, and showed that only monomeric PEX7 binds PTS2. The
      interaction is reduced by cysteine alkylation and impaired by N-terminal
      truncation.
    action: ACCEPT
    reason: >-
      Direct demonstration of PEX7-PTS2 binding with characterization of
      binding requirements.
    supported_by:
      - reference_id: PMID:11931631
        supporting_text: "Specific binding of human Pex7p to PTS2 could be demonstrated only when Pex7p was formed in vitro by a coupled transcription/translation system or synthesized in vivo in Chinese hamster ovary K1 cells"
      - reference_id: PMID:11931631
        supporting_text: "only monomeric Pex7p binds to PTS2. The interaction is reduced upon cysteine alkylation and is impaired upon truncation of the N-terminus of Pex7p."

- term:
    id: GO:0005782
    label: peroxisomal matrix
  evidence_type: IDA
  original_reference_id: PMID:11931631
  review:
    summary: >-
      IDA annotation for peroxisomal matrix localization from Ghys et al.
      (2002). GFP-tagged PEX7 was directly observed in the peroxisomal
      lumen.
    action: ACCEPT
    reason: >-
      Direct visualization of PEX7-GFP in the peroxisomal lumen.
    supported_by:
      - reference_id: PMID:11931631
        supporting_text: "Pex7p-GFP was located both in the lumen of peroxisomes and in the cytosol."

- term:
    id: GO:0005829
    label: cytosol
  evidence_type: IDA
  original_reference_id: PMID:11931631
  review:
    summary: >-
      IDA annotation for cytosol localization from Ghys et al. (2002).
      GFP-tagged PEX7 was observed in both peroxisomes and cytosol.
    action: ACCEPT
    reason: >-
      Direct visualization of PEX7-GFP in the cytosol.
    supported_by:
      - reference_id: PMID:11931631
        supporting_text: "Pex7p-GFP was located both in the lumen of peroxisomes and in the cytosol."

- term:
    id: GO:0019899
    label: enzyme binding
  evidence_type: IPI
  original_reference_id: PMID:11931631
  review:
    summary: >-
      IPI annotation for enzyme binding from Ghys et al. (2002). This
      reflects PEX7 binding to PTS2-carrying enzymes (thiolase, PHYH,
      AGPS). However, this binding is specifically mediated through the
      PTS2 signal on these enzymes, making GO:0005053 (PTS2 binding) the
      more appropriate and informative term.
    action: MODIFY
    reason: >-
      "Enzyme binding" is technically not wrong since PEX7 does bind
      enzymes (thiolase, PHYH, AGPS), but it mischaracterizes the nature
      of the interaction. PEX7 binds these proteins specifically through
      their PTS2 signals, not through enzyme-specific features. The more
      informative and accurate term is GO:0005053 (PTS2 binding).
    proposed_replacement_terms:
      - id: GO:0005053
        label: peroxisome matrix targeting signal-2 binding
    supported_by:
      - reference_id: PMID:11931631
        supporting_text: "Pex7p is a WD40-containing protein involved in peroxisomal import of proteins containing an N-terminal peroxisome-targeting signal (PTS2)"

- term:
    id: GO:0042803
    label: protein homodimerization activity
  evidence_type: IDA
  original_reference_id: PMID:11931631
  review:
    summary: >-
      IDA annotation for protein homodimerization from Ghys et al. (2002).
      This is problematic. The same paper explicitly states that "only
      monomeric Pex7p binds to PTS2," and that interaction of Pex7p with
      other peroxins "could not be demonstrated in bacterial or yeast
      two-hybrid screens, or in pull-down binding assays." While some
      homodimerization may have been detected, the paper emphasizes that the
      functionally active form is the monomer. This annotation likely
      represents an over-annotation of an observation that is not
      functionally relevant.
    action: MARK_AS_OVER_ANNOTATED
    reason: >-
      While some PEX7 homodimerization may be detected, the same paper
      (PMID:11931631) states that only monomeric PEX7 binds PTS2,
      indicating that homodimerization is not functionally important for
      PEX7's known biological roles. This likely represents an
      over-annotation.
    supported_by:
      - reference_id: PMID:11931631
        supporting_text: "only monomeric Pex7p binds to PTS2"

