PEX26

Existing Annotations Review

GO Term	Evidence	Action	Reason
GO:0005777 peroxisome	IBA GO_REF:0000033	ACCEPT	Summary: PEX26 is an integral peroxisomal membrane protein. Multiple experimental studies confirm its localization to peroxisomes (PMID:12717447, PMID:16257970, PMID:16763195). The IBA annotation for peroxisome is well-supported by phylogenetic inference and consistent with all experimental evidence. However, PEX26 more specifically localizes to the peroxisomal membrane (GO:0005778), so this broader term is acceptable but less informative than the more specific IDA-supported annotations. Reason: PEX26 is a bona fide peroxisomal protein. While GO:0005778 (peroxisomal membrane) is more precise, this broader CC annotation is not incorrect and is well-supported by phylogenetic analysis across vertebrates. Multiple IDA annotations also support peroxisomal localization (PMID:12717447, PMID:16257970, PMID:16763195). Supporting Evidence: PMID:12717447 Expression of PEX26 restores peroxisomal protein import in the fibroblasts of an individual with PBD of CG8 PMID:16763195 Here we analyzed targeting of the human peroxisomal tail-anchored protein PEX26
GO:0016558 protein import into peroxisome matrix	IBA GO_REF:0000033	ACCEPT	Summary: PEX26 is essential for peroxisomal matrix protein import. PEX26-deficient cells show impaired import of both PTS1- and PTS2-targeted matrix proteins (PMID:15858711, PMID:12717447). The IBA annotation correctly captures a core biological process for PEX26. However, the more specific child term GO:0016562 (protein import into peroxisome matrix, receptor recycling) more accurately describes PEX26's specific role in this process. Reason: PEX26 is required for peroxisomal matrix protein import. While GO:0016562 (receptor recycling) is more specific to PEX26's mechanism, this broader term is not incorrect. The IBA annotation is phylogenetically sound. Multiple experimental papers confirm PEX26's role in this process (PMID:12717447, PMID:15858711, PMID:16257970). Supporting Evidence: PMID:15858711 PEX26 deficiency impairs peroxisomal import of both PTS1- and PTS2-targeted matrix proteins PMID:12717447 Expression of PEX26 restores peroxisomal protein import in the fibroblasts of an individual with PBD of CG8
GO:0051117 ATPase binding	IBA GO_REF:0000033	ACCEPT	Summary: PEX26 directly binds PEX6, an AAA+ ATPase, and indirectly recruits PEX1, another AAA+ ATPase, through PEX6 (PMID:12717447, PMID:16257970, PMID:16854980). The IBA annotation for ATPase binding is well-supported and represents a core molecular function of PEX26. Reason: PEX26 directly interacts with PEX6 (an AAA+ ATPase) and indirectly with PEX1 (also an AAA+ ATPase). This ATPase binding activity is central to PEX26's function as the membrane anchor for the PEX1-PEX6 complex. IBA is phylogenetically sound, and experimental IPI evidence from PMID:16257970 also supports this annotation. Supporting Evidence: PMID:12717447 Pex6 and Pex1 of the AAA ATPase family co-immunoprecipitate with Pex26 PMID:16257970 insufficient binding to Pex1p x Pex6p complexes...is most likely responsible for the CG8 PBDs
GO:0005778 peroxisomal membrane	IEA GO_REF:0000120	ACCEPT	Summary: PEX26 is an integral peroxisomal membrane protein with a single C-terminal transmembrane domain (residues 247-267 per UniProt). This IEA annotation is correct and well-supported by multiple experimental studies demonstrating peroxisomal membrane localization (PMID:12717447, PMID:16257970). Reason: The automated annotation is correct. PEX26 is a type II integral membrane protein of the peroxisomal membrane, confirmed by multiple IDA studies. The IEA annotation is redundant with IDA annotations but not incorrect. Supporting Evidence: PMID:12717447 we have isolated human PEX26 encoding a type II peroxisomal membrane protein
GO:0015031 protein transport	IEA GO_REF:0000043	ACCEPT	Summary: PEX26 is involved in protein transport -- specifically the import of peroxisomal matrix proteins. This IEA annotation from UniProt keyword mapping (Protein transport keyword) is correct but very general. More specific terms such as GO:0016558 (protein import into peroxisome matrix) or GO:0016562 (receptor recycling) better describe PEX26's role. Reason: While overly broad, this IEA annotation is not incorrect. PEX26 is involved in protein transport (specifically peroxisomal matrix protein import). The more specific annotations from IDA/IBA evidence are more informative, but this general IEA annotation is acceptable as a broader parent annotation.
GO:0044877 protein-containing complex binding	IEA GO_REF:0000002	ACCEPT	Summary: PEX26 binds the PEX1-PEX6 AAA+ ATPase complex. The InterPro-derived IEA annotation for protein-containing complex binding is correct in that PEX26 binds the PEX1-PEX6 hexameric complex (PMID:16854980). However, the more specific GO:0051117 (ATPase binding) better describes the molecular function. Reason: PEX26 does bind a protein-containing complex (the PEX1-PEX6 heterohexamer). This IEA is consistent with experimental evidence from PMID:16854980 showing PEX26 binds the assembled PEX1-PEX6 complex. While ATPase binding (GO:0051117) is more specific, this broader term is acceptable for an IEA annotation. Supporting Evidence: PMID:16854980 PEX26 responsible for peroxisome biogenesis disorders of CG8 encodes Pex26p, the recruiter of Pex1p.Pex6p complexes to peroxisomes
GO:0045046 protein import into peroxisome membrane	IEA GO_REF:0000002	REMOVE	Summary: This IEA annotation from InterPro suggests PEX26 is involved in protein import into the peroxisome membrane (i.e., PMP import). However, PEX26's established function is in peroxisomal matrix protein import (specifically receptor recycling after matrix protein import), not in peroxisomal membrane protein import. PEX26 itself is a PMP that is imported into the peroxisome membrane via PEX19/PEX3, but PEX26 does not facilitate PMP import. This annotation conflates PEX26 being a PMP with PEX26 functioning in PMP import. Reason: PEX26 is not involved in importing proteins into the peroxisomal membrane. PEX26's role is in peroxisomal matrix protein import via receptor recycling. PEX26 is itself a substrate of the PEX19/PEX3 PMP import pathway (PMID:16763195), but it does not facilitate PMP import for other proteins. This IEA annotation likely results from an overly broad InterPro domain annotation. Supporting Evidence: PMID:16763195 we show that PEX19 is essential for PEX26 import PMID:12717447 Pex26 recruits Pex6-Pex1 complexes to peroxisomes
GO:0005515 protein binding	IPI PMID:16189514 Towards a proteome-scale map of the human protein-protein in...	MARK AS OVER ANNOTATED	Summary: PMID:16189514 is a large-scale Y2H interactome mapping study (Rual et al. 2005). Protein binding is uninformative as a GO term and does not describe PEX26's specific molecular interactions. The more informative terms ATPase binding (GO:0051117) and protein-membrane adaptor activity (GO:0043495) better capture PEX26's function. Reason: Per curation guidelines, protein binding (GO:0005515) is uninformative and should be replaced with more specific MF terms. PEX26's key binding interactions are captured by GO:0051117 (ATPase binding) for its interaction with PEX1/PEX6. This large-scale screen (PMID:16189514) likely detected many non-physiological interactions alongside any real ones.
GO:0005515 protein binding	IPI PMID:20531392 The peroxisomal receptor Pex19p forms a helical mPTS recogni...	MARK AS OVER ANNOTATED	Summary: PMID:20531392 (Schueller et al. 2010) describes the structural basis for PEX19 recognition of mPTS signals. PEX26 is identified as a PEX19 binding partner via its C-terminal mPTS. While the interaction with PEX19 is real and physiologically relevant for PEX26 targeting to peroxisomes, protein binding is uninformative. Reason: Protein binding is uninformative. The interaction between PEX26 and PEX19 is real and relates to PEX26's targeting to peroxisomes (PMID:16763195, PMID:20531392), but should be annotated with a more specific term if one exists. PEX26 is a client of PEX19 for membrane insertion, not the other way around.
GO:0005515 protein binding	IPI PMID:32296183 A reference map of the human binary protein interactome.	MARK AS OVER ANNOTATED	Summary: PMID:32296183 (Luck et al. 2020) is a large-scale binary interactome mapping study. Protein binding is uninformative and the interactions detected in high-throughput screens may not reflect physiological PEX26 interactions. Reason: Protein binding is uninformative per curation guidelines. High-throughput interactome studies detect many interactions that may not be physiologically relevant to PEX26's core function.
GO:0005515 protein binding	IPI PMID:32814053 Interactome Mapping Provides a Network of Neurodegenerative ...	MARK AS OVER ANNOTATED	Summary: PMID:32814053 (Haenig et al. 2020) is a neurodegenerative disease interactome mapping study. Protein binding is uninformative and the interactions detected may not be specific to PEX26's function. Reason: Protein binding is uninformative per curation guidelines. This high-throughput interactome study is focused on neurodegenerative disease networks and any PEX26 interactions detected may be incidental.
GO:0005778 peroxisomal membrane	NAS PMID:35805150 Insights into the Structure and Function of the Pex1/Pex6 AA...	ACCEPT	Summary: PMID:35805150 (Judy et al. 2022) is a review article on PEX1/PEX6 structure and function that describes PEX26 as the membrane anchor that recruits PEX1/PEX6 to the peroxisome membrane. The NAS annotation for peroxisomal membrane is correct and consistent with multiple experimental studies. Reason: PEX26 is well-established as a peroxisomal membrane protein. Although this NAS annotation is from a review (PMID:35805150), it is consistent with primary experimental evidence (PMID:12717447, PMID:16257970) and redundant with IDA annotations. Supporting Evidence: PMID:35805150 its partner protein—named Pex15 in S. cerevisiae or PEX26 in other organisms—that recruits Pex1/Pex6 to the peroxisome membrane
GO:0016562 protein import into peroxisome matrix, receptor recycling	NAS PMID:35805150 Insights into the Structure and Function of the Pex1/Pex6 AA...	ACCEPT	Summary: PEX26 is a key component of the receptor export module that enables PEX5 receptor recycling after cargo delivery. PMID:35805150 states that PEX1/PEX6 is necessary to extract Pex5 from the peroxisome membrane for subsequent rounds of import, and PEX26 is the membrane anchor for this complex. GO:0016562 is the most specific and accurate term for PEX26's role in peroxisomal biology. Reason: This is the most precise BP annotation for PEX26. PEX26 anchors the PEX1-PEX6 complex that drives PEX5 receptor recycling. The review (PMID:35805150) synthesizes extensive primary literature supporting this function. This term accurately describes PEX26's specific mechanistic role within the broader process of peroxisomal matrix protein import. Supporting Evidence: PMID:35805150 Pex1/Pex6 is necessary to extract Pex5 from the peroxisome membrane for subsequent rounds of import...Receptor recycling remains the canonical role for Pex1/Pex6 across eukaryotes
GO:0005778 peroxisomal membrane	IDA PMID:12717447 The pathogenic peroxin Pex26p recruits the Pex1p-Pex6p AAA A...	ACCEPT	Summary: Matsumoto et al. (2003) identified PEX26 as a type II peroxisomal membrane protein with a single C-terminal transmembrane domain. They demonstrated peroxisomal membrane localization using epitope-tagged constructs and immunofluorescence. Reason: This is a core CC annotation for PEX26. The original identification paper (PMID:12717447) directly demonstrated that PEX26 is an integral protein of the peroxisomal membrane with type II topology. Supporting Evidence: PMID:12717447 we have isolated human PEX26 encoding a type II peroxisomal membrane protein of relative molecular mass 34,000
GO:0016558 protein import into peroxisome matrix	IDA PMID:12717447 The pathogenic peroxin Pex26p recruits the Pex1p-Pex6p AAA A...	ACCEPT	Summary: Matsumoto et al. (2003) showed that expression of PEX26 restores peroxisomal protein import in CG8 patient fibroblasts. This directly demonstrates PEX26's requirement for peroxisomal matrix protein import. Reason: Direct experimental evidence showing PEX26 expression rescues peroxisomal protein import in PEX26-deficient cells. This is a core biological process for PEX26. Supporting Evidence: PMID:12717447 Expression of PEX26 restores peroxisomal protein import in the fibroblasts of an individual with PBD of CG8
GO:0022615 protein to membrane docking	IDA PMID:12717447 The pathogenic peroxin Pex26p recruits the Pex1p-Pex6p AAA A...	ACCEPT	Summary: PEX26 recruits the PEX1-PEX6 AAA ATPase complex to the peroxisomal membrane, which can be described as a docking function. Matsumoto et al. showed that PEX6 and PEX1 colocalize with peroxisomes in wild-type cells but not in PEX26-defective cells, and that PEX26 expression restores this colocalization. This term describes PEX26's role in mediating the association of soluble PEX1-PEX6 with the peroxisomal membrane. Reason: PEX26 functions as the membrane docking receptor for the PEX1-PEX6 complex. This is a core function supported by direct evidence showing that PEX26 is required for peroxisomal localization of PEX6 and PEX1 (PMID:12717447). Supporting Evidence: PMID:12717447 Epitope-tagged Pex6 and Pex1 are discernible as puncta in normal CHO-K1 cells, but not in PEX26-defective cells. PEX26 expression in ZP167 cells re-establishes colocalization of Pex6 and Pex1 with Pex26
