PEX14

Existing Annotations Review

GO Term	Evidence	Action	Reason
GO:0005778 peroxisomal membrane	IBA GO_REF:0000033	ACCEPT	Summary: PEX14 localization to the peroxisomal membrane is the most well-established aspect of this protein. It is an integral peroxisomal membrane protein with a single transmembrane helix (aa ~109-126) and is carbonate-resistant [PMID:10022913, PMID:12488033]. IBA annotation from phylogenetic inference is consistent with extensive direct experimental evidence. Reason: Core localization annotation. PEX14 is an integral peroxisomal membrane protein demonstrated by multiple IDA studies (PMID:10022913, PMID:19197237, PMID:28765278) and deeply conserved across eukaryotes. The IBA annotation is correct and at the right level of specificity. Supporting Evidence: PMID:10022913 HsPex14p is a carbonate-resistant peroxisomal membrane protein with its C terminus exposed to the cytosol. PMID:9653144 Immunoblot analysis of rat liver subcellular fractions demonstrated that this protein was present exclusively in peroxisomal membranes.
GO:0016560 protein import into peroxisome matrix, docking	IBA GO_REF:0000033	ACCEPT	Summary: PEX14 is the primary docking factor for PEX5 at the peroxisomal membrane, binding via WxxxF/Y motifs in PEX5 with nanomolar affinity [PMID:11438541]. This is the most conserved and best-characterized function of PEX14 across eukaryotes. Reason: Core biological process for PEX14. The docking function is demonstrated by extensive experimental data showing PEX14 as the initial docking site for cargo-loaded PEX5 (PMID:9653144, PMID:11438541, PMID:24235149, PMID:28765278). IBA annotation is well-supported phylogenetically and experimentally. Supporting Evidence: PMID:11438541 each of the seven di-aromatic pentapeptides of human PEX5 interacts separately at the same binding site in the N terminus of PEX14 with equilibrium dissociation constants in the low nanomolar range PMID:9653144 this peroxin interacts with Pex5p and Pex13p(SH3) and is directly required for peroxisomal protein import
GO:0005102 signaling receptor binding	IBA GO_REF:0000033	MODIFY	Summary: This term is intended to capture PEX14 binding to the PEX5 receptor at the peroxisomal membrane. However, signaling receptor binding is misleading for PEX14 because PEX5 is a cargo import receptor, not a signaling receptor. PEX14 is a docking factor for a transport receptor, not a signaling receptor ligand. Reason: The term 'signaling receptor binding' is not appropriate for PEX14-PEX5 interaction. PEX5 is a peroxisomal import receptor, not a signaling receptor. A more accurate term would describe PEX14's role as a docking factor for the import receptor PEX5. The term 'protein-macromolecule adaptor activity' (GO:0030674) or the more specific PEX5-binding aspect is better captured elsewhere. This IBA annotation likely reflects incorrect term propagation. Proposed replacements: protein-macromolecule adaptor activity
GO:1990429 peroxisomal importomer complex	IBA GO_REF:0000033	ACCEPT	Summary: PEX14 is a core component of the peroxisomal importomer/DTM complex, which includes PEX13, PEX14, and the RING finger peroxins PEX2/PEX10/PEX12 [PMID:28765278]. This is a well-characterized complex with structural and biochemical evidence. Reason: PEX14 is a bona fide component of the peroxisomal importomer complex (DTM). This is strongly supported by biochemical co-purification studies (PMID:21525035, PMID:28765278) and is a deeply conserved feature of peroxisome biology. Supporting Evidence: PMID:28765278 the peroxisomal membrane docking/translocation module (DTM) comprising PEX13, PEX14
GO:0005778 peroxisomal membrane	IEA GO_REF:0000120	ACCEPT	Summary: IEA annotation for peroxisomal membrane localization, consistent with extensive experimental evidence. Redundant with IBA and IDA annotations but not incorrect. Reason: Correct annotation, consistent with all other evidence for peroxisomal membrane localization. IEA is broader but not wrong.
GO:0015031 protein transport	IEA GO_REF:0000043	ACCEPT	Summary: IEA annotation from UniProt keyword mapping. PEX14 is involved in protein transport (specifically peroxisomal matrix protein import). This is a very broad term but not incorrect. Reason: Correct but very general. More specific child terms (protein import into peroxisome matrix, docking/translocation) are already annotated. The IEA is acceptable as a broad parent annotation.
GO:0016558 protein import into peroxisome matrix	IPI PMID:10022913 Identification and characterization of the human orthologue ...	ACCEPT	Summary: Will et al. (1999) identified human PEX14 and demonstrated it binds PEX5 (PTS1 receptor) and that overexpression leads to mislocalization of catalase to the cytosol, implicating PEX14 in peroxisomal matrix protein import. Reason: Core function. The paper demonstrates PEX14 binds PEX5 and overexpression disrupts matrix protein import, supporting PEX14's role in this process. Supporting Evidence: PMID:10022913 HsPex14p overexpression leads to the decoration of tubular structures and mislocalization of peroxisomal catalase to the cytosol
GO:0005515 protein binding	IPI PMID:10704444 PEX19 binds multiple peroxisomal membrane proteins, is predo...	MARK AS OVER ANNOTATED	Summary: Sacksteder et al. (2000) demonstrated that PEX19 binds multiple PMPs including PEX14. This is a biologically meaningful interaction (PEX19 is the PMP import receptor/chaperone), but 'protein binding' is uninformative. Reason: The PEX14-PEX19 interaction is real and biologically meaningful (PEX19 is required for PMP targeting), but GO:0005515 'protein binding' is too vague to be informative. The specific interaction is better captured by other annotations.
