PEX1 is a peroxisomal AAA+ ATPase that forms a heterohexameric complex with PEX6, anchored to the peroxisomal membrane by PEX26. It is a core component of the receptor export module (REM) that mediates ATP-dependent extraction and recycling of the monoubiquitinated PTS1 receptor PEX5 from the peroxisomal docking/translocation module (DTM). PEX1 specifically recognizes PEX5 monoubiquitinated at Cys-11 through its ubiquitin moiety and unfolds PEX5 by processive threading through the central pore of the PEX1-PEX6 hexamer. PEX1 also exists as a homo-oligomer in the cytosol, which dissociates upon PEX6 binding. PEX1 is the most commonly mutated gene in Zellweger spectrum disorders, accounting for approximately 65% of cases. Mutations cause a spectrum of peroxisome biogenesis disorders from severe Zellweger syndrome to mild Heimler syndrome.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0016887 ATP hydrolysis activity | IBA GO_REF:0000033 | ACCEPT | Summary: PEX1 is a well-established AAA+ ATPase with demonstrated ATP hydrolysis activity. UniProt records catalytic activity (EC 3.6.4.-) with experimental evidence from PMID:16854980. Walker motif mutagenesis (K605E, D662N, K887E, D940N) confirmed that both D1 and D2 AAA cassettes are functional ATPase domains. Reason: ATP hydrolysis is a core molecular function of PEX1. IBA annotation is well-supported by phylogenetic conservation and direct experimental evidence showing that Walker motif mutations abolish ATP binding and hydrolysis (PMID:16854980, PMID:21362118). Supporting Evidence: PMID:16854980 ATP binding in both AAA cassettes but not ATP hydrolysis in D2 of both Pex1p and Pex6p was prerequisite for Pex1p-Pex6p interaction and their peroxisomal localization. PMID:21362118 Pex1p is targeted to peroxisomes in a manner dependent on ATP hydrolysis |
| GO:0016558 protein import into peroxisome matrix | IBA GO_REF:0000033 | ACCEPT | Summary: PEX1 is essential for peroxisomal matrix protein import. Loss of PEX1 function results in severe defects in matrix protein import (PMID:9398847). PEX1 specifically functions at the receptor recycling step, which is required for continuous import cycles (PMID:16314507, PMID:29884772). Reason: Protein import into peroxisome matrix is a core biological process for PEX1. Although PEX1 acts specifically at the receptor recycling step rather than the import step per se, the broader term is appropriate since PEX1 is absolutely required for sustained import. IBA annotation is phylogenetically sound and well-supported experimentally. Supporting Evidence: PMID:9398847 Expression of human PEX1 restored peroxisomal protein import in fibroblasts from 30 CG1 patients PMID:16314507 Pex1 and Pex6 of the AAA ATPase family and their recruiter, Pex26, were essential for Pex5 export |
| GO:0043335 protein unfolding | IBA GO_REF:0000033 | ACCEPT | Summary: PEX1/PEX6 unfolds PEX5 during ATP-dependent extraction from the peroxisomal membrane. Pedrosa et al. (PMID:29884772) showed that the PEX5 polypeptide chain is globally unfolded during the dislocation event, and that fusing a stabilized DHFR domain to PEX5 arrests export. The PEX1-PEX6 hexamer processes substrates by processive threading through its central pore (PMID:35805150). Reason: Protein unfolding is a core mechanistic activity of PEX1 as part of the PEX1-PEX6 AAA ATPase complex. IBA annotation is consistent with direct experimental evidence showing global unfolding of PEX5 during extraction. Supporting Evidence: PMID:29884772 the PEX5 polypeptide chain is globally unfolded during the ATP-dependent extraction event PMID:35805150 Pex1 and Pex6 form a heterohexameric AAA-ATPase capable of unfolding substrate proteins via processive threading through a central pore |
| GO:0005778 peroxisomal membrane | IBA GO_REF:0000033 | ACCEPT | Summary: PEX1 localizes to the peroxisomal membrane where it performs its receptor recycling function. It is recruited to peroxisomes via PEX26 in complex with PEX6 (PMID:16854980, PMID:21362118). Multiple studies confirm peroxisomal membrane localization. Reason: Peroxisomal membrane is a core localization for PEX1 where it carries out its primary function. Well-supported by IBA and multiple experimental studies. Supporting Evidence: PMID:16854980 endogenous Pex1p was partly localized likely as a homo-oligomer in the cytoplasm PMID:21362118 A peroxisomal C-tail-anchored type-II membrane protein, Pex26p, recruits AAA ATPase Pex1p-Pex6p complexes to peroxisomes |