GO:0043495 protein-membrane adaptor activity	IDA PMID:12717447 The pathogenic peroxin Pex26p recruits the Pex1p-Pex6p AAA A...	ACCEPT	Summary: PEX26 acts as an adaptor that recruits the cytosolic PEX1-PEX6 complex to the peroxisomal membrane. Matsumoto et al. demonstrated that PEX26 co-immunoprecipitates with PEX6 and PEX1, and that PEX26 expression in PEX26-deficient cells restores peroxisomal localization of PEX6 and PEX1. This is the most appropriate MF term for PEX26's core molecular function. Reason: Protein-membrane adaptor activity is the most accurate MF term for PEX26. It serves as an integral membrane protein that recruits a soluble protein complex (PEX1-PEX6) to the peroxisomal membrane. This is the central molecular function of PEX26. Supporting Evidence: PMID:12717447 Pex26 recruits Pex6-Pex1 complexes to peroxisomes
GO:0043495 protein-membrane adaptor activity	IDA PMID:16257970 Mutations in the peroxin Pex26p responsible for peroxisome b...	ACCEPT	Summary: Furuki et al. (2006) characterized disease-causing PEX26 mutations and showed they impair PEX26's interaction with the PEX1-PEX6 complex, its stability, and/or its peroxisomal localization. This further validates PEX26's protein-membrane adaptor function by showing that mutations disrupting this function cause disease. Reason: Additional experimental support for PEX26's core MF of protein-membrane adaptor activity. Disease-causing mutations that disrupt PEX26's binding to PEX1-PEX6 or its membrane localization cause peroxisome biogenesis disorders (PMID:16257970). Supporting Evidence: PMID:16257970 the instability, insufficient binding to Pex1p x Pex6p complexes, or mislocalization of patient-derived Pex26p mutants is most likely responsible for the CG8 PBDs
GO:0005829 cytosol	TAS Reactome:R-HSA-9603775	KEEP AS NON CORE	Summary: This Reactome annotation reflects PEX26's involvement in the PEX3:PEX19:class I PMP dissociation reaction, where PEX19-bound PMPs (including PEX26) transit through the cytosol before membrane insertion. PEX26 is synthesized in the cytosol and transiently present there before insertion into the peroxisomal membrane via the PEX19/PEX3 pathway. However, PEX26's functional localization is the peroxisomal membrane. Reason: PEX26 does transit through the cytosol as part of the PEX19-mediated PMP import pathway, so the annotation is technically correct. However, the cytosol is not the primary functional location of PEX26; it is a transient localization during membrane targeting. Interestingly, Weller et al. (PMID:15858711) showed that a cytosolic PEX26 isoform (PEX26-deltaex5) lacking the transmembrane domain is functional, suggesting some PEX26 activity can occur in the cytosol. Supporting Evidence: PMID:15858711 PEX26-Deltaex5 rescues peroxisome biogenesis in PEX26-deficient cells as efficiently as does PEX26-FL
GO:0005829 cytosol	TAS Reactome:R-HSA-9603784	KEEP AS NON CORE	Summary: Another Reactome annotation for PEX19:class I PMP binding to PEX3, reflecting the cytosolic transit of PEX26 during PMP import. Same considerations as above. Reason: Cytosolic localization is transient for PEX26 during its PEX19-mediated targeting to peroxisomes. Not the primary functional location but technically correct.
GO:0005829 cytosol	TAS Reactome:R-HSA-9603804	KEEP AS NON CORE	Summary: Reactome annotation reflecting PEX19 binding to class I PMPs (including PEX26) in the cytosol. Same considerations as the other cytosol annotations. Reason: Cytosolic localization is a transient step in PEX26's biogenesis pathway. Not its primary functional location.
GO:0005778 peroxisomal membrane	TAS Reactome:R-HSA-9033499	ACCEPT	Summary: This Reactome reaction describes PEX1:PEX6:PEX26:ZFAND6 dissociating Ub:PEX5L and PEX7 from the docking/translocation module (PEX14:PEX13:PEX2:PEX10:PEX12). PEX26 is correctly annotated to the peroxisomal membrane in this context as part of the receptor export module. Reason: Peroxisomal membrane is the correct functional localization for PEX26 during receptor recycling. This Reactome annotation accurately reflects PEX26's role as part of the membrane-bound PEX1-PEX6-PEX26 receptor export module.
GO:0005778 peroxisomal membrane	TAS Reactome:R-HSA-9033516	ACCEPT	Summary: Reactome reaction describing binding of the ubiquitinated PEX5L:PEX7 docking complex to PEX1:PEX6:PEX26 and ZFAND6 at the peroxisomal membrane. Correctly places PEX26 at the peroxisomal membrane. Reason: Correct localization of PEX26 during its functional role in receptor recycling at the peroxisomal membrane. Redundant with IDA annotation but consistent.
GO:0005778 peroxisomal membrane	TAS Reactome:R-HSA-9033533	ACCEPT	Summary: Reactome reaction for PEX5S/L receptor recycling at the peroxisomal membrane. Same context as other Reactome peroxisomal membrane annotations. Reason: Correct and consistent with PEX26's established peroxisomal membrane localization.
GO:0005778 peroxisomal membrane	TAS Reactome:R-HSA-9603775	ACCEPT	Summary: Reactome reaction for PEX3:PEX19:class I PMP dissociation. PEX26 is annotated to peroxisomal membrane as the destination of PMP import. Correct. Reason: PEX26 is correctly localized to the peroxisomal membrane after PEX19/PEX3-mediated insertion.
GO:0005777 peroxisome	IDA PMID:16763195 Targeting of the tail-anchored peroxisomal membrane proteins...	ACCEPT	Summary: Halbach et al. (2006) analyzed PEX26 targeting to peroxisomes and showed it occurs through C-terminal PEX19-binding sites. They demonstrated PEX26 localizes to peroxisomes and identified two PEX19-binding sites required for correct targeting. Reason: Direct experimental evidence for PEX26 localization to peroxisomes. While GO:0005778 (peroxisomal membrane) is more specific, the broader peroxisome annotation is not incorrect and is supported by the immunofluorescence data in this study. Supporting Evidence: PMID:16763195 Here we analyzed targeting of the human peroxisomal tail-anchored protein PEX26. Its C-terminal-targeting signal contains two binding sites for PEX19
GO:0016558 protein import into peroxisome matrix	IDA PMID:16257970 Mutations in the peroxin Pex26p responsible for peroxisome b...	ACCEPT	Summary: Furuki et al. (2006) showed that pathogenic PEX26 mutations impair peroxisomal protein import, further confirming PEX26's essential role in this process. Temperature-sensitive mutations showed milder phenotypes than null mutations. Reason: Direct experimental evidence that PEX26 mutations impair peroxisomal matrix protein import. This complements the IDA annotation from PMID:12717447. Supporting Evidence: PMID:16257970 Pex26p functions in recruiting to peroxisomes the complexes of the AAA ATPase peroxins, Pex1p and Pex6p
GO:0005515 protein binding	IPI PMID:16257970 Mutations in the peroxin Pex26p responsible for peroxisome b...	MARK AS OVER ANNOTATED	Summary: PMID:16257970 documents PEX26 interactions with PEX1 and PEX6 in the context of disease-causing mutations. The specific interaction with PEX6/PEX1 is better captured by GO:0051117 (ATPase binding) which is already annotated. Reason: Protein binding is uninformative. PEX26's interaction with PEX1/PEX6 is better captured by GO:0051117 (ATPase binding) and GO:0043495 (protein-membrane adaptor activity), both of which are already annotated from this same reference.
GO:0005515 protein binding	IPI PMID:16763195 Targeting of the tail-anchored peroxisomal membrane proteins...	MARK AS OVER ANNOTATED	Summary: PMID:16763195 (Halbach et al. 2006) demonstrates PEX26 interaction with PEX19 through C-terminal binding sites. This is a real and physiologically important interaction for PEX26 membrane targeting, but protein binding is uninformative. Reason: Protein binding is uninformative per curation guidelines. The PEX26-PEX19 interaction is real and important for PEX26 targeting, but should ideally be annotated with a more specific term. PEX26 is a client/cargo of PEX19 for membrane insertion.
GO:0005777 peroxisome	IDA PMID:16257970 Mutations in the peroxin Pex26p responsible for peroxisome b...	ACCEPT	Summary: Furuki et al. (2006) confirmed PEX26 peroxisomal localization and showed that certain disease-causing mutations impair this localization. Reason: Additional IDA evidence for PEX26 peroxisomal localization. Disease mutations that impair localization provide further support for the physiological significance of this annotation. Supporting Evidence: PMID:16257970 mislocalization of patient-derived Pex26p mutants is most likely responsible for the CG8 PBDs
GO:0051117 ATPase binding	IPI PMID:16257970 Mutations in the peroxin Pex26p responsible for peroxisome b...	ACCEPT	Summary: Furuki et al. (2006) characterized PEX26 disease mutations and showed they impair interaction with the PEX1-PEX6 AAA ATPase complex. This provides strong experimental evidence for PEX26's ATPase binding activity. Reason: Direct experimental IPI evidence for PEX26 binding to PEX1/PEX6 AAA ATPases. Disease mutations that reduce this binding cause peroxisome biogenesis disorders, confirming the physiological importance of this interaction. Supporting Evidence: PMID:16257970 insufficient binding to Pex1p x Pex6p complexes...is most likely responsible for the CG8 PBDs
GO:0005515 protein binding	IPI PMID:15713480 Analysis of human Pex19p's domain structure by pentapeptide ...	MARK AS OVER ANNOTATED	Summary: PMID:15713480 (Fransen et al. 2005) analyzed PEX19 domain structure and identified PEX26 as one of multiple PMPs that interact with PEX19's C-terminal domain. This reflects the PEX19-PEX26 interaction for membrane targeting. Protein binding is uninformative. Reason: Protein binding is uninformative per curation guidelines. The PEX19-PEX26 interaction is documented but better captured by more specific terms. PEX26 is a client of PEX19 for peroxisomal membrane insertion. Supporting Evidence: PMID:15713480 a carboxy-terminal domain that interacts with multiple PMPs including Pex3p, Pex11pbeta, Pex12p, Pex13p, Pex16p, and Pex26p
GO:0005777 peroxisome	IDA PMID:15858711 Alternative splicing suggests extended function of PEX26 in ...	ACCEPT	Summary: Weller et al. (2005) showed full-length PEX26 localizes to peroxisomes but the alternatively spliced PEX26-deltaex5 (lacking the transmembrane domain) is cytosolic yet functional. This study confirms peroxisomal localization of the full-length protein. Reason: IDA evidence for PEX26 peroxisomal localization from the full-length protein. While an alternatively spliced cytosolic isoform also exists, the main isoform is peroxisomal. Supporting Evidence: PMID:15858711 it encodes an integral peroxisomal membrane protein with a single C-terminal transmembrane domain and a cytosolic N-terminus
GO:0016558 protein import into peroxisome matrix	IMP PMID:15858711 Alternative splicing suggests extended function of PEX26 in ...	ACCEPT	Summary: Weller et al. (2005) performed quantitative studies showing PEX26-deficient cells have substantial defects in import of PTS1-targeted proteins (PECI, HAOX1, catalase) and PTS2-targeted proteins (PAHX). They showed both PTS1 and PTS2 import are impaired in CG8 cells, correcting earlier reports that only PTS2 and catalase import were affected. Reason: Strong IMP evidence from quantitative import assays showing PEX26 deficiency impairs both PTS1 and PTS2 peroxisomal matrix protein import. This is a core function. Supporting Evidence: PMID:15858711 PEX26 deficiency impairs peroxisomal import of both PTS1- and PTS2-targeted matrix proteins PMID:15858711 our results show a clear and substantial defect in all three PTS1-targeted reporters, most severe for catalase but substantial for PECI and HAOX1
GO:0005515 protein binding	IPI PMID:16854980 Dynamic and functional assembly of the AAA peroxins, Pex1p a...	MARK AS OVER ANNOTATED	Summary: PMID:16854980 (Tamura et al. 2006) studied the dynamic assembly of PEX1, PEX6, and PEX26. PEX26 interaction with PEX1/PEX6 is better captured by GO:0051117 (ATPase binding) and GO:0043495 (protein-membrane adaptor activity). Protein binding is uninformative. Reason: Protein binding is uninformative per curation guidelines. The PEX26-PEX1/PEX6 interactions described in PMID:16854980 are better captured by the already-annotated GO:0051117 (ATPase binding) and GO:0044877 (protein-containing complex binding).
GO:0044877 protein-containing complex binding	IDA PMID:16854980 Dynamic and functional assembly of the AAA peroxins, Pex1p a...	ACCEPT	Summary: Tamura et al. (2006) demonstrated that PEX26 binds the assembled PEX1-PEX6 complex and showed that endogenous PEX6 and PEX26 are predominantly localized on peroxisomes, while PEX1 forms homo-oligomers in the cytoplasm that undergo conformational change upon interaction with PEX6. Reason: PEX26 binds the PEX1-PEX6 heterohexameric complex. This IDA annotation captures PEX26's ability to bind a multi-subunit protein complex, which is its core function as the membrane docking receptor for the PEX1-PEX6 ATPase complex. Supporting Evidence: PMID:16854980 PEX26 responsible for peroxisome biogenesis disorders of CG8 encodes Pex26p, the recruiter of Pex1p.Pex6p complexes to peroxisomes PMID:16854980 endogenous Pex1p was partly localized likely as a homo-oligomer in the cytoplasm, while Pex6p and Pex26p were predominantly localized on peroxisomes