GO:0005515 protein binding	IPI PMID:12096124 Analysis of mammalian peroxin interactions using a non-trans...	MARK AS OVER ANNOTATED	Summary: Fransen et al. (2002) used a bacterial two-hybrid system to map peroxin interactions. They found PEX14 interacts with PEX5, PEX13, PEX19, and itself. 'Protein binding' does not capture the specificity of these interactions. Reason: Protein binding is uninformative. The specific PEX14 interactions with PEX5, PEX13, and PEX19 are biologically meaningful and better captured by more specific MF terms (adaptor activity, identical protein binding) or BP terms (docking/translocation).
GO:0005515 protein binding	IPI PMID:19197237 Structural basis for competitive interactions of Pex14 with ...	MARK AS OVER ANNOTATED	Summary: Neufeld et al. (2009) solved the NMR structure of PEX14 N-terminal domain in complex with PEX5 and PEX19, showing competitive binding at the same surface. Protein binding is uninformative for this detailed structural interaction study. Reason: GO:0005515 protein binding is too vague. The PEX14-PEX5 and PEX14-PEX19 interactions are better captured by more specific terms like protein-macromolecule adaptor activity (GO:0030674).
GO:0005515 protein binding	IPI PMID:21525035 PEX14 is required for microtubule-based peroxisome motility ...	MARK AS OVER ANNOTATED	Summary: Bharti et al. (2011) demonstrated PEX14 directly binds tubulin (alpha/beta tubulin). This is a functionally important interaction for peroxisome motility, but 'protein binding' does not capture the specificity. Reason: The tubulin-binding interaction is captured by the more specific GO:0008017 (microtubule binding) and GO:0048487 (beta-tubulin binding) annotations. GO:0005515 is uninformative.
GO:0005515 protein binding	IPI PMID:29997244 LuTHy: a double-readout bioluminescence-based two-hybrid tec...	MARK AS OVER ANNOTATED	Summary: LuTHy is a high-throughput binary interactome mapping technology. The specific interactions detected are not detailed in the context of PEX14 biology. Reason: High-throughput protein-protein interaction study. GO:0005515 is uninformative and does not tell us which proteins PEX14 interacts with.
GO:0005515 protein binding	IPI PMID:31467278 Maximizing binary interactome mapping with a minimal number ...	MARK AS OVER ANNOTATED	Summary: High-throughput interactome mapping study. Protein binding is uninformative. Reason: High-throughput study. GO:0005515 is too vague to be useful.
GO:0005515 protein binding	IPI PMID:32296183 A reference map of the human binary protein interactome.	MARK AS OVER ANNOTATED	Summary: Reference map of the human binary protein interactome. Protein binding is uninformative. Reason: High-throughput study. GO:0005515 is too vague to be useful.
GO:0005515 protein binding	IPI PMID:37398436 AI-guided pipeline for protein-protein interaction drug disc...	MARK AS OVER ANNOTATED	Summary: AI-guided pipeline study for PPI drug discovery focused on SARS-CoV-2. Not directly relevant to PEX14 core function. Reason: High-throughput study not specific to PEX14 biology. GO:0005515 is uninformative.
GO:0042802 identical protein binding	IPI PMID:12096124 Analysis of mammalian peroxin interactions using a non-trans...	ACCEPT	Summary: Fransen et al. (2002) demonstrated PEX14 homo-oligomerization using a bacterial two-hybrid system, showing "the latter molecule exists predominantly as a dimer in vivo." Reason: PEX14 self-interaction/oligomerization is well-established and functionally important for forming the DTM complex. Homo-oligomerization through the coiled-coil domain (aa 147-278) is documented (PMID:12488033). This is a biologically meaningful annotation. Supporting Evidence: PMID:12096124 the latter molecule exists predominantly as a dimer in vivo PMID:12488033 Heterologous expressed Pex14p was found to be a homopolymer of variable stoichiometry
GO:0005777 peroxisome	IEA GO_REF:0000120	ACCEPT	Summary: IEA annotation for peroxisome localization, consistent with the more specific peroxisomal membrane annotation. PEX14 is a peroxisomal protein. Reason: Correct parent term. PEX14 is a peroxisomal membrane protein and thus is correctly annotated to the parent term peroxisome as well.
GO:0030674 protein-macromolecule adaptor activity	IEA GO_REF:0000107	ACCEPT	Summary: IEA annotation from Ensembl Compara transfer. PEX14 functions as an adaptor bridging PEX5 (cytosolic receptor) to the peroxisomal membrane import machinery. Reason: PEX14 does function as an adaptor/docking factor, bridging the PEX5 receptor to the membrane translocation machinery. This is supported by extensive experimental data (PMID:11438541, PMID:24235149, PMID:28765278).