| GO:0005829 cytosol | IBA GO_REF:0000033 | ACCEPT | Summary: PEX1 is found in the cytosol as a homo-oligomer that dissociates upon interaction with PEX6 (PMID:16854980). UniProt confirms cytosol localization with experimental evidence. Reason: Cytosol is a well-established localization for PEX1. The protein exists in two pools: a cytosolic homo-oligomeric form and a peroxisome membrane-associated heterohexamer with PEX6. Supporting Evidence: PMID:16854980 endogenous Pex1p was partly localized likely as a homo-oligomer in the cytoplasm |
| GO:0000166 nucleotide binding | IEA GO_REF:0000043 | ACCEPT | Summary: PEX1 contains two AAA cassettes (D1 and D2) each with Walker A and B motifs for nucleotide binding. UniProt annotates ATP binding sites at positions 599-606 and 881-888. This IEA annotation is more general than the IBA/IMP annotations for ATP binding. Reason: Nucleotide binding is a parent term of ATP binding and is correct for PEX1. While more specific terms exist (ATP binding), this IEA annotation based on keyword mapping is not incorrect and is acceptable as a broader electronic annotation. |
| GO:0005524 ATP binding | IEA GO_REF:0000120 | ACCEPT | Summary: PEX1 binds ATP via its two AAA cassettes. ATP binding is required for PEX1-PEX6 interaction and peroxisomal localization (PMID:16854980). Walker A mutants (K605E, K887E) abolish ATP binding. Reason: ATP binding is a core molecular function of PEX1. This IEA annotation is consistent with experimental IMP evidence from PMID:16854980. Supporting Evidence: PMID:16854980 ATP binding in both AAA cassettes but not ATP hydrolysis in D2 of both Pex1p and Pex6p was prerequisite for Pex1p-Pex6p interaction |
| GO:0005777 peroxisome | IEA GO_REF:0000120 | ACCEPT | Summary: PEX1 is associated with peroxisomes, specifically the peroxisomal membrane. This IEA annotation is broader than the more specific peroxisomal membrane annotation but is not incorrect. Reason: Peroxisome localization is correct for PEX1. This is a broader term than peroxisomal membrane but acceptable as an electronic annotation consistent with experimental data. |
| GO:0005778 peroxisomal membrane | IEA GO_REF:0000120 | ACCEPT | Summary: Duplicate of the IBA annotation for peroxisomal membrane. PEX1 is recruited to the peroxisomal membrane by PEX26 in complex with PEX6. Reason: Peroxisomal membrane localization is well-established for PEX1. This IEA annotation is consistent with IBA and multiple experimental annotations. |
| GO:0005829 cytosol | IEA GO_REF:0000044 | ACCEPT | Summary: PEX1 is found in the cytosol as a homo-oligomer. This IEA annotation from UniProt subcellular location mapping is consistent with IBA and experimental evidence. Reason: Cytosol localization is well-established for PEX1. Consistent with the IBA annotation and direct experimental evidence. |
| GO:0007031 peroxisome organization | IEA GO_REF:0000120 | ACCEPT | Summary: PEX1 is essential for peroxisome biogenesis and organization. Loss of PEX1 leads to reduced peroxisome abundance and enlarged remnant peroxisomes (PMID:16449325). PEX1 mutations cause a spectrum of peroxisome biogenesis disorders. Reason: Peroxisome organization is a consequence of PEX1 function in receptor recycling. This IEA annotation is consistent with the IMP annotation from PMID:11439091. |
| GO:0015031 protein transport | IEA GO_REF:0000043 | ACCEPT | Summary: PEX1 is involved in protein transport, specifically the recycling of the PEX5 receptor. This term is very broad; more specific terms exist (protein import into peroxisome matrix, receptor recycling). Reason: Protein transport is a valid parent term. While more specific annotations exist, this IEA annotation from keyword mapping is not incorrect and is acceptable. |
| GO:0016787 hydrolase activity | IEA GO_REF:0000043 | ACCEPT | Summary: PEX1 has ATPase (hydrolase) activity. This is a very broad term; more specific terms (ATP hydrolysis activity) are available. Reason: Hydrolase activity is a parent term of ATP hydrolysis activity and is technically correct. While very general, this IEA annotation from keyword mapping is acceptable. |