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:0000120

Combined Automated Annotation using Multiple IEA Methods

PMID:12717447

The pathogenic peroxin Pex26p recruits the Pex1p-Pex6p AAA ATPase complexes to peroxisomes.

PMID:15713480

Analysis of human Pex19p's domain structure by pentapeptide scanning mutagenesis.

PMID:15858711

Alternative splicing suggests extended function of PEX26 in peroxisome biogenesis.

PMID:16189514

Towards a proteome-scale map of the human protein-protein interaction network.

PMID:16257970

Mutations in the peroxin Pex26p responsible for peroxisome biogenesis disorders of complementation group 8 impair its stability, peroxisomal localization, and interaction with the Pex1p x Pex6p complex.

PMID:16763195

Targeting of the tail-anchored peroxisomal membrane proteins PEX26 and PEX15 occurs through C-terminal PEX19-binding sites.

PMID:16854980

Dynamic and functional assembly of the AAA peroxins, Pex1p and Pex6p, and their membrane receptor Pex26p.

PMID:20531392

The peroxisomal receptor Pex19p forms a helical mPTS recognition domain.

PMID:32296183

A reference map of the human binary protein interactome.

PMID:32814053

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

PMID:35805150

Insights into the Structure and Function of the Pex1/Pex6 AAA-ATPase in Peroxisome Homeostasis.

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-9033516

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

Reactome:R-HSA-9033533

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

Reactome:R-HSA-9603775

PEX3:PEX19:class I PMP dissociates

Reactome:R-HSA-9603784

PEX19:class I PMP binds PEX3

Reactome:R-HSA-9603804

PEX19 binds class I peroxisomal membrane proteins

Deep Research

Falcon

(PEX26-deep-research-falcon.md)

this with annotations you find in gene/protein databases, but these can be outdated or inaccurate. Falcon Edison Scientific Literature 20 citations 2026-03-05T00:33:58.171843

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 PEX26 (UniProt Q7Z412) — functional annotation

0) Identity verification (mandatory)

The literature gathered here describes human PEX26/peroxin-26 as a ~34 kDa, ~305 aa peroxisomal membrane protein with a single C-terminal transmembrane domain (TMD) and a cytosolic N-terminus, functioning as the membrane recruiter/anchor for the PEX1–PEX6 AAA+ ATPase complex during peroxisome biogenesis, consistent with UniProt Q7Z412 (peroxisome assembly protein 26; peroxin-26) (weller2005alternativesplicingsuggests pages 1-2, guder2019isoformspecificdomainorganization pages 1-5, nashiro2011recruitingmechanismof pages 1-2).

1) Key concepts and current understanding

1.1 Peroxisome biogenesis and the PEX1–PEX6 “exportomer”

Peroxisomal matrix proteins are imported via receptors (notably PEX5 for PTS1 cargo), which must be recycled for repeated rounds of import. A key step is mono-ubiquitination of PEX5 (at a conserved N-terminal cysteine) by a peroxisomal membrane E3 ligase complex, enabling engagement by the PEX1–PEX6 AAA ATPases that use ATP hydrolysis to extract/recycle the receptor (kumar2024theperoxisomean pages 10-11).

In mammals, the PEX1–PEX6 AAA ATPases are anchored to the peroxisomal membrane by PEX26, and the ATPase ring can apply mechanical unfolding/extraction to ubiquitinated PEX5 during recycling (kumar2024theperoxisomean pages 10-11). Thus, PEX26 is not an enzyme, but an assembly/anchoring factor that positions the AAA ATPase motor on peroxisomes and supports receptor recycling and import competence (kumar2024theperoxisomean pages 10-11).

1.2 Tail-anchored peroxisomal membrane protein targeting: PEX19/PEX3 and PEX26 insertion

PEX26 is a tail-anchored (TA) peroxisomal membrane protein (single C-terminal TMD). Recent mechanistic work shows PEX26 insertion occurs via the PEX19/PEX3 pathway: PEX19 chaperones PEX26, prevents improper exposure of the PEX26 TMD, and interaction with the cytosolic domain of PEX3 triggers PEX26 release at the peroxisomal membrane (oh2024adualrole pages 1-2). This clarifies a key upstream step required for PEX26’s downstream function as a PEX1/PEX6 recruiter.