GO:0032991 protein-containing complex	IEA GO_REF:0000107	ACCEPT	Summary: IEA annotation indicating PEX14 is part of a protein complex. This is correct but extremely generic. The more specific GO:1990429 (peroxisomal importomer complex) is preferred. Reason: Correct but very generic parent term. More specific complex annotations exist (peroxisomal importomer complex). Acceptable as a broad IEA annotation.
GO:0005777 peroxisome	IDA GO_REF:0000052	ACCEPT	Summary: IDA based on curation of immunofluorescence data showing peroxisomal localization. Reason: Correct localization. PEX14 is a peroxisomal membrane protein confirmed by immunofluorescence and subcellular fractionation.
GO:0005778 peroxisomal membrane	IDA PMID:37165185 Peroxisome biogenesis initiated by protein phase separation.	ACCEPT	Summary: Ravindran et al. (2023) studied the phase separation mechanism of peroxisomal import in yeast, with imaging showing GFP-Pex14 at the peroxisome membrane. While this is a yeast study, the annotation is for human PEX14 localization which is well-established. Reason: Peroxisomal membrane localization of PEX14 is extensively documented. Supporting Evidence: PMID:37165185 imaging fluorescence cross-correlation spectroscopy shows that cargo import correlates with transient focusing of GFP-Pex13 and GFP-Pex14 on the peroxisome membrane
GO:0016560 protein import into peroxisome matrix, docking	NAS PMID:37165185 Peroxisome biogenesis initiated by protein phase separation.	ACCEPT	Summary: Ravindran et al. (2023) describe Pex14 as part of the minimum transport machinery for peroxisomal protein import. NAS annotation is consistent with the well-established docking function. Reason: Consistent with PEX14's core function as part of the docking machinery.
GO:0005778 peroxisomal membrane	IDA PMID:28765278 The peroxisomal matrix protein translocon is a large cavity-...	ACCEPT	Summary: Dias et al. (2017) study the DTM architecture and identify PEX14 as a major DTM component at the peroxisomal membrane. Membrane localization is confirmed by alkaline extraction resistance of PEX5-PEX14 interaction. Reason: Core localization confirmed by biochemical studies. Supporting Evidence: PMID:28765278 the interaction between PEX5 and PEX14, a major DTM component, is stable at pH 11.5
GO:0008320 protein transmembrane transporter activity	IDA PMID:28765278 The peroxisomal matrix protein translocon is a large cavity-...	MODIFY	Summary: Dias et al. (2017) demonstrate that PEX14 is a major component of the DTM that forms a large cavity-forming assembly through which PEX5 enters to release its cargo. The paper supports PEX14 as part of a translocation channel. Reason: While PEX14 contributes to the translocon/DTM, calling it a 'transmembrane protein transporter' may overstate its individual role. The current consensus is that PEX13 may provide the principal conduit while PEX14 provides docking and contributes to the pore architecture. PEX14 is better described as a component of the translocon complex rather than having transporter activity per se. A more accurate term would be 'protein-macromolecule adaptor activity' or annotation to the DTM complex component. Proposed replacements: protein-macromolecule adaptor activity Supporting Evidence: PMID:28765278 these results suggest that the DTM is best described as a large cavity-forming protein assembly into which cytosolic PEX5 can enter to release its cargo
GO:0016560 protein import into peroxisome matrix, docking	IDA PMID:28765278 The peroxisomal matrix protein translocon is a large cavity-...	ACCEPT	Summary: Dias et al. (2017) provide direct evidence for PEX14's role in docking PEX5 at the DTM. They demonstrate PEX5 enters the DTM through interactions primarily with PEX14. Reason: Core function of PEX14, well-supported by this and many other studies. Supporting Evidence: PMID:28765278 the first set of interactions that are established between a single PEX5 molecule and the DTM during the docking/insertion steps, most of them likely involving PEX14
GO:0016561 protein import into peroxisome matrix, translocation	IDA PMID:28765278 The peroxisomal matrix protein translocon is a large cavity-...	ACCEPT	Summary: Dias et al. (2017) show the DTM is a large cavity into which PEX5 enters for cargo release. PEX14 contributes to translocation as part of the DTM architecture, though the mechanistic division between docking and translocation for PEX14 specifically is debated. Reason: PEX14 contributes to translocation as part of the DTM complex. While the precise division of labor between PEX13 and PEX14 in translocation is still debated, PEX14 is clearly part of the translocation machinery. Supporting Evidence: PMID:28765278 the DTM is best described as a large cavity-forming protein assembly into which cytosolic PEX5 can enter to release its cargo
GO:0030674 protein-macromolecule adaptor activity	IDA PMID:28765278 The peroxisomal matrix protein translocon is a large cavity-...	ACCEPT	Summary: Dias et al. (2017) demonstrate PEX14 bridges PEX5 to the peroxisomal membrane translocation machinery. PEX14 functions as an adaptor connecting the cytosolic receptor to the membrane pore. Reason: Accurate description of PEX14's molecular function as an adaptor that bridges PEX5 (receptor) to the membrane import machinery.