| GO:0016887 ATP hydrolysis activity | IEA GO_REF:0000002 | ACCEPT | Summary: PEX1 has ATP hydrolysis activity via its two AAA cassettes. This IEA annotation from InterPro mapping is consistent with IBA and IMP evidence. Reason: ATP hydrolysis activity is a core function of PEX1. This IEA annotation is consistent with the IBA and IMP annotations. |
| GO:0044877 protein-containing complex binding | IEA GO_REF:0000117 | ACCEPT | Summary: PEX1 binds protein-containing complexes, particularly the PEX5-PEX14 DTM complex and the PEX6-PEX26 complex. This term is somewhat vague but captures the interaction of PEX1 with the DTM complex on the peroxisomal membrane. Reason: PEX1 does interact with protein-containing complexes (DTM, PEX1-PEX6-PEX26 complex). This IEA annotation from ARBA is consistent with the IDA annotation from PMID:16854980. |
| GO:0005515 protein binding | IPI PMID:32814053 Interactome Mapping Provides a Network of Neurodegenerative ... | REMOVE | Summary: PMID:32814053 is a large-scale interactome mapping study of neurodegenerative disease proteins. PEX1 was identified as an interactor in this high-throughput screen. The term protein binding is uninformative. Reason: Protein binding is uninformative per curation guidelines. This annotation from a large-scale interactome screen does not provide specific mechanistic insight into PEX1 function. PEX1 interactions are better captured by more specific terms. Supporting Evidence: PMID:32814053 an interactome map that focuses on neurodegenerative disease (ND), connects ∼5,000 human proteins via ∼30,000 candidate interactions and is generated by systematic yeast two-hybrid interaction screening of ∼500 ND-related proteins and integration of literature interactions |
| GO:0005515 protein binding | IPI PMID:9588209 A cytoplasmic AAA family peroxin, Pex1p, interacts with Pex6... | REMOVE | Summary: PMID:9588209 demonstrated PEX1-PEX6 interaction by co-immunoprecipitation. While the interaction is real and important, the term protein binding is uninformative. The PEX1-PEX6 interaction is better captured by the heterohexameric complex formation and the specific molecular functions that depend on it. Reason: Protein binding is uninformative per curation guidelines. The PEX1-PEX6 interaction demonstrated in PMID:9588209 is well-established but better represented by more specific functional annotations. Supporting Evidence: PMID:9588209 Immunoprecipitation of Pex1p using anti-Pex1p antibody resulted in concomitant recovery of 35S-Pex6p |
| GO:0005777 peroxisome | IDA GO_REF:0000052 | ACCEPT | Summary: Peroxisome localization based on curation of immunofluorescence data (HPA). PEX1 is found at peroxisomes, specifically the peroxisomal membrane. Reason: Peroxisome localization is well-established for PEX1. The IDA from immunofluorescence data is consistent with other evidence. |
| GO:0005778 peroxisomal membrane | NAS PMID:35805150 Insights into the Structure and Function of the Pex1/Pex6 AA... | ACCEPT | Summary: PMID:35805150 is a comprehensive review article on Pex1/Pex6 structure and function. It summarizes that PEX1/PEX6 is recruited to the peroxisomal membrane by PEX26. Reason: Peroxisomal membrane localization is well-supported. While this specific annotation uses NAS from a review, the localization is confirmed by multiple IDA studies. Supporting Evidence: PMID:35805150 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: PMID:35805150 reviews the role of PEX1/PEX6 in receptor recycling, describing how the complex extracts monoubiquitinated PEX5 from the peroxisomal membrane. This is the canonical role of PEX1. Reason: Receptor recycling is the primary biological process for PEX1. This NAS annotation from a comprehensive review is well-supported and consistent with multiple IDA annotations. Supporting Evidence: PMID:35805150 Receptor recycling remains the canonical role for Pex1/Pex6 across eukaryotes |
| GO:0005778 peroxisomal membrane | IDA PMID:21362118 Recruiting mechanism of the AAA peroxins, Pex1p and Pex6p, t... | ACCEPT | Summary: Nashiro et al. (PMID:21362118) studied the recruiting mechanism of PEX1 and PEX6 to PEX26 on the peroxisomal membrane. They showed PEX1 targeting to peroxisomes is ATP hydrolysis-dependent and temperature-dependent. Reason: Direct experimental evidence for peroxisomal membrane localization of PEX1, showing the mechanism of recruitment via PEX26. Supporting Evidence: PMID:21362118 Pex1p is targeted to peroxisomes in a manner dependent on ATP hydrolysis, while Pex6p targeting requires ATP but not its hydrolysis |