# --- IMP annotations ---
- term:
    id: GO:0007031
    label: peroxisome organization
  evidence_type: IMP
  original_reference_id: PMID:10022913
  review:
    summary: >-
      IMP annotation for peroxisome organization from Will et al. (1999).
      This paper is primarily about HsPex14p, not PEX7. The annotation
      likely derives from the observation that PEX7 mutations (in RCDP
      patient cells) affect peroxisomal protein import and consequently
      peroxisome organization. However, PEX7 loss specifically disrupts
      PTS2-dependent protein import, not peroxisome organization broadly.
      Peroxisomes are still present and functional for PTS1-dependent
      import in RCDP cells.
    action: MARK_AS_OVER_ANNOTATED
    reason: >-
      PEX7 mutations cause specific PTS2 import deficiency, not global
      peroxisome organization defects. RCDP cells still have peroxisomes
      with normal PTS1 import. "Peroxisome organization" is too broad
      and implies a more general role than what PEX7 performs. The core
      process is "protein import into peroxisome matrix" (GO:0016558).
    supported_by:
      - reference_id: PMID:9090382
        supporting_text: "RCDP cells from CG11 cannot import a PTS2 reporter protein"
      - reference_id: PMID:9090383
        supporting_text: "the peroxisomal targeting and proteolytic removal of the amino-terminal type 2 peroxisomal targeting sequence (PTS2) of thiolase are defective, whereas the biogenesis of proteins targeted by carboxyterminal type 1 peroxisomal targeting sequences (PTS1) is unimpaired"

- term:
    id: GO:0005777
    label: peroxisome
  evidence_type: IDA
  original_reference_id: PMID:9090382
  review:
    summary: >-
      IDA annotation for peroxisome localization from Motley et al. (1997).
      This is one of the three simultaneous papers identifying human PEX7
      as the PTS2 receptor. The broader term "peroxisome" (GO:0005777) is
      acceptable as a parent term, though more specific terms
      (peroxisomal matrix, peroxisomal membrane) are also annotated.
    action: ACCEPT
    reason: >-
      Peroxisome localization is established. While more specific CC terms
      (peroxisomal matrix, peroxisomal membrane) exist, this broader term
      is acceptable as it was annotated from one of the foundational papers.
    supported_by:
      - reference_id: PMID:9090382
        supporting_text: "expression of PEX7 in RCDP fibroblasts from CG11 rescues the PTS2 protein import deficiency"

- term:
    id: GO:0008611
    label: ether lipid biosynthetic process
  evidence_type: IMP
  original_reference_id: PMID:12522768
  review:
    summary: >-
      IMP annotation for ether lipid biosynthesis from van den Brink et al.
      (2003). PEX7 mutations cause deficiency of plasmalogen synthesis due
      to failure to import AGPS (alkyldihydroxyacetonephosphate synthase),
      a PTS2-carrying enzyme involved in plasmalogen/ether lipid synthesis.
      The connection to ether lipid biosynthesis is indirect -- PEX7 imports
      the enzyme, not directly catalyzes the pathway.
    action: KEEP_AS_NON_CORE
    reason: >-
      PEX7 is not directly involved in ether lipid biosynthesis. The effect
      on ether lipid synthesis is an indirect consequence of failing to
      import the PTS2-carrying enzyme AGPS into peroxisomes. This is a
      downstream phenotypic consequence, not a core function of PEX7.
    supported_by:
      - reference_id: PMID:12522768
        supporting_text: "Biochemical analyses of the patients with RD revealed defects not only in phytanic acid alpha-oxidation but also in plasmalogen synthesis and peroxisomal thiolase."

- term:
    id: GO:0008611
    label: ether lipid biosynthetic process
  evidence_type: IMP
  original_reference_id: PMID:9090383
  review:
    summary: >-
      IMP annotation for ether lipid biosynthesis from Purdue et al. (1997).
      PEX7 expression in RCDP cells restores DHAP-AT activity (involved in
      plasmalogen/ether lipid synthesis) by enabling import of AGPS.
      The ether lipid deficiency is a downstream consequence of PTS2
      import failure.
    action: KEEP_AS_NON_CORE
    reason: >-
      Ether lipid biosynthesis is a downstream consequence of PEX7's role
      in PTS2 import, not a direct function. PEX7 imports AGPS which is
      needed for ether lipid synthesis, but PEX7 does not directly
      participate in the biosynthetic pathway.
    supported_by:
      - reference_id: PMID:9090383
        supporting_text: "expression of human PEX7 in RCDP cells rescues PTS2 targeting and restores some activity of dihydroxyacetone phosphate acyltransferase (DHAP-AT), a peroxisomal enzyme of plasmalogen biosynthesis"

- term:
    id: GO:0005053
    label: peroxisome matrix targeting signal-2 binding
  evidence_type: IDA
  original_reference_id: PMID:9090381
  review:
    summary: >-
      IDA annotation for PTS2 binding from Braverman et al. (1997). One
      of the original papers identifying human PEX7 as the PTS2 receptor.
      Demonstrated that PEX7 expression corrects the PTS2-import defect
      in RCDP cells, and identified RCDP-causing mutations in PEX7.
    action: ACCEPT
    reason: >-
      Foundational experimental evidence establishing PEX7 as the human
      PTS2 receptor.
    supported_by:
      - reference_id: PMID:9090381
        supporting_text: "PEX7, a candidate gene for RCDP identified in yeast, encodes the receptor for peroxisomal matrix proteins with the type-2 peroxisome targeting signal (PTS2)."