GO:0016560 protein import into peroxisome matrix, docking	IDA PMID:25538232 Mechanistic insights into PTS2-mediated peroxisomal protein ...	ACCEPT	Summary: Kunze et al. (2015) studied PTS2-mediated import and the role of PEX5L as co-receptor for PEX7. PEX14 is mentioned as part of the docking complex in the context of PTS2 import. Reason: PEX14 is part of the docking complex for both PTS1 and PTS2 import pathways. The PTS2 receptor PEX7 (with co-receptor PEX5L) also docks at PEX14-containing DTM.
GO:0030674 protein-macromolecule adaptor activity	IDA PMID:24235149 A novel Pex14 protein-interacting site of human Pex5 is crit...	ACCEPT	Summary: Neuhaus et al. (2014) identified a novel PEX14-binding site in PEX5 (LVXEF motif) critical for matrix protein import. PEX14 acts as an adaptor connecting PEX5 to the peroxisomal membrane. Reason: Directly demonstrates PEX14's adaptor function, showing it binds PEX5 through multiple motifs (WxxxF/Y and LVXEF) to mediate receptor docking. Supporting Evidence: PMID:24235149 Receptor-cargo docking occurs at the membrane-associated protein Pex14. In human cells, this interaction is mediated by seven conserved diaromatic penta-peptide motifs
GO:0030674 protein-macromolecule adaptor activity	IDA PMID:11438541 The di-aromatic pentapeptide repeats of the human peroxisome...	ACCEPT	Summary: Saidowsky et al. (2001) demonstrated that each of the seven WxxxF/Y motifs in PEX5 binds PEX14 N-terminal domain with nanomolar affinity. PEX14 serves as the adaptor docking PEX5 to the peroxisomal membrane. Reason: Key study establishing PEX14 as the high-affinity docking factor for PEX5. The adaptor function is directly demonstrated. Supporting Evidence: PMID:11438541 each of the seven di-aromatic pentapeptides of human PEX5 interacts separately at the same binding site in the N terminus of PEX14 with equilibrium dissociation constants in the low nanomolar range
GO:0034614 cellular response to reactive oxygen species	IDA PMID:26344566 ATM functions at the peroxisome to induce pexophagy in respo...	MARK AS OVER ANNOTATED	Summary: Zhang et al. (2015) studied ATM-mediated pexophagy in response to ROS. PEX14 protein levels decrease during ROS-induced pexophagy, used as a marker of peroxisome degradation. PEX14 is not itself a sensor or effector of ROS response; it is a passive target of pexophagy. Reason: PEX14 is used as a marker of pexophagy (its levels decrease when peroxisomes are degraded), but it is not an active participant in the ROS response pathway. The ROS response is mediated by ATM-PEX5-p62 signaling. PEX14 protein levels change as a consequence of peroxisome degradation, not because PEX14 has a specific role in ROS sensing or response. This is an over-annotation. Supporting Evidence: PMID:26344566 a concomitant decrease in peroxisomal proteins PEX1 and PEX14
GO:0005778 peroxisomal membrane	IDA PMID:19197237 Structural basis for competitive interactions of Pex14 with ...	ACCEPT	Summary: Neufeld et al. (2009) demonstrated PEX14 peroxisomal membrane localization by immunofluorescence and showed mutations in the N-terminal domain impair membrane targeting. Reason: Direct experimental demonstration of peroxisomal membrane localization. Supporting Evidence: PMID:19197237 The corresponding full-length Pex14 variants are impaired in peroxisomal membrane localisation in vivo
GO:0016560 protein import into peroxisome matrix, docking	IDA PMID:11438541 The di-aromatic pentapeptide repeats of the human peroxisome...	ACCEPT	Summary: Saidowsky et al. (2001) characterized the PEX5-PEX14 interaction at the molecular level, establishing PEX14 as the docking site for PEX5. Reason: Core function of PEX14 as the docking site for PEX5 import receptor. Supporting Evidence: PMID:11438541 the evolutionarily conserved pentapeptide repeat motifs, WX(E/D/Q/A/S)(E/D/Q)(F/Y), in PEX5 bind to PEX14 with high affinity
GO:0005515 protein binding	IPI PMID:24235149 A novel Pex14 protein-interacting site of human Pex5 is crit...	MARK AS OVER ANNOTATED	Summary: Neuhaus et al. (2014) demonstrate PEX14 binds PEX5 through a novel LVXEF motif. Protein binding is uninformative for this specific interaction. Reason: GO:0005515 is too vague. The PEX14-PEX5 interaction is better captured by the adaptor activity annotation.
GO:0005515 protein binding	IPI PMID:12488033 Mammalian Pex14p: membrane topology and characterisation of ...	MARK AS OVER ANNOTATED	Summary: Oliveira et al. (2002) characterized PEX14-PEX14 homo-oligomerization and PEX14-PEX5 interaction. Protein binding is uninformative. Reason: GO:0005515 is too vague. The self-interaction is captured by identical protein binding (GO:0042802) and PEX5 interaction by adaptor activity.