| GO:0016562 protein import into peroxisome matrix, receptor recycling | IDA PMID:21362118 Recruiting mechanism of the AAA peroxins, Pex1p and Pex6p, t... | ACCEPT | Summary: Nashiro et al. (PMID:21362118) demonstrated that PEX1 recruitment to peroxisomes via PEX26 is essential for receptor recycling. The study used in vitro transport assays and Walker-motif mutants to show that ATP hydrolysis by PEX1 is required for stable peroxisomal localization. Reason: Receptor recycling is the core biological process for PEX1. Direct experimental evidence from in vitro transport assays. Supporting Evidence: PMID:21362118 peroxisomal localization of Pex1p and Pex6p is indispensable for the transport of matrix proteins |
| GO:0016562 protein import into peroxisome matrix, receptor recycling | IDA PMID:29884772 Peroxisomal monoubiquitinated PEX5 interacts with the AAA AT... | ACCEPT | Summary: Pedrosa et al. (PMID:29884772) provided direct evidence that monoubiquitinated PEX5 (Ub-PEX5) is a bona fide substrate of the PEX1-PEX6 complex. Using cell-free in vitro assays, they showed Ub-PEX5 interacts directly with PEX1 and PEX6 and is extracted from the DTM in an ATP-dependent manner. Reason: Key experimental evidence demonstrating that PEX1 directly participates in receptor recycling by extracting Ub-PEX5 from the DTM. Supporting Evidence: PMID:29884772 DTM-embedded Ub-PEX5 interacts directly with both PEX1 and PEX6 through its ubiquitin moiety PMID:29884772 These findings strongly suggest that DTM-embedded Ub-PEX5 is a bona fide substrate of the PEX1-PEX6 complex |
| GO:0043335 protein unfolding | IDA PMID:29884772 Peroxisomal monoubiquitinated PEX5 interacts with the AAA AT... | ACCEPT | Summary: Pedrosa et al. (PMID:29884772) demonstrated that PEX5 is globally unfolded during ATP-dependent extraction from the peroxisomal membrane by the PEX1-PEX6 complex. PEX5 cysteine residues located far apart become exposed during dislocation, and fusing DHFR to PEX5 arrests export when DHFR is stabilized. Reason: Protein unfolding is a core mechanistic activity of PEX1 as demonstrated by direct experimental evidence. The PEX1-PEX6 complex unfolds its substrate PEX5 during extraction. Supporting Evidence: PMID:29884772 the PEX5 polypeptide chain is globally unfolded during the ATP-dependent extraction event PMID:29884772 fusing the N-terminal half of PEX5 (a domain fully functional in both the import and export steps ( 50 )) to mouse DHFR results in a protein that arrests at the export step particularly when the stability of DHFR is increased by MTX |
| GO:0140036 ubiquitin-modified protein reader activity | IDA PMID:29884772 Peroxisomal monoubiquitinated PEX5 interacts with the AAA AT... | ACCEPT | Summary: Pedrosa et al. (PMID:29884772) showed that the PEX1-PEX6 complex recognizes monoubiquitinated PEX5 (Ub-PEX5) through its ubiquitin moiety. Photocross-linking experiments demonstrated that DTM-embedded Ub-PEX5 interacts directly with both PEX1 and PEX6. Reason: Ubiquitin-modified protein reader activity is a core molecular function of PEX1. The PEX1-PEX6 complex specifically recognizes Ub-PEX5 through its ubiquitin moiety, which is essential for substrate engagement and extraction. Supporting Evidence: PMID:29884772 DTM-embedded Ub-PEX5 interacts directly with both PEX1 and PEX6 through its ubiquitin moiety |
| GO:0140318 protein transporter activity | IDA PMID:21362118 Recruiting mechanism of the AAA peroxins, Pex1p and Pex6p, t... | ACCEPT | Summary: Nashiro et al. (PMID:21362118) demonstrated that PEX1 functions as part of the receptor export module (REM) that transports PEX5 from the peroxisomal membrane to the cytosol. This annotation captures the protein dislocase/transporter activity of the PEX1-PEX6 complex. Reason: Protein transporter activity is an appropriate molecular function term for PEX1. The PEX1-PEX6 complex actively transports (dislocates) PEX5 from the peroxisomal membrane to the cytosol. Supporting Evidence: PMID:21362118 Pex26pDelta33-40 truncated in amino-acid residues at 33-40 abolishes the recruiting of Pex1p-Pex6p complex to peroxisomes and fails to complement the impaired phenotype |