2) Molecular function, interactions, and localization (evidence-based)

2.1 Subcellular localization and membrane topology

PEX26 is an integral peroxisomal membrane protein with one C-terminal transmembrane segment and a cytosolic N-terminal domain (weller2005alternativesplicingsuggests pages 1-2, nashiro2011recruitingmechanismof pages 1-2). Domain mapping work places the TMD around residues ~252–269 and supports a type II membrane topology (cytosol-facing N-terminus) (guder2019isoformspecificdomainorganization pages 1-5).

2.2 Key molecular interactions (PEX6/PEX1; PEX13/PEX14)

A consistent central interaction is with the AAA ATPase complex:
- PEX26 binds PEX6, thereby docking/recruiting the PEX1–PEX6 complex to peroxisomes (weller2005alternativesplicingsuggests pages 1-2, nashiro2011recruitingmechanismof pages 1-2).
- The PEX6-binding domain has been mapped to PEX26 residues ~29–174 in human (weller2005alternativesplicingsuggests pages 1-2, guder2019isoformspecificdomainorganization pages 1-5).

More recent structure–function mapping additionally reports that PEX26 can interact with the docking/translocation machinery components PEX13 and PEX14, with a C-terminal region implicated in these interactions and the TMD required for at least some binding (guder2019isoformspecificdomainorganization pages 20-23, guder2019isoformspecificdomainorganization pages 1-5).

2.3 Mechanism of recruiting the AAA ATPases (nucleotide-state dependence)

Mechanistic experiments indicate PEX26-mediated recruitment is regulated by the nucleotide state of the ATPases:
- Binding of PEX1/PEX6 to PEX26 depends on ATP binding (but not necessarily hydrolysis), while stable localization of PEX1 to peroxisomes requires ATP hydrolysis; PEX6 targeting requires ATP but not hydrolysis (nashiro2011recruitingmechanismof pages 1-2).
- PEX26 residues 33–40 are functionally important: truncation removing these residues disrupts recruitment and fails to complement a PEX26-deficient mammalian cell model (nashiro2011recruitingmechanismof pages 1-2).

2.4 Oligomerization and domain architecture (functional consequences)

PEX26 also exhibits self-association properties relevant to function:
- It forms homo-/hetero-oligomers; two oligomerization regions adjacent to the TMD contain conserved heptad-repeat/coiled-coil features (guder2019isoformspecificdomainorganization pages 20-23, guder2019isoformspecificdomainorganization pages 1-5).
- Disease-linked truncations that remove C-terminal oligomerization/TMD elements can retain in vitro PEX6 binding yet fail to homooligomerize, suggesting that correct assembly/targeting is crucial for in-cell function (guder2019isoformspecificdomainorganization pages 20-23).

3) Disease relevance: Zellweger spectrum/peroxisome biogenesis disorders (PEX26)

3.1 Genetic evidence and cellular phenotype

PEX26 defects are linked to peroxisome biogenesis disorders in the Zellweger spectrum, historically described as a Zellweger complementation group (CG8 in one classification). In human cell models/patient context, PEX26 deficiency impairs import of both PTS1 and PTS2 matrix proteins, consistent with a fundamental biogenesis defect (weller2005alternativesplicingsuggests pages 1-2).

3.2 Variant-level examples supported by retrieved sources

Exon 4 biallelic deletion (2024): A 2024 case report identified a homozygous (biallelic) in-frame deletion of PEX26 exon 4 (NM_001127649.3) detected by WES plus CNV analysis. The authors state exon 4 encodes the PEX26 transmembrane domain, and its absence is expected to disrupt anchoring/localization and function. The proband showed developmental delay, sensorineural hearing loss, retinal involvement/visual impairment, and hepatosplenic involvement with later hepatic dysfunction, interpreted as overlapping Zellweger spectrum and infantile Refsum disease features (yalcınkaya2024biallelicdeletionof pages 1-2). Visual evidence in the paper includes PCR/CNV confirmation and a protein schematic highlighting the deleted TMD region (yalcınkaya2024biallelicdeletionof media 670d0128, yalcınkaya2024biallelicdeletionof media cd75fe1b).
Truncating variants (mechanistic implication): Structure–function analysis reports truncating patient-associated variants (e.g., W99X, R192X) produce C-terminal truncations lacking oligomerization regions/TMD; these can bind PEX6 in vitro but fail to homooligomerize, offering a mechanistic rationale for pathogenicity via impaired assembly/targeting (guder2019isoformspecificdomainorganization pages 20-23, guder2020strukturelleundfunktionelle pages 16-16).

4) Recent developments (prioritizing 2023–2024)

4.1 Updated mechanistic synthesis (2024 review)

A 2024 review consolidates a contemporary model in which PEX26 anchors the PEX1–PEX6 AAA ATPase; ubiquitinated PEX5 directly engages the ATPase complex and is extracted/unfolded in an ATP-hydrolysis-dependent cycle that resets the import machinery (kumar2024theperoxisomean pages 10-11). This provides expert synthesis of how PEX26 fits into the receptor recycling pathway.

4.2 New mechanistic insight into PEX26 targeting (2024 iScience)

A 2024 primary study provides mechanistic detail of PEX19 handling of the PEX26 TMD and PEX3-triggered release for peroxisomal insertion, and argues PEX26 is not handled by the canonical ER TA chaperone Get3/TRC40 (oh2024adualrole pages 1-2). This is directly relevant to understanding how PEX26 reaches its functional location.

4.3 New clinical genotype expanding PEX26 spectrum (2024)

The 2024 PEX26 exon 4 deletion case emphasizes the utility of CNV-aware exome analysis for diagnosing PEX26-related disease, and highlights that loss of the transmembrane anchor can manifest with an atypical, later-evolving phenotype (yalcınkaya2024biallelicdeletionof pages 1-2, yalcınkaya2024biallelicdeletionof media 670d0128, yalcınkaya2024biallelicdeletionof media cd75fe1b).

5) Current applications and real-world implementations

5.1 Clinical genetics and diagnostic workflows

PEX26 is routinely included in gene panels/exome interpretation for suspected peroxisome biogenesis disorders/Zellweger spectrum. A practical implementation highlighted by recent case work is the need to incorporate copy-number (CNV) analysis into WES pipelines to detect single-exon deletions that may be missed by SNV-only approaches (yalcınkaya2024biallelicdeletionof pages 1-2, yalcınkaya2024biallelicdeletionof media 670d0128).

5.2 Genotype-to-mechanism interpretation

Mechanistic mapping studies provide a framework for interpreting variants by region/function: variants disrupting the TMD or nearby coiled-coil/oligomerization domains are predicted to compromise peroxisomal localization/assembly even if some PEX6 binding is retained, while variants affecting the N-terminal PEX6-binding region may directly impair recruitment of the PEX1–PEX6 motor (guder2019isoformspecificdomainorganization pages 20-23, guder2019isoformspecificdomainorganization pages 1-5, nashiro2011recruitingmechanismof pages 1-2).

6) Expert opinions and analysis (authoritative sources)

Review-level consensus places PEX26 as the membrane anchor for the PEX1–PEX6 AAA ATPase and a critical element of the receptor recycling system (kumar2024theperoxisomean pages 10-11).
Primary mechanistic studies support a regulated recruitment mechanism (ATP-state dependent) and define sequence elements required for recruitment/complementation (nashiro2011recruitingmechanismof pages 1-2), while newer cell biology work emphasizes the chaperone-mediated TA insertion pathway as a prerequisite for function (oh2024adualrole pages 1-2).

7) Relevant statistics and data from recent studies

A 2024 case report cites population prevalence estimates for peroxisome biogenesis disorders of approximately 1:133,000 (USA) and 1:500,000 (Japan) (yalcınkaya2024biallelicdeletionof pages 1-2).

8) Key references (with publication dates and URLs)

Weller et al. 2005-06. Alternative splicing suggests extended function of PEX26 in peroxisome biogenesis. Am J Hum Genet. https://doi.org/10.1086/430637 (weller2005alternativesplicingsuggests pages 1-2)
Nashiro et al. 2011-06. Recruiting mechanism of the AAA peroxins, Pex1p and Pex6p, to Pex26p on the peroxisomal membrane. Traffic. https://doi.org/10.1111/j.1600-0854.2011.01182.x (nashiro2011recruitingmechanismof pages 1-2)
Guder et al. 2019-03. Isoform-specific domain organization determines conformation and function of the peroxisomal biogenesis factor PEX26. BBA Mol Cell Res. https://doi.org/10.1016/j.bbamcr.2018.10.013 (guder2019isoformspecificdomainorganization pages 1-5)
Kumar et al. 2024-01. The peroxisome: an update on mysteries 3.0. Histochem Cell Biol. https://doi.org/10.1007/s00418-023-02259-5 (kumar2024theperoxisomean pages 10-11)
Oh et al. 2024-04. A dual role of the conserved PEX19 helix in safeguarding peroxisomal membrane proteins. iScience. https://doi.org/10.1016/j.isci.2024.109537 (oh2024adualrole pages 1-2)
Yalçınkaya et al. 2024-04. Biallelic Deletion of PEX26 Exon 4… Molecular Syndromology. https://doi.org/10.1159/000538676 (yalcınkaya2024biallelicdeletionof pages 1-2)

9) Scope limitations of this report

Within the retrieved evidence, the strongest 2023–2024 PEX26-specific advances are (i) the PEX19/PEX3 TA insertion mechanism and (ii) a 2024 CNV case report. Broad, high-quality 2023–2024 clinical reviews on Zellweger spectrum disorders and some biochemical-diagnostic advances were identified during searching but were not retrievable in full text within the current tool context; therefore, statistics on PEX26’s fraction of ZSD cases beyond the cited case-report prevalence estimates are not comprehensively synthesized here (yalcınkaya2024biallelicdeletionof pages 1-2).