GO:0042802 identical protein binding	IPI PMID:12488033 Mammalian Pex14p: membrane topology and characterisation of ...	ACCEPT	Summary: Oliveira et al. (2002) demonstrated PEX14 forms homo-oligomers of variable stoichiometry through aa 147-278 (coiled-coil region). Reason: Well-established self-interaction through the coiled-coil domain, important for DTM architecture. Supporting Evidence: PMID:12488033 Heterologous expressed Pex14p was found to be a homopolymer of variable stoichiometry. Finally, in vitro binding assays indicate that homopolymerisation of Pex14p involves a domain comprising amino acid residues 147-278
GO:0005515 protein binding	IPI PMID:21976670 PEX5 protein binds monomeric catalase blocking its tetrameri...	MARK AS OVER ANNOTATED	Summary: Freitas et al. (2011) show PEX14 N-terminal domain disrupts the PEX5-catalase interaction, triggering cargo release. This is a specific mechanistic interaction not well-captured by generic protein binding. Reason: GO:0005515 is uninformative. The study demonstrates PEX14's role in cargo release, better captured by the substrate release annotation (GO:0044721). Supporting Evidence: PMID:21976670 the PEX5-catalase interaction is disrupted by the N-terminal domain of PEX14, a component of the docking/translocation machinery
GO:0005829 cytosol	TAS Reactome:R-HSA-9603775	KEEP AS NON CORE	Summary: Reactome annotation indicating PEX14 is in the cytosol in the context of PEX3:PEX19:PMP dissociation. PEX14 is primarily a peroxisomal membrane protein but may transiently exist in the cytosol during its biogenesis (as a PEX19 cargo before membrane insertion). Reason: PEX14 is primarily a peroxisomal membrane protein. Cytosolic localization is transient during PMP biogenesis (when PEX14 is bound to PEX19 in the cytosol before membrane insertion). This is not the primary steady-state localization.
GO:0005829 cytosol	TAS Reactome:R-HSA-9603784	KEEP AS NON CORE	Summary: Reactome annotation for PEX19:class I PMP binding to PEX3. PEX14 is transiently cytosolic as a PEX19 cargo. Reason: Same as above - transient cytosolic presence during PMP biogenesis, not the primary localization.
GO:0005829 cytosol	TAS Reactome:R-HSA-9603804	KEEP AS NON CORE	Summary: Reactome annotation for PEX19 binding class I PMPs. PEX14 is transiently cytosolic when bound to PEX19. Reason: Transient cytosolic presence during PMP biogenesis.
GO:0005778 peroxisomal membrane	TAS Reactome:R-HSA-8953917	ACCEPT	Summary: Reactome annotation for PEX2:PEX10:PEX12 binding PEX5 in PEX5:PEX13:PEX14 complex. Confirms PEX14 at the peroxisomal membrane in the import complex. Reason: Correct localization, consistent with PEX14's role in the DTM complex at the peroxisomal membrane.
GO:0005778 peroxisomal membrane	TAS Reactome:R-HSA-8953946	ACCEPT	Summary: Reactome annotation for ubiquitination of PEX5 at the DTM. Reason: Correct localization.
GO:0005778 peroxisomal membrane	TAS Reactome:R-HSA-9033235	ACCEPT	Summary: Reactome annotation for cargo translocation to peroxisomal matrix. PEX14 is at the peroxisomal membrane as part of the DTM. Reason: Correct localization.
GO:0005778 peroxisomal membrane	TAS Reactome:R-HSA-9033236	ACCEPT	Summary: Reactome annotation for PEX5:Cargo binding DTM. Reason: Correct localization.
GO:0005778 peroxisomal membrane	TAS Reactome:R-HSA-9033485	ACCEPT	Summary: Reactome annotation for PEX5L ubiquitination at DTM. Reason: Correct localization.
GO:0005778 peroxisomal membrane	TAS Reactome:R-HSA-9033499	ACCEPT	Summary: Reactome annotation for PEX1:PEX6 dissociating PEX5 from PEX14:PEX13 complex. Reason: Correct localization.
GO:0005778 peroxisomal membrane	TAS Reactome:R-HSA-9033514	ACCEPT	Summary: Reactome annotation for PTS2 cargo translocation. Reason: Correct localization.
GO:0005778 peroxisomal membrane	TAS Reactome:R-HSA-9033516	ACCEPT	Summary: Reactome annotation for PEX1:PEX6:PEX26 binding DTM complex. Reason: Correct localization.
GO:0005778 peroxisomal membrane	TAS Reactome:R-HSA-9033527	ACCEPT	Summary: Reactome annotation for PEX2:PEX10:PEX12 binding PEX5L in DTM context. Reason: Correct localization.
GO:0005778 peroxisomal membrane	TAS Reactome:R-HSA-9033533	ACCEPT	Summary: Reactome annotation for PEX1:PEX6:PEX26 binding to ubiquitinated PEX5:PEX13:PEX14. Reason: Correct localization.