| GO:0140318 protein transporter activity | IDA PMID:29884772 Peroxisomal monoubiquitinated PEX5 interacts with the AAA AT... | ACCEPT | Summary: Pedrosa et al. (PMID:29884772) demonstrated that the PEX1-PEX6 complex extracts Ub-PEX5 from the peroxisomal DTM into the cytosol, consistent with protein transporter activity. Reason: Consistent with the other protein transporter activity annotation. PEX1 functions as a protein dislocase that extracts PEX5 from the membrane. Supporting Evidence: PMID:29884772 Their role is to extract monoubiquitinated PEX5, the peroxisomal protein-shuttling receptor, from the peroxisomal membrane docking/translocation module (DTM) |
| GO:0016562 protein import into peroxisome matrix, receptor recycling | IDA PMID:16854980 Dynamic and functional assembly of the AAA peroxins, Pex1p a... | ACCEPT | Summary: Tamura et al. (PMID:16854980) characterized the functional assembly of PEX1-PEX6 complex and showed that both AAA cassettes are essential for peroxisome-restoring activity, which depends on receptor recycling. Reason: Receptor recycling is the primary function of PEX1. This study provided key mechanistic insights into how PEX1 assembles with PEX6 and PEX26 to carry out this function. Supporting Evidence: PMID:16854980 The AAA cassettes, D1 and D2, were essential for peroxisome-restoring activity of Pex1p and Pex6p |
| GO:0016562 protein import into peroxisome matrix, receptor recycling | IDA PMID:19208625 Properties of the ubiquitin-pex5p thiol ester conjugate. | ACCEPT | Summary: Grou et al. (PMID:19208625) characterized the ubiquitin-PEX5 thiol ester conjugate and showed that monoubiquitination is required for ATP-dependent export of PEX5, which is the receptor recycling step mediated by PEX1-PEX6. Reason: This study provides evidence that the PEX1-PEX6 mediated export step requires monoubiquitination of PEX5, consistent with PEX1 function in receptor recycling. Supporting Evidence: PMID:19208625 Pex5p is monoubiquitinated at a conserved cysteine residue, a requisite for its subsequent ATP-dependent export back into the cytosol |
| GO:0140036 ubiquitin-modified protein reader activity | IDA PMID:19208625 Properties of the ubiquitin-pex5p thiol ester conjugate. | ACCEPT | Summary: Grou et al. (PMID:19208625) showed that monoubiquitination of PEX5 at Cys-11 is essential for ATP-dependent export, implicating the PEX1-PEX6 complex as a reader of ubiquitin-modified PEX5. The study demonstrated that the C11K mutant (producing isopeptide-linked ubiquitin) is functional. Reason: This annotation is consistent with PEX1 recognizing monoubiquitinated PEX5. The requirement for ubiquitination before ATP-dependent export supports PEX1 as a ubiquitin reader. Supporting Evidence: PMID:19208625 Pex5p is monoubiquitinated at a conserved cysteine residue, a requisite for its subsequent ATP-dependent export back into the cytosol |
| GO:0043335 protein unfolding | IDA PMID:16854980 Dynamic and functional assembly of the AAA peroxins, Pex1p a... | ACCEPT | Summary: Tamura et al. (PMID:16854980) showed that PEX1-PEX6 interaction involves conformational changes and dissociation of PEX1 homo-oligomers. While this paper demonstrates conformational changes, the direct evidence for substrate unfolding by PEX1-PEX6 came from later work (PMID:29884772). Reason: While the primary evidence for protein unfolding came from PMID:29884772, this annotation from PMID:16854980 is consistent with the protein unfolding function, as the conformational changes described are part of the PEX1 mechanistic cycle. Supporting Evidence: PMID:16854980 Interaction of Pex1p with Pex6p conferred a conformational change and dissociation of the Pex1p oligomer |
| GO:0140318 protein transporter activity | IDA PMID:16854980 Dynamic and functional assembly of the AAA peroxins, Pex1p a... | ACCEPT | Summary: Tamura et al. (PMID:16854980) demonstrated the assembly and function of PEX1-PEX6 complex with PEX26, showing that this complex is essential for peroxisome biogenesis, specifically the transport/extraction of PEX5 from the membrane. Reason: Protein transporter activity is appropriate for PEX1 as it functions in extracting PEX5 from the peroxisomal membrane. Supporting Evidence: PMID:16854980 Pex26p, the recruiter of Pex1p.Pex6p complexes to peroxisomes |