- term:
    id: GO:0016558
    label: protein import into peroxisome matrix
  evidence_type: IMP
  original_reference_id: PMID:12522768
  review:
    summary: >-
      IMP annotation for peroxisomal protein import from van den Brink et al.
      (2003). PEX7 mutations in Refsum disease patients cause defects in
      PTS2-dependent protein import (thiolase, PHYH, AGPS import failures).
    action: ACCEPT
    reason: >-
      Mutations in PEX7 in human patients cause PTS2-dependent import
      deficiency, confirming PEX7's role in peroxisomal protein import.
    supported_by:
      - reference_id: PMID:12522768
        supporting_text: "mutations in the PEX7 gene may result in a broad clinical spectrum ranging from severe rhizomelic chondrodysplasia punctata to relatively mild RD"

- term:
    id: GO:0016558
    label: protein import into peroxisome matrix
  evidence_type: IDA
  original_reference_id: PMID:9090381
  review:
    summary: >-
      IDA annotation for peroxisomal protein import from Braverman et al.
      (1997). Expression of PEX7 corrects the PTS2-import defect in RCDP
      cells, directly demonstrating PEX7's role in peroxisomal import.
    action: ACCEPT
    reason: >-
      Direct experimental evidence: PEX7 expression corrects PTS2 import
      defect in RCDP cells.
    supported_by:
      - reference_id: PMID:9090381
        supporting_text: "expression of either corrects the PTS2-import defect characteristic of RCDP cells"

references:
- id: GO_REF:0000002
  title: Gene Ontology annotation through association of InterPro records with GO
    terms
  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:0000120
  title: Combined Automated Annotation using Multiple IEA Methods
  findings: []
- id: PMID:10022913
  title: Identification and characterization of the human orthologue of yeast Pex14p.
  findings:
    - statement: >-
        Characterized HsPex14p as a peroxisomal membrane protein that binds PEX5
        (PTS1 receptor). Notably, interaction of HsPex14p with the PTS2-receptor
        (PEX7) was not observed, distinguishing the human system from yeast.
- id: PMID:11546814
  title: Domain mapping of human PEX5 reveals functional and structural similarities
    to Saccharomyces cerevisiae Pex18p and Pex21p.
  findings:
    - statement: >-
        Mapped PEX5L regions for PTS2 import (aa 1-230), PEX7 interaction
        (aa 191-222), and peroxisomal targeting (aa 1-214). Identified a
        21-amino acid motif shared with yeast Pex18p/Pex21p. Demonstrated
        PEX5L as the essential co-receptor for PEX7 in mammalian PTS2 import.
- 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:
    - statement: >-
        Demonstrated specific PEX7-PTS2 binding, showed only monomeric PEX7
        binds PTS2, confirmed dual localization (cytosol and peroxisomal
        matrix) using GFP-tagged PEX7. PEX7-GFP restored PTS2 import in
        RCDP fibroblasts.
- id: PMID:12522768
  title: Identification of PEX7 as the second gene involved in Refsum disease.
  findings:
    - statement: >-
        Identified PEX7 mutations as a cause of Refsum disease (mild PBD),
        showing that PEX7 mutations produce a clinical spectrum from severe
        RCDP to mild Refsum disease. Biochemical defects include phytanic
        acid oxidation, plasmalogen synthesis, and thiolase import.
- id: PMID:22057399
  title: Structural requirements for interaction of peroxisomal targeting signal 2
    and its receptor PEX7.
  findings:
    - statement: >-
        Identified the PTS2 as an amphipathic helix binding to a conserved
        groove on PEX7. Glu-113 and Glu-200 in PEX7 are critical for PTS2
        binding. E113R abolished PEX7 function in complementation of RCDP
        cells. Identified KChIP4 as a novel peroxisomal protein.
- 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:
    - statement: >-
        PEX5L increases PEX7-cargo interaction about 20-fold. Cargo binding
        is prerequisite for PEX7-PEX5L interaction. E287R mutation in PEX7
        specifically disrupts PEX5L interaction while retaining some cargo
        binding. Sequential assembly of trimeric complex prevents futile
        PEX7 cycling.
- id: PMID:28514442
  title: Architecture of the human interactome defines protein communities and disease
    networks.
  findings:
    - statement: >-
        High-throughput interactome study (BioPlex). Detected protein
        interactions with PEX7 in an unbiased manner.
- id: PMID:30204880
  title: A newly isolated Pex7-binding, atypical PTS2 protein P7BP2 is a novel dynein-type
    AAA+ protein.
  findings:
    - statement: >-
        Identified VWA8 as a novel PEX7-binding protein with an atypical PTS2.
        VWA8 is transported to peroxisomes via PEX5L-PEX7 pathway. Demonstrates
        that PEX7 recognizes atypical PTS2 variants.
- id: PMID:32814053
  title: Interactome Mapping Provides a Network of Neurodegenerative Disease Proteins
    and Uncovers Widespread Protein Aggregation in Affected Brains.
  findings:
    - statement: >-
        High-throughput interactome study detecting protein interactions
        in the context of neurodegenerative disease networks.
- id: PMID:33961781
  title: Dual proteome-scale networks reveal cell-specific remodeling of the human
    interactome.
  findings:
    - statement: >-
        BioPlex 3.0 high-throughput interactome study detecting
        protein-protein interactions across cell types.
- id: PMID:40739340
  title: PEX39 facilitates the peroxisomal import of PTS2-containing proteins.
  findings:
    - statement: >-
        Identified PEX39 as a novel peroxin that facilitates PTS2-dependent
        protein import. PEX39 interacts with PEX7 and the PTS2 import
        machinery.
- id: PMID:9090381
  title: Human PEX7 encodes the peroxisomal PTS2 receptor and is responsible for rhizomelic
    chondrodysplasia punctata.
  findings:
    - statement: >-
        Foundational paper identifying human PEX7 as the PTS2 receptor.
        Expression corrects PTS2 import defect in RCDP cells. Identified
        RCDP-causing mutations (L292ter, A218V, G217R).
- id: PMID:9090382
  title: Rhizomelic chondrodysplasia punctata is a peroxisomal protein targeting disease
    caused by a non-functional PTS2 receptor.
  findings:
    - statement: >-
        Cloned human PEX7, demonstrated PTS2-specific import deficiency in
        RCDP (PTS1 import unaffected). Expression rescues PTS2 import in
        RCDP fibroblasts. Identified mutations in PEX7 in RCDP CG11 patients.
- id: PMID:9090383
  title: Rhizomelic chondrodysplasia punctata is caused by deficiency of human PEX7,
    a homologue of the yeast PTS2 receptor.
  findings:
    - statement: >-
        Identified human PEX7 as the yeast Pex7p orthologue. Expression in
        RCDP cells rescues PTS2 targeting and DHAP-AT activity. Multiple
        peroxisomal proteins use PTS2 signals recognized by PEX7.
- id: Reactome:R-HSA-9033232
  title: PEX7 binds cargo proteins containing PTS2
  findings: []
- id: Reactome:R-HSA-9033485
  title: PEX2:PEX10:PEX12 monoubiquitinates PEX5L at cysteine-11
  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-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-NUL-9033857
  title: Pex14 binds PEX5L (in PEX5L:PEX7:Acaa1a)
  findings: []
- id: Reactome:R-NUL-9033896
  title: PEX5L binds PEX7:Acaa1a
  findings: []