GO:0005778 peroxisomal membrane	TAS Reactome:R-HSA-9603775	ACCEPT	Summary: Reactome annotation for PEX3:PEX19:PMP dissociation at the peroxisomal membrane. Reason: Correct localization.
GO:0016020 membrane	HDA PMID:19946888 Defining the membrane proteome of NK cells.	ACCEPT	Summary: High-throughput proteomics study defining the membrane proteome of NK cells. PEX14 was identified as a membrane protein. This is consistent with its known peroxisomal membrane localization, though very generic. Reason: Correct but very generic. PEX14 is a membrane protein (specifically peroxisomal membrane). Acceptable as a broad HDA annotation.
GO:0044721 protein import into peroxisome matrix, substrate release	IDA PMID:21976670 PEX5 protein binds monomeric catalase blocking its tetrameri...	ACCEPT	Summary: Freitas et al. (2011) demonstrated that the N-terminal domain of PEX14 disrupts the PEX5-catalase interaction, triggering cargo release at the peroxisomal membrane. This provides direct evidence for PEX14's role in substrate release. Reason: Important mechanistic insight showing PEX14 participates in cargo release. PEX14's N-terminal domain competes with catalase for binding to PEX5, effectively triggering cargo release at the DTM. Supporting Evidence: PMID:21976670 the PEX5-catalase interaction is disrupted by the N-terminal domain of PEX14, a component of the docking/translocation machinery
GO:0036250 peroxisome transport along microtubule	IDA PMID:21525035 PEX14 is required for microtubule-based peroxisome motility ...	ACCEPT	Summary: Bharti et al. (2011) demonstrated that PEX14 is required for microtubule-based peroxisome motility. PEX14-deficient cells showed peroxisomal remnants that lost their ability to move along microtubules. Reason: Well-established secondary function of PEX14. Direct experimental evidence showing PEX14 is required for peroxisome motility along microtubules. Supporting Evidence: PMID:21525035 peroxisomal remnants in PEX14-deficient cells have lost their ability to move along microtubules
GO:0032991 protein-containing complex	IDA PMID:19584060 Solution structure of human Pex5.Pex14.PTS1 protein complexe...	ACCEPT	Summary: Shiozawa et al. (2009) determined the solution structure of the Pex5-Pex14-PTS1 complex by SAXS, showing a 1:6 stoichiometry. This demonstrates PEX14 forms a specific protein complex. Reason: Correct annotation. PEX14 forms a defined complex with PEX5 (1:6 stoichiometry). Though generic, the more specific importomer complex annotation exists elsewhere. Supporting Evidence: PMID:19584060 Titration studies yielded a 1:6 stoichiometry for the Pex5p.Pex14p complex
GO:0005515 protein binding	IPI PMID:19584060 Solution structure of human Pex5.Pex14.PTS1 protein complexe...	MARK AS OVER ANNOTATED	Summary: Shiozawa et al. (2009) demonstrate PEX14-PEX5 interaction by SAXS. Protein binding is uninformative. Reason: GO:0005515 is too vague. The PEX5-PEX14 complex is captured by other annotations.
GO:0005777 peroxisome	IDA PMID:21375735 The Peroxisomal Targeting Signal 1 in sterol carrier protein...	ACCEPT	Summary: Danpure et al. (2011) studied PTS1 recognition in the context of sterol carrier protein 2. PEX14 peroxisomal localization confirmed. Reason: Correct localization.
GO:0005778 peroxisomal membrane	IDA PMID:11669066 Identification of a novel human peroxisomal 2,4-dienoyl-CoA ...	ACCEPT	Summary: Amery et al. (2001) used phage display to identify peroxisomal proteins and confirmed PEX14 at the peroxisomal membrane. Reason: Correct localization.
GO:0005778 peroxisomal membrane	IDA PMID:18346465 Comparison of the PTS1- and Rab8b-binding properties of Pex5...	ACCEPT	Summary: Study comparing PTS1 and Rab8b binding of Pex5p and Pex5Rp/TRIP8b. PEX14 peroxisomal membrane localization confirmed in the context of PEX5 binding studies. Reason: Correct localization.
GO:0005778 peroxisomal membrane	HDA PMID:21525035 PEX14 is required for microtubule-based peroxisome motility ...	ACCEPT	Summary: Bharti et al. (2011) performed mass spectrometric analysis of PEX14 complexes purified from peroxisomal membranes. Reason: Correct localization confirmed by proteomics.