| GO:0016562 protein import into peroxisome matrix, receptor recycling | IDA PMID:16314507 Shuttling mechanism of peroxisome targeting signal type 1 re... | ACCEPT | Summary: Miyata and Fujiki (PMID:16314507) established a cell-free PEX5 translocation system and showed that PEX1, PEX6, and PEX26 are essential for ATP-dependent PEX5 export from peroxisomes. PEX5 was imported into peroxisome remnants of PEX1-defective cells but could not be exported. Reason: This study directly demonstrated that PEX1 is required for PEX5 export/receptor recycling, a core function of PEX1. Supporting Evidence: PMID:16314507 (35)S-Pex5 was imported into the peroxisome remnants of PEX1-, PEX6-, and PEX26-defective cell mutants, including those from patients with peroxisome biogenesis disorders, from which, however, (35)S-Pex5 was not exported |
| GO:0005829 cytosol | TAS Reactome:R-HSA-9033499 | ACCEPT | Summary: Reactome pathway annotation for the PEX1:PEX6:PEX26:ZFAND6 complex activity in dissociating Ub:PEX5L from the DTM and translocating PEX5L to the cytosol. PEX1 is present in the cytosol as part of this pathway. Reason: Cytosol localization is well-established for PEX1. Reactome pathway is consistent with known biology. |
| GO:0005829 cytosol | TAS Reactome:R-HSA-9033516 | ACCEPT | Summary: Reactome pathway annotation for PEX1:PEX6:PEX26 complex binding to the DTM complex. PEX1 participates in this reaction in the cytosol/at the peroxisomal membrane. Reason: Duplicate cytosol annotation from Reactome. Consistent with known PEX1 biology. |
| GO:0005829 cytosol | TAS Reactome:R-HSA-9033533 | ACCEPT | Summary: Another Reactome pathway annotation for PEX1:PEX6:PEX26 complex binding. Reason: Duplicate cytosol annotation from Reactome. Consistent with known PEX1 biology. |
| GO:0070062 extracellular exosome | HDA PMID:18570454 Proteomic analysis of exosomes from human neural stem cells ... | MARK AS OVER ANNOTATED | Summary: PMID:18570454 is a proteomic analysis of exosomes from human neural stem cells. PEX1 was identified in exosome fractions by mass spectrometry. PEX1 is not known to have any function related to exosomes; this is likely a contaminant or incidental finding from a high-throughput proteomics study. Reason: PEX1 is a peroxisomal/cytosolic protein with no known function in exosomes. Detection in exosome fractions by mass spectrometry in a high-throughput study likely represents contamination or incidental incorporation rather than a biologically meaningful localization. Supporting Evidence: PMID:18570454 Exosomal lysates of each fraction were digested and analyzed using nanoflow LC-ESI-MS-MS for protein identification |
| GO:0005778 peroxisomal membrane | HDA PMID:21525035 PEX14 is required for microtubule-based peroxisome motility ... | ACCEPT | Summary: Bharti et al. (PMID:21525035) identified PEX1 as a constituent of PEX14 complexes at the peroxisomal membrane by mass spectrometry. This is consistent with PEX1 localization to the peroxisomal membrane as part of the import/export machinery. Reason: Peroxisomal membrane localization confirmed by mass spectrometric analysis of PEX14 complexes. Consistent with known biology of PEX1 functioning at the peroxisomal membrane. Supporting Evidence: PMID:21525035 almost all known human peroxins involved in protein import were identified as constituents of the PEX14 complexes |
| GO:0005515 protein binding | IPI PMID:16257970 Mutations in the peroxin Pex26p responsible for peroxisome b... | REMOVE | Summary: Furuki et al. (PMID:16257970) studied PEX26 mutations and showed that PEX26 interacts with the PEX1-PEX6 complex. This study demonstrates PEX1-PEX26 interaction (indirect, via PEX6). Reason: Protein binding is uninformative per curation guidelines. The interaction between PEX1 and PEX26 (indirect, via PEX6) is better captured by the functional annotations describing the PEX1-PEX6-PEX26 receptor export module. Supporting Evidence: PMID:16257970 Pex26p functions in recruiting to peroxisomes the complexes of the AAA ATPase peroxins, Pex1p and Pex6p |
| GO:0016558 protein import into peroxisome matrix | IMP PMID:9398847 Mutations in PEX1 are the most common cause of peroxisome bi... | ACCEPT | Summary: Reuber et al. (PMID:9398847) identified PEX1 as the most commonly mutated gene in peroxisome biogenesis disorders and showed that PEX1 expression restored peroxisomal protein import in CG1 patient fibroblasts. PEX1-deficient cells had severe defects in peroxisomal matrix protein import. Reason: This foundational study demonstrated that PEX1 is required for peroxisomal matrix protein import. The IMP evidence from complementation of patient cells is strong. Supporting Evidence: PMID:9398847 Expression of human PEX1 restored peroxisomal protein import in fibroblasts from 30 CG1 patients PMID:9398847 PEX1-deficient cells revealed severe defects in peroxisomal matrix protein import |