References

(weller2005alternativesplicingsuggests pages 1-2): Sabine Weller, Ivelisse Cajigas, James Morrell, Cassandra Obie, Gary Steel, Stephen J. Gould, and David Valle. Alternative splicing suggests extended function of pex26 in peroxisome biogenesis. American journal of human genetics, 76 6:987-1007, Jun 2005. URL: https://doi.org/10.1086/430637, doi:10.1086/430637. This article has 73 citations and is from a highest quality peer-reviewed journal.
(guder2019isoformspecificdomainorganization pages 1-5): Philipp Guder, Amelie S. Lotz-Havla, Mathias Woidy, Dunja D. Reiß, Marta K. Danecka, Ulrich A. Schatz, Marc Becker, Regina Ensenauer, Philipp Pagel, Lars Büttner, Ania C. Muntau, and Søren W. Gersting. Isoform-specific domain organization determines conformation and function of the peroxisomal biogenesis factor pex26. Biochimica et biophysica acta. Molecular cell research, 1866 3:518-531, Mar 2019. URL: https://doi.org/10.1016/j.bbamcr.2018.10.013, doi:10.1016/j.bbamcr.2018.10.013. This article has 16 citations.
(nashiro2011recruitingmechanismof pages 1-2): Chika Nashiro, Astuko Kashiwagi, Takashi Matsuzaki, Shigehiko Tamura, and Yukio Fujiki. Recruiting mechanism of the aaa peroxins, pex1p and pex6p, to pex26p on the peroxisomal membrane. Traffic, 12:774-788, Jun 2011. URL: https://doi.org/10.1111/j.1600-0854.2011.01182.x, doi:10.1111/j.1600-0854.2011.01182.x. This article has 35 citations and is from a peer-reviewed journal.
(kumar2024theperoxisomean pages 10-11): Rechal Kumar, Markus Islinger, Harley Worthy, Ruth Carmichael, and Michael Schrader. The peroxisome: an update on mysteries 3.0. Histochemistry and Cell Biology, 161:99-132, Jan 2024. URL: https://doi.org/10.1007/s00418-023-02259-5, doi:10.1007/s00418-023-02259-5. This article has 73 citations and is from a peer-reviewed journal.
(oh2024adualrole pages 1-2): Jeonghyun Oh, Do Kyung Kim, Seung Hae Ahn, Ho Min Kim, and Hyunju Cho. A dual role of the conserved pex19 helix in safeguarding peroxisomal membrane proteins. Apr 2024. URL: https://doi.org/10.1016/j.isci.2024.109537, doi:10.1016/j.isci.2024.109537. This article has 5 citations and is from a peer-reviewed journal.
(guder2019isoformspecificdomainorganization pages 20-23): Philipp Guder, Amelie S. Lotz-Havla, Mathias Woidy, Dunja D. Reiß, Marta K. Danecka, Ulrich A. Schatz, Marc Becker, Regina Ensenauer, Philipp Pagel, Lars Büttner, Ania C. Muntau, and Søren W. Gersting. Isoform-specific domain organization determines conformation and function of the peroxisomal biogenesis factor pex26. Biochimica et biophysica acta. Molecular cell research, 1866 3:518-531, Mar 2019. URL: https://doi.org/10.1016/j.bbamcr.2018.10.013, doi:10.1016/j.bbamcr.2018.10.013. This article has 16 citations.
(yalcınkaya2024biallelicdeletionof pages 1-2): Burhanettin Yalçınkaya, Kübra Adanur Sağlam, Kerem Terali, Emine Tekin, Hava Taslak, and Ayberk Türkyılmaz. Biallelic deletion of pex26 exon 4 in a boy with phenotypic features of both zellweger syndrome and infantile refsum disease. Molecular Syndromology, 15:380-388, Apr 2024. URL: https://doi.org/10.1159/000538676, doi:10.1159/000538676. This article has 0 citations and is from a peer-reviewed journal.
(yalcınkaya2024biallelicdeletionof media 670d0128): Burhanettin Yalçınkaya, Kübra Adanur Sağlam, Kerem Terali, Emine Tekin, Hava Taslak, and Ayberk Türkyılmaz. Biallelic deletion of pex26 exon 4 in a boy with phenotypic features of both zellweger syndrome and infantile refsum disease. Molecular Syndromology, 15:380-388, Apr 2024. URL: https://doi.org/10.1159/000538676, doi:10.1159/000538676. This article has 0 citations and is from a peer-reviewed journal.
(yalcınkaya2024biallelicdeletionof media cd75fe1b): Burhanettin Yalçınkaya, Kübra Adanur Sağlam, Kerem Terali, Emine Tekin, Hava Taslak, and Ayberk Türkyılmaz. Biallelic deletion of pex26 exon 4 in a boy with phenotypic features of both zellweger syndrome and infantile refsum disease. Molecular Syndromology, 15:380-388, Apr 2024. URL: https://doi.org/10.1159/000538676, doi:10.1159/000538676. This article has 0 citations and is from a peer-reviewed journal.
(guder2020strukturelleundfunktionelle pages 16-16): P Guder. Strukturelle und funktionelle charakterisierung des humanen peroxins pex26. Unknown journal, 2020.

Citations

kumar2024theperoxisomean pages 10-11
oh2024adualrole pages 1-2
guder2019isoformspecificdomainorganization pages 1-5
nashiro2011recruitingmechanismof pages 1-2
guder2019isoformspecificdomainorganization pages 20-23
weller2005alternativesplicingsuggests pages 1-2
yalcınkaya2024biallelicdeletionof pages 1-2
guder2020strukturelleundfunktionelle pages 16-16
https://doi.org/10.1086/430637
https://doi.org/10.1111/j.1600-0854.2011.01182.x
https://doi.org/10.1016/j.bbamcr.2018.10.013
https://doi.org/10.1007/s00418-023-02259-5
https://doi.org/10.1016/j.isci.2024.109537
https://doi.org/10.1159/000538676
https://doi.org/10.1086/430637,
https://doi.org/10.1016/j.bbamcr.2018.10.013,
https://doi.org/10.1111/j.1600-0854.2011.01182.x,
https://doi.org/10.1007/s00418-023-02259-5,
https://doi.org/10.1016/j.isci.2024.109537,
https://doi.org/10.1159/000538676,

📄 View Raw YAML

id: Q7Z412
gene_symbol: PEX26
product_type: PROTEIN
status: IN_PROGRESS
taxon:
  id: NCBITaxon:9606
  label: Homo sapiens
description: >-
  PEX26 encodes peroxin-26, a tail-anchored peroxisomal membrane protein that functions as
  the membrane docking factor for the PEX1-PEX6 AAA+ ATPase complex. PEX26 directly binds
  PEX6 via its N-terminal cytoplasmic domain (residues 29-174) and indirectly recruits PEX1
  through PEX6. The PEX1-PEX6-PEX26 complex is essential for extracting the ubiquitinated
  PEX5 receptor from the peroxisomal membrane after cargo delivery, thereby enabling receptor
  recycling and continued rounds of peroxisomal matrix protein import. PEX26 is a vertebrate-specific
  gene that is functionally analogous (but not homologous) to yeast PEX15. It is targeted to
  the peroxisomal membrane via C-terminal PEX19-binding sites. Mutations in PEX26 cause
  Zellweger spectrum disorders (complementation group 8), accounting for approximately 5%
  of peroxisome biogenesis disorder cases. PEX26 is widely expressed, with highest levels
  in kidney, liver, brain, and skeletal muscle.
alternative_products:
- name: '1'
  id: Q7Z412-1
- name: '2'
  id: Q7Z412-2
  sequence_note: VSP_053499
existing_annotations:
# --- IBA annotations (phylogenetic) ---
- term:
    id: GO:0005777
    label: peroxisome
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  review:
    summary: >-
      PEX26 is an integral peroxisomal membrane protein. Multiple experimental studies
      confirm its localization to peroxisomes (PMID:12717447, PMID:16257970, PMID:16763195).
      The IBA annotation for peroxisome is well-supported by phylogenetic inference and
      consistent with all experimental evidence. However, PEX26 more specifically localizes
      to the peroxisomal membrane (GO:0005778), so this broader term is acceptable but
      less informative than the more specific IDA-supported annotations.
    action: ACCEPT
    reason: >-
      PEX26 is a bona fide peroxisomal protein. While GO:0005778 (peroxisomal membrane)
      is more precise, this broader CC annotation is not incorrect and is well-supported
      by phylogenetic analysis across vertebrates. Multiple IDA annotations also support
      peroxisomal localization (PMID:12717447, PMID:16257970, PMID:16763195).
    supported_by:
      - reference_id: PMID:12717447
        supporting_text: >-
          Expression of PEX26 restores peroxisomal protein import in the fibroblasts of
          an individual with PBD of CG8
      - reference_id: PMID:16763195
        supporting_text: >-
          Here we analyzed targeting of the human peroxisomal tail-anchored protein PEX26

- term:
    id: GO:0016558
    label: protein import into peroxisome matrix
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  review:
    summary: >-
      PEX26 is essential for peroxisomal matrix protein import. PEX26-deficient cells show
      impaired import of both PTS1- and PTS2-targeted matrix proteins (PMID:15858711,
      PMID:12717447). The IBA annotation correctly captures a core biological process for
      PEX26. However, the more specific child term GO:0016562 (protein import into peroxisome
      matrix, receptor recycling) more accurately describes PEX26's specific role in this
      process.
    action: ACCEPT
    reason: >-
      PEX26 is required for peroxisomal matrix protein import. While GO:0016562 (receptor
      recycling) is more specific to PEX26's mechanism, this broader term is not incorrect.
      The IBA annotation is phylogenetically sound. Multiple experimental papers confirm
      PEX26's role in this process (PMID:12717447, PMID:15858711, PMID:16257970).
    supported_by:
      - reference_id: PMID:15858711
        supporting_text: >-
          PEX26 deficiency impairs peroxisomal import of both PTS1- and PTS2-targeted
          matrix proteins
      - reference_id: PMID:12717447
        supporting_text: >-
          Expression of PEX26 restores peroxisomal protein import in the fibroblasts of
          an individual with PBD of CG8

- term:
    id: GO:0051117
    label: ATPase binding
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  review:
    summary: >-
      PEX26 directly binds PEX6, an AAA+ ATPase, and indirectly recruits PEX1, another
      AAA+ ATPase, through PEX6 (PMID:12717447, PMID:16257970, PMID:16854980). The IBA
      annotation for ATPase binding is well-supported and represents a core molecular
      function of PEX26.
    action: ACCEPT
    reason: >-
      PEX26 directly interacts with PEX6 (an AAA+ ATPase) and indirectly with PEX1 (also
      an AAA+ ATPase). This ATPase binding activity is central to PEX26's function as the
      membrane anchor for the PEX1-PEX6 complex. IBA is phylogenetically sound, and
      experimental IPI evidence from PMID:16257970 also supports this annotation.
    supported_by:
      - reference_id: PMID:12717447
        supporting_text: >-
          Pex6 and Pex1 of the AAA ATPase family co-immunoprecipitate with Pex26
      - reference_id: PMID:16257970
        supporting_text: >-
          insufficient binding to Pex1p x Pex6p complexes...is most likely responsible
          for the CG8 PBDs