GO:0008017 microtubule binding	IDA PMID:21525035 PEX14 is required for microtubule-based peroxisome motility ...	ACCEPT	Summary: Bharti et al. (2011) demonstrated direct binding of PEX14 to tubulin and that PEX14 serves as a membrane anchor for microtubules at peroxisomes. Reason: Well-documented secondary function. PEX14 directly binds tubulin through its N-terminal domain, mediating peroxisome-microtubule attachment. Supporting Evidence: PMID:21525035 tubulin was discovered to be the major PEX14-associated protein, and direct binding of the proteins was demonstrated
GO:0005102 signaling receptor binding	IPI PMID:21525035 PEX14 is required for microtubule-based peroxisome motility ...	MODIFY	Summary: This annotation from the Bharti et al. (2011) study likely refers to PEX14 binding to tubulin or PEX5. However, 'signaling receptor binding' is inappropriate for PEX14's interactions. Reason: PEX14 does not bind signaling receptors. Its interactions are with the import receptor PEX5 and with tubulin, neither of which are signaling receptors. The tubulin interaction is better captured by microtubule binding (GO:0008017). Proposed replacements: microtubule binding
GO:0016561 protein import into peroxisome matrix, translocation	IDA PMID:21525035 PEX14 is required for microtubule-based peroxisome motility ...	ACCEPT	Summary: Bharti et al. (2011) focused primarily on PEX14's role in microtubule-based peroxisome motility, but also characterized PEX14 import complexes, confirming its role in the translocation machinery. Reason: PEX14 is part of the translocation machinery (DTM). The study confirmed PEX14 complexes contain import machinery components. Supporting Evidence: PMID:21525035 almost all known human peroxins involved in protein import were identified as constituents of the PEX14 complexes
GO:0034453 microtubule anchoring	IDA PMID:21525035 PEX14 is required for microtubule-based peroxisome motility ...	ACCEPT	Summary: Bharti et al. (2011) demonstrated PEX14 serves as a membrane anchor for microtubules at peroxisomes, directly binding tubulin through its N-terminal domain. Reason: Well-supported secondary function. PEX14 anchors microtubules to peroxisomes through direct tubulin binding. Supporting Evidence: 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
GO:0048487 beta-tubulin binding	IPI PMID:21525035 PEX14 is required for microtubule-based peroxisome motility ...	ACCEPT	Summary: Bharti et al. (2011) identified tubulin as the major PEX14-associated protein by mass spectrometry and demonstrated direct binding. The N-terminal domain of PEX14 mediates the interaction. Reason: Well-supported specific molecular function. PEX14 binds tubulin directly through its N-terminal domain to mediate peroxisome motility. Supporting Evidence: PMID:21525035 tubulin was discovered to be the major PEX14-associated protein, and direct binding of the proteins was demonstrated. Accordingly, peroxisomal remnants in PEX14-deficient cells have lost their ability to move along microtubules. In vivo and in vitro analyses indicate that the physical binding to tubulin is mediated by the conserved N-terminal domain of PEX14
GO:0065003 protein-containing complex assembly	IDA PMID:21525035 PEX14 is required for microtubule-based peroxisome motility ...	KEEP AS NON CORE	Summary: Bharti et al. (2011) established a procedure for isolating native PEX14 complexes and showed distinct multimeric PEX14 assemblies at the peroxisomal membrane. Reason: PEX14 does form multimeric assemblies, but this is a rather generic annotation. The complex assembly aspect is inherent to PEX14's function as part of the DTM but is not its primary core function. Supporting Evidence: PMID:21525035 Size-exclusion chromatography revealed the existence of distinct multimeric PEX14 assemblies at the peroxisomal membrane
GO:0005778 peroxisomal membrane	IDA PMID:10022913 Identification and characterization of the human orthologue ...	ACCEPT	Summary: Will et al. (1999) identified human PEX14 as a carbonate-resistant peroxisomal membrane protein. Reason: Core localization. Supporting Evidence: PMID:10022913 HsPex14p is a carbonate-resistant peroxisomal membrane protein with its C terminus exposed to the cytosol
GO:0005777 peroxisome	IDA PMID:17881773 Peroxisomes in human and mouse testis: differential expressi...	ACCEPT	Summary: Study on peroxisomal protein expression in testis. PEX14 peroxisomal localization confirmed by immunostaining. Reason: Correct localization.
GO:0005777 peroxisome	IDA PMID:19197237 Structural basis for competitive interactions of Pex14 with ...	ACCEPT	Summary: Neufeld et al. (2009) confirm PEX14 peroxisomal localization by immunofluorescence. Reason: Correct localization.
GO:0005778 peroxisomal membrane	ISS GO_REF:0000024	ACCEPT	Summary: ISS annotation transferred from orthologs. Consistent with extensive direct experimental evidence for human PEX14. Reason: Correct localization, supported by direct evidence in human.
GO:0007031 peroxisome organization	ISS GO_REF:0000024	ACCEPT	Summary: ISS annotation for peroxisome organization transferred from orthologs. PEX14 is essential for peroxisome biogenesis/import; mutations cause Zellweger spectrum disorder with absence of functional peroxisomes [PMID:15146459]. Reason: PEX14 is essential for peroxisome organization/biogenesis. PEX14 deficiency results in peroxisome biogenesis disorders (PMID:15146459). Correct annotation at an appropriate level. Supporting Evidence: PMID:15146459 the role of PEX14 is also essential in humans
GO:0016020 membrane	ISS GO_REF:0000024	ACCEPT	Summary: Very generic ISS annotation. PEX14 is a membrane protein. Reason: Correct but extremely generic. More specific terms exist.
GO:0032991 protein-containing complex	ISS GO_REF:0000024	ACCEPT	Summary: ISS annotation indicating PEX14 is part of a protein complex. Very generic. Reason: Correct. PEX14 is part of the DTM complex. More specific terms exist (peroxisomal importomer complex).