| GO:0005737 cytoplasm | IDA PMID:9588209 A cytoplasmic AAA family peroxin, Pex1p, interacts with Pex6... | ACCEPT | Summary: Tamura et al. (PMID:9588209) showed by immunofluorescent microscopy that flag-tagged PEX1 expressed in CHO-K1 cells was localized in the cytoplasm. Reason: Cytoplasm localization is correct. PEX1 exists in the cytoplasm as a homo-oligomer and is recruited to peroxisomes. This is a broader term than cytosol but is consistent with the experimental observation by immunofluorescence. Supporting Evidence: PMID:9588209 Pex1p was localized in the cytoplasm, as assessed by immunofluorescent microscopy |
| GO:0005515 protein binding | IPI PMID:16854980 Dynamic and functional assembly of the AAA peroxins, Pex1p a... | REMOVE | Summary: Tamura et al. (PMID:16854980) demonstrated PEX1-PEX6 interaction and mapped the binding regions. While the interaction is important, the term protein binding is uninformative. Reason: Protein binding is uninformative per curation guidelines. The PEX1-PEX6 interaction is better represented by the specific functional annotations describing the PEX1-PEX6 AAA ATPase complex activities. Supporting Evidence: PMID:16854980 We herein assigned the binding regions between human Pex1p and Pex6p |
| GO:0005524 ATP binding | IMP PMID:16854980 Dynamic and functional assembly of the AAA peroxins, Pex1p a... | ACCEPT | Summary: Tamura et al. (PMID:16854980) showed that Walker A mutations (K605E, K887E) abolish ATP binding in the D1 and D2 cassettes respectively, demonstrating that PEX1 binds ATP and that this binding is essential for function. Reason: ATP binding is a core molecular function of PEX1. IMP evidence from Walker A mutants is strong. Supporting Evidence: PMID:16854980 ATP binding in both AAA cassettes but not ATP hydrolysis in D2 of both Pex1p and Pex6p was prerequisite for Pex1p-Pex6p interaction and their peroxisomal localization |
| GO:0005777 peroxisome | IDA PMID:16854980 Dynamic and functional assembly of the AAA peroxins, Pex1p a... | ACCEPT | Summary: Tamura et al. (PMID:16854980) showed that endogenous PEX1 localizes to peroxisomes (and cytoplasm) in HEK293 cells. Reason: Peroxisome localization is well-established for PEX1. Direct experimental evidence. Supporting Evidence: PMID:16854980 endogenous Pex1p was partly localized likely as a homo-oligomer in the cytoplasm, while Pex6p and Pex26p were predominantly localized on peroxisomes |
| GO:0005778 peroxisomal membrane | IDA PMID:11439091 Phenotype-genotype relationships in peroxisome biogenesis di... | ACCEPT | Summary: Tamura et al. (PMID:11439091) studied PEX1-PEX6 interaction and showed that PEX1 localizes to the peroxisomal membrane. The study demonstrated that PEX1 disease mutants have impaired PEX6 binding, which affects peroxisomal localization. Reason: Peroxisomal membrane localization is a core localization for PEX1. The study provides evidence that PEX1-PEX6 interaction is required for proper localization. Supporting Evidence: PMID:11439091 Pex1p-G843D interacted with Pex6p at approx. 50% of the level of normal Pex1p, whereas Pex1p from ZS patients mostly showing non-temperature-sensitive peroxisome biogenesis hardly bound to Pex6p |
| GO:0005829 cytosol | IDA PMID:16854980 Dynamic and functional assembly of the AAA peroxins, Pex1p a... | ACCEPT | Summary: Tamura et al. (PMID:16854980) showed that endogenous PEX1 is partly localized as a homo-oligomer in the cytoplasm/cytosol. Reason: Cytosol localization is well-established for PEX1. Direct experimental evidence from subcellular fractionation and immunofluorescence. Supporting Evidence: PMID:16854980 endogenous Pex1p was partly localized likely as a homo-oligomer in the cytoplasm |
| GO:0006625 protein targeting to peroxisome | IMP PMID:11439091 Phenotype-genotype relationships in peroxisome biogenesis di... | ACCEPT | Summary: Tamura et al. (PMID:11439091) demonstrated that PEX1 mutations cause defective peroxisome biogenesis, including impaired protein targeting to peroxisomes. Temperature-sensitive PEX1 mutants showed reduced protein targeting at 37C but improved targeting at permissive temperatures. Reason: Protein targeting to peroxisome is a consequence of PEX1 function in receptor recycling. Loss of PEX1 impairs PEX5 recycling which prevents ongoing matrix protein targeting. This is a core process for PEX1. Supporting Evidence: PMID:11439091 temperature-sensitive peroxisome assembly is responsible for the mildness of the clinical features of IRD |