# --- IEA annotations (electronic) ---
- term:
    id: GO:0005778
    label: peroxisomal membrane
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  review:
    summary: >-
      PEX26 is an integral peroxisomal membrane protein with a single C-terminal
      transmembrane domain (residues 247-267 per UniProt). This IEA annotation is correct
      and well-supported by multiple experimental studies demonstrating peroxisomal membrane
      localization (PMID:12717447, PMID:16257970).
    action: ACCEPT
    reason: >-
      The automated annotation is correct. PEX26 is a type II integral membrane protein
      of the peroxisomal membrane, confirmed by multiple IDA studies. The IEA annotation
      is redundant with IDA annotations but not incorrect.
    supported_by:
      - reference_id: PMID:12717447
        supporting_text: >-
          we have isolated human PEX26 encoding a type II peroxisomal membrane protein

- term:
    id: GO:0015031
    label: protein transport
  evidence_type: IEA
  original_reference_id: GO_REF:0000043
  review:
    summary: >-
      PEX26 is involved in protein transport -- specifically the import of peroxisomal
      matrix proteins. This IEA annotation from UniProt keyword mapping (Protein transport
      keyword) is correct but very general. More specific terms such as GO:0016558 (protein
      import into peroxisome matrix) or GO:0016562 (receptor recycling) better describe
      PEX26's role.
    action: ACCEPT
    reason: >-
      While overly broad, this IEA annotation is not incorrect. PEX26 is involved in
      protein transport (specifically peroxisomal matrix protein import). The more specific
      annotations from IDA/IBA evidence are more informative, but this general IEA
      annotation is acceptable as a broader parent annotation.

- term:
    id: GO:0044877
    label: protein-containing complex binding
  evidence_type: IEA
  original_reference_id: GO_REF:0000002
  review:
    summary: >-
      PEX26 binds the PEX1-PEX6 AAA+ ATPase complex. The InterPro-derived IEA annotation
      for protein-containing complex binding is correct in that PEX26 binds the PEX1-PEX6
      hexameric complex (PMID:16854980). However, the more specific GO:0051117 (ATPase
      binding) better describes the molecular function.
    action: ACCEPT
    reason: >-
      PEX26 does bind a protein-containing complex (the PEX1-PEX6 heterohexamer). This
      IEA is consistent with experimental evidence from PMID:16854980 showing PEX26 binds
      the assembled PEX1-PEX6 complex. While ATPase binding (GO:0051117) is more specific,
      this broader term is acceptable for an IEA annotation.
    supported_by:
      - reference_id: PMID:16854980
        supporting_text: >-
          PEX26 responsible for peroxisome biogenesis disorders of CG8 encodes Pex26p,
          the recruiter of Pex1p.Pex6p complexes to peroxisomes

- term:
    id: GO:0045046
    label: protein import into peroxisome membrane
  evidence_type: IEA
  original_reference_id: GO_REF:0000002
  review:
    summary: >-
      This IEA annotation from InterPro suggests PEX26 is involved in protein import
      into the peroxisome membrane (i.e., PMP import). However, PEX26's established
      function is in peroxisomal matrix protein import (specifically receptor recycling
      after matrix protein import), not in peroxisomal membrane protein import. PEX26
      itself is a PMP that is imported into the peroxisome membrane via PEX19/PEX3, but
      PEX26 does not facilitate PMP import. This annotation conflates PEX26 being a PMP
      with PEX26 functioning in PMP import.
    action: REMOVE
    reason: >-
      PEX26 is not involved in importing proteins into the peroxisomal membrane. PEX26's
      role is in peroxisomal matrix protein import via receptor recycling. PEX26 is itself
      a substrate of the PEX19/PEX3 PMP import pathway (PMID:16763195), but it does not
      facilitate PMP import for other proteins. This IEA annotation likely results from
      an overly broad InterPro domain annotation.
    supported_by:
      - reference_id: PMID:16763195
        supporting_text: >-
          we show that PEX19 is essential for PEX26 import
      - reference_id: PMID:12717447
        supporting_text: >-
          Pex26 recruits Pex6-Pex1 complexes to peroxisomes

# --- IPI protein binding annotations ---
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:16189514
  review:
    summary: >-
      PMID:16189514 is a large-scale Y2H interactome mapping study (Rual et al. 2005).
      Protein binding is uninformative as a GO term and does not describe PEX26's specific
      molecular interactions. The more informative terms ATPase binding (GO:0051117) and
      protein-membrane adaptor activity (GO:0043495) better capture PEX26's function.
    action: MARK_AS_OVER_ANNOTATED
    reason: >-
      Per curation guidelines, protein binding (GO:0005515) is uninformative and should
      be replaced with more specific MF terms. PEX26's key binding interactions are
      captured by GO:0051117 (ATPase binding) for its interaction with PEX1/PEX6. This
      large-scale screen (PMID:16189514) likely detected many non-physiological
      interactions alongside any real ones.

- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:20531392
  review:
    summary: >-
      PMID:20531392 (Schueller et al. 2010) describes the structural basis for PEX19
      recognition of mPTS signals. PEX26 is identified as a PEX19 binding partner via
      its C-terminal mPTS. While the interaction with PEX19 is real and physiologically
      relevant for PEX26 targeting to peroxisomes, protein binding is uninformative.
    action: MARK_AS_OVER_ANNOTATED
    reason: >-
      Protein binding is uninformative. The interaction between PEX26 and PEX19 is real
      and relates to PEX26's targeting to peroxisomes (PMID:16763195, PMID:20531392),
      but should be annotated with a more specific term if one exists. PEX26 is a client
      of PEX19 for membrane insertion, not the other way around.

- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:32296183
  review:
    summary: >-
      PMID:32296183 (Luck et al. 2020) is a large-scale binary interactome mapping study.
      Protein binding is uninformative and the interactions detected in high-throughput
      screens may not reflect physiological PEX26 interactions.
    action: MARK_AS_OVER_ANNOTATED
    reason: >-
      Protein binding is uninformative per curation guidelines. High-throughput interactome
      studies detect many interactions that may not be physiologically relevant to PEX26's
      core function.

- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:32814053
  review:
    summary: >-
      PMID:32814053 (Haenig et al. 2020) is a neurodegenerative disease interactome mapping
      study. Protein binding is uninformative and the interactions detected may not be
      specific to PEX26's function.
    action: MARK_AS_OVER_ANNOTATED
    reason: >-
      Protein binding is uninformative per curation guidelines. This high-throughput
      interactome study is focused on neurodegenerative disease networks and any PEX26
      interactions detected may be incidental.

# --- NAS annotations ---
- term:
    id: GO:0005778
    label: peroxisomal membrane
  evidence_type: NAS
  original_reference_id: PMID:35805150
  review:
    summary: >-
      PMID:35805150 (Judy et al. 2022) is a review article on PEX1/PEX6 structure and
      function that describes PEX26 as the membrane anchor that recruits PEX1/PEX6 to the
      peroxisome membrane. The NAS annotation for peroxisomal membrane is correct and
      consistent with multiple experimental studies.
    action: ACCEPT
    reason: >-
      PEX26 is well-established as a peroxisomal membrane protein. Although this NAS
      annotation is from a review (PMID:35805150), it is consistent with primary experimental
      evidence (PMID:12717447, PMID:16257970) and redundant with IDA annotations.
    supported_by:
      - reference_id: PMID:35805150
        supporting_text: >-
          its partner protein—named Pex15 in S. cerevisiae or PEX26 in other organisms—that
          recruits Pex1/Pex6 to the peroxisome membrane

- term:
    id: GO:0016562
    label: protein import into peroxisome matrix, receptor recycling
  evidence_type: NAS
  original_reference_id: PMID:35805150
  review:
    summary: >-
      PEX26 is a key component of the receptor export module that enables PEX5 receptor
      recycling after cargo delivery. PMID:35805150 states that PEX1/PEX6 is necessary to
      extract Pex5 from the peroxisome membrane for subsequent rounds of import, and PEX26
      is the membrane anchor for this complex. GO:0016562 is the most specific and accurate
      term for PEX26's role in peroxisomal biology.
    action: ACCEPT
    reason: >-
      This is the most precise BP annotation for PEX26. PEX26 anchors the PEX1-PEX6 complex
      that drives PEX5 receptor recycling. The review (PMID:35805150) synthesizes extensive
      primary literature supporting this function. This term accurately describes PEX26's
      specific mechanistic role within the broader process of peroxisomal matrix protein
      import.
    supported_by:
      - reference_id: PMID:35805150
        supporting_text: >-
          Pex1/Pex6 is necessary to extract Pex5 from the peroxisome membrane for subsequent
          rounds of import...Receptor recycling remains the canonical role for Pex1/Pex6
          across eukaryotes

# --- IDA annotations from PMID:12717447 (Matsumoto et al. 2003) ---
- term:
    id: GO:0005778
    label: peroxisomal membrane
  evidence_type: IDA
  original_reference_id: PMID:12717447
  review:
    summary: >-
      Matsumoto et al. (2003) identified PEX26 as a type II peroxisomal membrane protein
      with a single C-terminal transmembrane domain. They demonstrated peroxisomal membrane
      localization using epitope-tagged constructs and immunofluorescence.
    action: ACCEPT
    reason: >-
      This is a core CC annotation for PEX26. The original identification paper (PMID:12717447)
      directly demonstrated that PEX26 is an integral protein of the peroxisomal membrane with
      type II topology.
    supported_by:
      - reference_id: PMID:12717447
        supporting_text: >-
          we have isolated human PEX26 encoding a type II peroxisomal membrane protein of
          relative molecular mass 34,000

- term:
    id: GO:0016558
    label: protein import into peroxisome matrix
  evidence_type: IDA
  original_reference_id: PMID:12717447
  review:
    summary: >-
      Matsumoto et al. (2003) showed that expression of PEX26 restores peroxisomal protein
      import in CG8 patient fibroblasts. This directly demonstrates PEX26's requirement for
      peroxisomal matrix protein import.
    action: ACCEPT
    reason: >-
      Direct experimental evidence showing PEX26 expression rescues peroxisomal protein import
      in PEX26-deficient cells. This is a core biological process for PEX26.
    supported_by:
      - reference_id: PMID:12717447
        supporting_text: >-
          Expression of PEX26 restores peroxisomal protein import in the fibroblasts of an
          individual with PBD of CG8