PEX7

Gene Description

Existing Annotations Review

References

Deep Research

Falcon

Research Report: Human PEX7 (UniProt O00628) — Functional Annotation (PTS2 Receptor/Peroxin-7)

0) Target verification (gene/protein identity)

1) Key concepts and definitions (current understanding)

1.1 Peroxisomal matrix protein import and targeting signals

1.2 What PEX7 does (primary molecular function)

1.3 Structural/biophysical concepts relevant to PEX7

1.4 Co-receptor requirement in humans: PEX5L

2) Mechanism, pathway placement, and subcellular localization

2.1 Where PEX7 acts

2.2 Core import cycle for PEX7-dependent cargo (current model)

2.3 Experimental evidence for a receptor-associated pore (relevant to PEX7 pathway convergence)

3) Key cargos and biological processes supported by PEX7

3.1 Canonical PTS2 enzyme cargos (human disease-relevant)

4) Human disease relevance: PEX7 and RCDP1 (Rhizomelic Chondrodysplasia Punctata type 1)

4.1 Definition and clinical phenotype

4.2 Biochemical hallmarks and mechanistic interpretation

4.3 Prognosis and survival statistics

4.4 Epidemiology and prevalence statistics

4.5 Genotype–phenotype correlations and notable alleles

4.6 Diagnostics and real-world implementation

5) Recent developments and latest research (prioritizing 2023–2024)

5.1 2023: Updated mechanistic view of PTS2 import and pore dynamics

5.2 2024: Expansion of PEX7-dependent cargo space to cholesterol metabolism (HMGCR)

6) Current applications and real-world implementations

6.1 Clinical genetics and metabolic diagnostics

6.2 Prenatal imaging + molecular confirmation

6.3 Translational implications of the HMGCR finding

7) Expert opinions and authoritative synthesis

8) Key statistics and data points (from cited studies)

9) Source details (URLs and publication dates where available)

10) Summary for functional annotation

Citations

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