| GO:0006625 protein targeting to peroxisome | IMP PMID:16854980 Dynamic and functional assembly of the AAA peroxins, Pex1p a... | ACCEPT | Summary: Tamura et al. (PMID:16854980) showed that Walker motif mutations in PEX1 impair peroxisome-restoring activity, demonstrating that PEX1 ATPase activity is required for protein targeting to peroxisomes. Reason: Consistent with other annotations. PEX1 ATPase activity is essential for sustained protein targeting to peroxisomes via receptor recycling. Supporting Evidence: PMID:16854980 The AAA cassettes, D1 and D2, were essential for peroxisome-restoring activity of Pex1p and Pex6p |
| GO:0007031 peroxisome organization | IMP PMID:11439091 Phenotype-genotype relationships in peroxisome biogenesis di... | ACCEPT | Summary: Tamura et al. (PMID:11439091) showed that PEX1 mutations lead to impaired peroxisome biogenesis/organization, with the severity correlating with the degree of PEX1-PEX6 interaction impairment. Reason: Peroxisome organization is a downstream consequence of PEX1 function. Loss of PEX1 leads to peroxisome biogenesis disorders with reduced peroxisome abundance and function. Supporting Evidence: PMID:11439091 Failure in Pex1p-Pex6p interaction gives rise to more severe abnormalities, such as those manifested by patients with ZS |
| GO:0016887 ATP hydrolysis activity | IMP PMID:16854980 Dynamic and functional assembly of the AAA peroxins, Pex1p a... | ACCEPT | Summary: Tamura et al. (PMID:16854980) demonstrated PEX1 ATPase activity through Walker B mutations (D662N, D940N) that abolish ATP hydrolysis. UniProt assigns EC 3.6.4.- based on this reference. Reason: ATP hydrolysis is a core molecular function of PEX1. IMP evidence from Walker B mutants directly demonstrates ATPase activity. Supporting Evidence: PMID:16854980 ATP binding in both AAA cassettes but not ATP hydrolysis in D2 of both Pex1p and Pex6p was prerequisite for Pex1p-Pex6p interaction |
| GO:0044877 protein-containing complex binding | IDA PMID:16854980 Dynamic and functional assembly of the AAA peroxins, Pex1p a... | ACCEPT | Summary: Tamura et al. (PMID:16854980) showed that PEX1 interacts with PEX6 to form a heterohexameric complex, and this complex interacts with PEX26 on the peroxisomal membrane. The term captures PEX1 binding to the PEX6-PEX26 complex. Reason: PEX1 does bind protein-containing complexes, particularly the PEX6-PEX26 complex and the DTM. While somewhat vague, this annotation captures a real and important aspect of PEX1 function. Supporting Evidence: PMID:16854980 Pex26p, the recruiter of Pex1p.Pex6p complexes to peroxisomes |
| GO:0060152 microtubule-based peroxisome localization | IMP PMID:16449325 Failure of microtubule-mediated peroxisome division and traf... | KEEP AS NON CORE | Summary: Nguyen et al. (PMID:16449325) showed that PEX1-null cells have peroxisomal remnants that exhibit clustering and loss of alignment along peripheral microtubules. However, this is an indirect consequence of peroxisome dysfunction rather than a direct role of PEX1 in microtubule-based peroxisome localization. The defect is shared with other peroxisome biogenesis disorders and D-BP deficiency. Reason: The defect in microtubule-based peroxisome localization in PEX1-null cells is a secondary consequence of impaired peroxisome biogenesis rather than a direct function of PEX1. Nguyen et al. showed similar defects in D-BP deficiency (a single-enzyme defect), suggesting this is a general consequence of peroxisome dysfunction rather than specific to PEX1. PEX14, not PEX1, was later shown to be the actual mediator of peroxisome-microtubule interaction (PMID:21525035). Supporting Evidence: PMID:16449325 remnant peroxisomes in fibroblasts from patients with PEX1-null Zellweger syndrome or D-BP deficiency exhibited clustering and loss of alignment along peripheral microtubules PMID:21525035 human PEX14 is a multi-tasking protein that not only facilitates peroxisomal protein import but is also required for peroxisome motility by serving as membrane anchor for microtubules |
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