- term:
    id: GO:0022615
    label: protein to membrane docking
  evidence_type: IDA
  original_reference_id: PMID:12717447
  review:
    summary: >-
      PEX26 recruits the PEX1-PEX6 AAA ATPase complex to the peroxisomal membrane, which
      can be described as a docking function. Matsumoto et al. showed that PEX6 and PEX1
      colocalize with peroxisomes in wild-type cells but not in PEX26-defective cells, and
      that PEX26 expression restores this colocalization. This term describes PEX26's role
      in mediating the association of soluble PEX1-PEX6 with the peroxisomal membrane.
    action: ACCEPT
    reason: >-
      PEX26 functions as the membrane docking receptor for the PEX1-PEX6 complex. This is
      a core function supported by direct evidence showing that PEX26 is required for
      peroxisomal localization of PEX6 and PEX1 (PMID:12717447).
    supported_by:
      - reference_id: PMID:12717447
        supporting_text: >-
          Epitope-tagged Pex6 and Pex1 are discernible as puncta in normal CHO-K1 cells,
          but not in PEX26-defective cells. PEX26 expression in ZP167 cells re-establishes
          colocalization of Pex6 and Pex1 with Pex26

- term:
    id: GO:0043495
    label: protein-membrane adaptor activity
  evidence_type: IDA
  original_reference_id: PMID:12717447
  review:
    summary: >-
      PEX26 acts as an adaptor that recruits the cytosolic PEX1-PEX6 complex to the
      peroxisomal membrane. Matsumoto et al. demonstrated that PEX26 co-immunoprecipitates
      with PEX6 and PEX1, and that PEX26 expression in PEX26-deficient cells restores
      peroxisomal localization of PEX6 and PEX1. This is the most appropriate MF term for
      PEX26's core molecular function.
    action: ACCEPT
    reason: >-
      Protein-membrane adaptor activity is the most accurate MF term for PEX26. It serves
      as an integral membrane protein that recruits a soluble protein complex (PEX1-PEX6)
      to the peroxisomal membrane. This is the central molecular function of PEX26.
    supported_by:
      - reference_id: PMID:12717447
        supporting_text: >-
          Pex26 recruits Pex6-Pex1 complexes to peroxisomes

# --- IDA annotations from PMID:16257970 (Furuki et al. 2006) ---
- term:
    id: GO:0043495
    label: protein-membrane adaptor activity
  evidence_type: IDA
  original_reference_id: PMID:16257970
  review:
    summary: >-
      Furuki et al. (2006) characterized disease-causing PEX26 mutations and showed they
      impair PEX26's interaction with the PEX1-PEX6 complex, its stability, and/or its
      peroxisomal localization. This further validates PEX26's protein-membrane adaptor
      function by showing that mutations disrupting this function cause disease.
    action: ACCEPT
    reason: >-
      Additional experimental support for PEX26's core MF of protein-membrane adaptor
      activity. Disease-causing mutations that disrupt PEX26's binding to PEX1-PEX6
      or its membrane localization cause peroxisome biogenesis disorders (PMID:16257970).
    supported_by:
      - reference_id: PMID:16257970
        supporting_text: >-
          the instability, insufficient binding to Pex1p x Pex6p complexes, or
          mislocalization of patient-derived Pex26p mutants is most likely responsible
          for the CG8 PBDs

# --- Reactome TAS annotations for cytosol ---
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-9603775
  review:
    summary: >-
      This Reactome annotation reflects PEX26's involvement in the PEX3:PEX19:class I PMP
      dissociation reaction, where PEX19-bound PMPs (including PEX26) transit through the
      cytosol before membrane insertion. PEX26 is synthesized in the cytosol and transiently
      present there before insertion into the peroxisomal membrane via the PEX19/PEX3
      pathway. However, PEX26's functional localization is the peroxisomal membrane.
    action: KEEP_AS_NON_CORE
    reason: >-
      PEX26 does transit through the cytosol as part of the PEX19-mediated PMP import
      pathway, so the annotation is technically correct. However, the cytosol is not the
      primary functional location of PEX26; it is a transient localization during membrane
      targeting. Interestingly, Weller et al. (PMID:15858711) showed that a cytosolic
      PEX26 isoform (PEX26-deltaex5) lacking the transmembrane domain is functional,
      suggesting some PEX26 activity can occur in the cytosol.
    supported_by:
      - reference_id: PMID:15858711
        supporting_text: >-
          PEX26-Deltaex5 rescues peroxisome biogenesis in PEX26-deficient cells as
          efficiently as does PEX26-FL

- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-9603784
  review:
    summary: >-
      Another Reactome annotation for PEX19:class I PMP binding to PEX3, reflecting the
      cytosolic transit of PEX26 during PMP import. Same considerations as above.
    action: KEEP_AS_NON_CORE
    reason: >-
      Cytosolic localization is transient for PEX26 during its PEX19-mediated targeting
      to peroxisomes. Not the primary functional location but technically correct.

- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-9603804
  review:
    summary: >-
      Reactome annotation reflecting PEX19 binding to class I PMPs (including PEX26) in
      the cytosol. Same considerations as the other cytosol annotations.
    action: KEEP_AS_NON_CORE
    reason: >-
      Cytosolic localization is a transient step in PEX26's biogenesis pathway. Not its
      primary functional location.

# --- Reactome TAS annotations for peroxisomal membrane ---
- term:
    id: GO:0005778
    label: peroxisomal membrane
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-9033499
  review:
    summary: >-
      This Reactome reaction describes PEX1:PEX6:PEX26:ZFAND6 dissociating Ub:PEX5L and
      PEX7 from the docking/translocation module (PEX14:PEX13:PEX2:PEX10:PEX12). PEX26
      is correctly annotated to the peroxisomal membrane in this context as part of the
      receptor export module.
    action: ACCEPT
    reason: >-
      Peroxisomal membrane is the correct functional localization for PEX26 during receptor
      recycling. This Reactome annotation accurately reflects PEX26's role as part of the
      membrane-bound PEX1-PEX6-PEX26 receptor export module.

- term:
    id: GO:0005778
    label: peroxisomal membrane
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-9033516
  review:
    summary: >-
      Reactome reaction describing binding of the ubiquitinated PEX5L:PEX7 docking complex
      to PEX1:PEX6:PEX26 and ZFAND6 at the peroxisomal membrane. Correctly places PEX26
      at the peroxisomal membrane.
    action: ACCEPT
    reason: >-
      Correct localization of PEX26 during its functional role in receptor recycling at
      the peroxisomal membrane. Redundant with IDA annotation but consistent.

- term:
    id: GO:0005778
    label: peroxisomal membrane
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-9033533
  review:
    summary: >-
      Reactome reaction for PEX5S/L receptor recycling at the peroxisomal membrane.
      Same context as other Reactome peroxisomal membrane annotations.
    action: ACCEPT
    reason: >-
      Correct and consistent with PEX26's established peroxisomal membrane localization.

- term:
    id: GO:0005778
    label: peroxisomal membrane
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-9603775
  review:
    summary: >-
      Reactome reaction for PEX3:PEX19:class I PMP dissociation. PEX26 is annotated to
      peroxisomal membrane as the destination of PMP import. Correct.
    action: ACCEPT
    reason: >-
      PEX26 is correctly localized to the peroxisomal membrane after PEX19/PEX3-mediated
      insertion.

# --- IDA annotation from PMID:16763195 (Halbach et al. 2006) ---
- term:
    id: GO:0005777
    label: peroxisome
  evidence_type: IDA
  original_reference_id: PMID:16763195
  review:
    summary: >-
      Halbach et al. (2006) analyzed PEX26 targeting to peroxisomes and showed it occurs
      through C-terminal PEX19-binding sites. They demonstrated PEX26 localizes to
      peroxisomes and identified two PEX19-binding sites required for correct targeting.
    action: ACCEPT
    reason: >-
      Direct experimental evidence for PEX26 localization to peroxisomes. While GO:0005778
      (peroxisomal membrane) is more specific, the broader peroxisome annotation is not
      incorrect and is supported by the immunofluorescence data in this study.
    supported_by:
      - reference_id: PMID:16763195
        supporting_text: >-
          Here we analyzed targeting of the human peroxisomal tail-anchored protein PEX26.
          Its C-terminal-targeting signal contains two binding sites for PEX19

# --- IDA annotation from PMID:16257970 (Furuki et al. 2006) ---
- term:
    id: GO:0016558
    label: protein import into peroxisome matrix
  evidence_type: IDA
  original_reference_id: PMID:16257970
  review:
    summary: >-
      Furuki et al. (2006) showed that pathogenic PEX26 mutations impair peroxisomal protein
      import, further confirming PEX26's essential role in this process. Temperature-sensitive
      mutations showed milder phenotypes than null mutations.
    action: ACCEPT
    reason: >-
      Direct experimental evidence that PEX26 mutations impair peroxisomal matrix protein
      import. This complements the IDA annotation from PMID:12717447.
    supported_by:
      - reference_id: PMID:16257970
        supporting_text: >-
          Pex26p functions in recruiting to peroxisomes the complexes of the AAA ATPase
          peroxins, Pex1p and Pex6p

# --- IPI protein binding from PMID:16257970 ---
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:16257970
  review:
    summary: >-
      PMID:16257970 documents PEX26 interactions with PEX1 and PEX6 in the context of
      disease-causing mutations. The specific interaction with PEX6/PEX1 is better captured
      by GO:0051117 (ATPase binding) which is already annotated.
    action: MARK_AS_OVER_ANNOTATED
    reason: >-
      Protein binding is uninformative. PEX26's interaction with PEX1/PEX6 is better
      captured by GO:0051117 (ATPase binding) and GO:0043495 (protein-membrane adaptor
      activity), both of which are already annotated from this same reference.

# --- IPI protein binding from PMID:16763195 ---
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:16763195
  review:
    summary: >-
      PMID:16763195 (Halbach et al. 2006) demonstrates PEX26 interaction with PEX19
      through C-terminal binding sites. This is a real and physiologically important
      interaction for PEX26 membrane targeting, but protein binding is uninformative.
    action: MARK_AS_OVER_ANNOTATED
    reason: >-
      Protein binding is uninformative per curation guidelines. The PEX26-PEX19 interaction
      is real and important for PEX26 targeting, but should ideally be annotated with a
      more specific term. PEX26 is a client/cargo of PEX19 for membrane insertion.

# --- IDA peroxisome from PMID:16257970 ---
- term:
    id: GO:0005777
    label: peroxisome
  evidence_type: IDA
  original_reference_id: PMID:16257970
  review:
    summary: >-
      Furuki et al. (2006) confirmed PEX26 peroxisomal localization and showed that certain
      disease-causing mutations impair this localization.
    action: ACCEPT
    reason: >-
      Additional IDA evidence for PEX26 peroxisomal localization. Disease mutations that
      impair localization provide further support for the physiological significance of
      this annotation.
    supported_by:
      - reference_id: PMID:16257970
        supporting_text: >-
          mislocalization of patient-derived Pex26p mutants is most likely responsible
          for the CG8 PBDs

# --- IPI ATPase binding from PMID:16257970 ---
- term:
    id: GO:0051117
    label: ATPase binding
  evidence_type: IPI
  original_reference_id: PMID:16257970
  review:
    summary: >-
      Furuki et al. (2006) characterized PEX26 disease mutations and showed they impair
      interaction with the PEX1-PEX6 AAA ATPase complex. This provides strong experimental
      evidence for PEX26's ATPase binding activity.
    action: ACCEPT
    reason: >-
      Direct experimental IPI evidence for PEX26 binding to PEX1/PEX6 AAA ATPases. Disease
      mutations that reduce this binding cause peroxisome biogenesis disorders, confirming
      the physiological importance of this interaction.
    supported_by:
      - reference_id: PMID:16257970
        supporting_text: >-
          insufficient binding to Pex1p x Pex6p complexes...is most likely responsible
          for the CG8 PBDs

# --- IPI protein binding from PMID:15713480 ---
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:15713480
  review:
    summary: >-
      PMID:15713480 (Fransen et al. 2005) analyzed PEX19 domain structure and identified
      PEX26 as one of multiple PMPs that interact with PEX19's C-terminal domain. This
      reflects the PEX19-PEX26 interaction for membrane targeting. Protein binding is
      uninformative.
    action: MARK_AS_OVER_ANNOTATED
    reason: >-
      Protein binding is uninformative per curation guidelines. The PEX19-PEX26 interaction
      is documented but better captured by more specific terms. PEX26 is a client of PEX19
      for peroxisomal membrane insertion.
    supported_by:
      - reference_id: PMID:15713480
        supporting_text: >-
          a carboxy-terminal domain that interacts with multiple PMPs including Pex3p,
          Pex11pbeta, Pex12p, Pex13p, Pex16p, and Pex26p

# --- IDA peroxisome from PMID:15858711 (Weller et al. 2005) ---
- term:
    id: GO:0005777
    label: peroxisome
  evidence_type: IDA
  original_reference_id: PMID:15858711
  review:
    summary: >-
      Weller et al. (2005) showed full-length PEX26 localizes to peroxisomes but the
      alternatively spliced PEX26-deltaex5 (lacking the transmembrane domain) is cytosolic
      yet functional. This study confirms peroxisomal localization of the full-length protein.
    action: ACCEPT
    reason: >-
      IDA evidence for PEX26 peroxisomal localization from the full-length protein. While
      an alternatively spliced cytosolic isoform also exists, the main isoform is
      peroxisomal.
    supported_by:
      - reference_id: PMID:15858711
        supporting_text: >-
          it encodes an integral peroxisomal membrane protein with a single C-terminal
          transmembrane domain and a cytosolic N-terminus

# --- IMP protein import into peroxisome matrix from PMID:15858711 ---
- term:
    id: GO:0016558
    label: protein import into peroxisome matrix
  evidence_type: IMP
  original_reference_id: PMID:15858711
  review:
    summary: >-
      Weller et al. (2005) performed quantitative studies showing PEX26-deficient cells have
      substantial defects in import of PTS1-targeted proteins (PECI, HAOX1, catalase) and
      PTS2-targeted proteins (PAHX). They showed both PTS1 and PTS2 import are impaired in
      CG8 cells, correcting earlier reports that only PTS2 and catalase import were affected.
    action: ACCEPT
    reason: >-
      Strong IMP evidence from quantitative import assays showing PEX26 deficiency impairs
      both PTS1 and PTS2 peroxisomal matrix protein import. This is a core function.
    supported_by:
      - reference_id: PMID:15858711
        supporting_text: >-
          PEX26 deficiency impairs peroxisomal import of both PTS1- and PTS2-targeted
          matrix proteins
      - reference_id: PMID:15858711
        supporting_text: >-
          our results show a clear and substantial defect in all three PTS1-targeted
          reporters, most severe for catalase but substantial for PECI and HAOX1

# --- IPI protein binding from PMID:16854980 ---
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:16854980
  review:
    summary: >-
      PMID:16854980 (Tamura et al. 2006) studied the dynamic assembly of PEX1, PEX6, and
      PEX26. PEX26 interaction with PEX1/PEX6 is better captured by GO:0051117 (ATPase
      binding) and GO:0043495 (protein-membrane adaptor activity). Protein binding is
      uninformative.
    action: MARK_AS_OVER_ANNOTATED
    reason: >-
      Protein binding is uninformative per curation guidelines. The PEX26-PEX1/PEX6
      interactions described in PMID:16854980 are better captured by the already-annotated
      GO:0051117 (ATPase binding) and GO:0044877 (protein-containing complex binding).

# --- IDA protein-containing complex binding from PMID:16854980 ---
- term:
    id: GO:0044877
    label: protein-containing complex binding
  evidence_type: IDA
  original_reference_id: PMID:16854980
  review:
    summary: >-
      Tamura et al. (2006) demonstrated that PEX26 binds the assembled PEX1-PEX6 complex
      and showed that endogenous PEX6 and PEX26 are predominantly localized on peroxisomes,
      while PEX1 forms homo-oligomers in the cytoplasm that undergo conformational change
      upon interaction with PEX6.
    action: ACCEPT
    reason: >-
      PEX26 binds the PEX1-PEX6 heterohexameric complex. This IDA annotation captures
      PEX26's ability to bind a multi-subunit protein complex, which is its core function
      as the membrane docking receptor for the PEX1-PEX6 ATPase complex.
    supported_by:
      - reference_id: PMID:16854980
        supporting_text: >-
          PEX26 responsible for peroxisome biogenesis disorders of CG8 encodes Pex26p,
          the recruiter of Pex1p.Pex6p complexes to peroxisomes
      - reference_id: PMID:16854980
        supporting_text: >-
          endogenous Pex1p was partly localized likely as a homo-oligomer in the cytoplasm,
          while Pex6p and Pex26p were predominantly localized on peroxisomes

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:0000120
  title: Combined Automated Annotation using Multiple IEA Methods
  findings: []
- id: PMID:12717447
  title: The pathogenic peroxin Pex26p recruits the Pex1p-Pex6p AAA ATPase complexes
    to peroxisomes.
  findings: []
- id: PMID:15713480
  title: Analysis of human Pex19p's domain structure by pentapeptide scanning mutagenesis.
  findings: []
- id: PMID:15858711
  title: Alternative splicing suggests extended function of PEX26 in peroxisome biogenesis.
  findings: []
- id: PMID:16189514
  title: Towards a proteome-scale map of the human protein-protein interaction network.
  findings: []
- id: PMID:16257970
  title: Mutations in the peroxin Pex26p responsible for peroxisome biogenesis disorders
    of complementation group 8 impair its stability, peroxisomal localization, and
    interaction with the Pex1p x Pex6p complex.
  findings: []
- id: PMID:16763195
  title: Targeting of the tail-anchored peroxisomal membrane proteins PEX26 and PEX15
    occurs through C-terminal PEX19-binding sites.
  findings: []
- id: PMID:16854980
  title: Dynamic and functional assembly of the AAA peroxins, Pex1p and Pex6p, and
    their membrane receptor Pex26p.
  findings: []
- id: PMID:20531392
  title: The peroxisomal receptor Pex19p forms a helical mPTS recognition domain.
  findings: []
- id: PMID:32296183
  title: A reference map of the human binary protein interactome.
  findings: []
- id: PMID:32814053
  title: Interactome Mapping Provides a Network of Neurodegenerative Disease Proteins
    and Uncovers Widespread Protein Aggregation in Affected Brains.
  findings: []
- id: PMID:35805150
  title: Insights into the Structure and Function of the Pex1/Pex6 AAA-ATPase in Peroxisome
    Homeostasis.
  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-9033516
  title: PEX2:PEX10:PEX12:Ub:PEX5L:PEX7:PEX13:PEX14 binds PEX1:PEX6:PEX26 and ZFAND6
  findings: []
- id: Reactome:R-HSA-9033533
  title: PEX2:PEX10:PEX12:Ub:PEX5S,L:PEX13:PEX14 binds PEX1:PEX6:PEX26 and ZFAND6
  findings: []
- id: Reactome:R-HSA-9603775
  title: PEX3:PEX19:class I PMP dissociates
  findings: []
- id: Reactome:R-HSA-9603784
  title: PEX19:class I PMP binds PEX3
  findings: []
- id: Reactome:R-HSA-9603804
  title: PEX19 binds class I peroxisomal membrane proteins
  findings: []

Gene Description

Existing Annotations Review

References

Deep Research

Falcon

Research report: Human PEX26 (UniProt Q7Z412) — functional annotation

0) Identity verification (mandatory)

1) Key concepts and current understanding

1.1 Peroxisome biogenesis and the PEX1–PEX6 “exportomer”

1.2 Tail-anchored peroxisomal membrane protein targeting: PEX19/PEX3 and PEX26 insertion

2) Molecular function, interactions, and localization (evidence-based)

2.1 Subcellular localization and membrane topology

2.2 Key molecular interactions (PEX6/PEX1; PEX13/PEX14)

2.3 Mechanism of recruiting the AAA ATPases (nucleotide-state dependence)

2.4 Oligomerization and domain architecture (functional consequences)

3) Disease relevance: Zellweger spectrum/peroxisome biogenesis disorders (PEX26)

3.1 Genetic evidence and cellular phenotype

3.2 Variant-level examples supported by retrieved sources

4) Recent developments (prioritizing 2023–2024)

4.1 Updated mechanistic synthesis (2024 review)

4.2 New mechanistic insight into PEX26 targeting (2024 iScience)

4.3 New clinical genotype expanding PEX26 spectrum (2024)

5) Current applications and real-world implementations

5.1 Clinical genetics and diagnostic workflows

5.2 Genotype-to-mechanism interpretation

6) Expert opinions and analysis (authoritative sources)

7) Relevant statistics and data from recent studies

8) Key references (with publication dates and URLs)

9) Scope limitations of this report

Citations

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