GO:0045892 negative regulation of DNA-templated transcription	IDA PMID:11863372 NAPP2, a peroxisomal membrane protein, is also a transcripti...	MARK AS OVER ANNOTATED	Summary: Gavva et al. (2002) identified PEX14 (NAPP2) as a transcriptional corepressor that interacts with HDAC1 and inhibits p45/NF-E2-directed transcription. This is a single study that has not been widely replicated. PEX14 is primarily a peroxisomal membrane protein, and the physiological relevance of nuclear/ transcriptional functions is unclear. Reason: This annotation is based on a single study (Gavva et al. 2002) that identified PEX14 as 'NAPP2' and showed it could repress transcription when ectopically expressed. However, PEX14 is an integral peroxisomal membrane protein with no established nuclear function. The UniProt entry does not include this as a validated function. No subsequent studies have confirmed a physiological role for PEX14 in transcriptional regulation. This likely represents an over-annotation based on an overexpression artifact. Supporting Evidence: PMID:11863372 In mammalian cell culture, ectopically expressed NAPP2 inhibited p45-directed transcriptional activation
GO:0005515 protein binding	IPI PMID:11863372 NAPP2, a peroxisomal membrane protein, is also a transcripti...	MARK AS OVER ANNOTATED	Summary: Gavva et al. (2002) showed PEX14 (NAPP2) interacts with p45/NF-E2 and HDAC1. The physiological relevance of these interactions for a peroxisomal membrane protein is questionable. Reason: GO:0005515 is uninformative. The reported interactions with p45 and HDAC1 are from a single study and are of uncertain physiological relevance for PEX14, which is primarily a peroxisomal membrane protein.
GO:0005634 nucleus	NAS PMID:11863372 NAPP2, a peroxisomal membrane protein, is also a transcripti...	REMOVE	Summary: Gavva et al. (2002) suggested PEX14 may localize to the nucleus based on the presence of a nuclear localization signal and its reported transcriptional corepressor activity. This is not supported by subsequent studies. Reason: Nuclear localization of PEX14 is not supported by mainstream literature. PEX14 is an integral peroxisomal membrane protein with a transmembrane helix. The NAS evidence is weak (no direct demonstration), and no subsequent studies have confirmed nuclear localization. UniProt annotates PEX14 exclusively to the peroxisome membrane. This is likely an artifact of the NAPP2 study.
GO:0016558 protein import into peroxisome matrix	IMP PMID:15146459 Identification of a new complementation group of the peroxis...	ACCEPT	Summary: Shimozawa et al. (2004) identified a patient with PEX14 deficiency (p.Q185X nonsense mutation) as a new complementation group of PBD. PEX14 expression rescued PTS1 and PTS2 import in patient fibroblasts. Reason: Strong genetic evidence from a human patient. Loss of PEX14 causes Zellweger syndrome with complete loss of peroxisomal matrix protein import. Complementation with PEX14 rescues import. Supporting Evidence: PMID:15146459 human PEX14 rescues the import of a PTS1-dependent as well as a PTS2-dependent protein into the peroxisomes in fibroblasts from a patient with Zellweger syndrome
GO:0005515 protein binding	IPI PMID:10562279 PEX12 interacts with PEX5 and PEX10 and acts downstream of r...	MARK AS OVER ANNOTATED	Summary: Chang et al. (1999) studied PEX12 interactions with PEX5 and PEX10. PEX14 is mentioned in the context of receptor docking but the specific PEX14 interaction is not the focus. Reason: GO:0005515 is uninformative. The PEX14-PEX5 docking interaction is better captured by other annotations.
GO:0005515 protein binding	IPI PMID:9653144 Identification of a human PTS1 receptor docking protein dire...	MARK AS OVER ANNOTATED	Summary: Fransen et al. (1998) demonstrated PEX14 binds PEX5 and PEX13 in the original characterization of human PEX14. Protein binding is uninformative. Reason: GO:0005515 is too vague. The PEX5 and PEX13 interactions are captured by more specific annotations (adaptor activity, docking).
GO:0005777 peroxisome	IDA PMID:16449325 Failure of microtubule-mediated peroxisome division and traf...	ACCEPT	Summary: Study on microtubule-mediated peroxisome division and trafficking in disorders with reduced peroxisome abundance. PEX14 peroxisomal localization confirmed. Reason: Correct localization.
GO:0005778 peroxisomal membrane	IDA PMID:16449325 Failure of microtubule-mediated peroxisome division and traf...	ACCEPT	Summary: PEX14 peroxisomal membrane localization confirmed by immunofluorescence. Reason: Correct localization.

Gene Description

Existing Annotations Review

Core Functions

PEX14 serves as the primary high-affinity docking site for the PTS1 import receptor PEX5 at the peroxisomal membrane. It binds PEX5 WxxxF/Y motifs via its N-terminal domain with nanomolar affinity and functions as the initial docking factor for cargo-loaded import receptors.

PEX14 directly binds tubulin via a region overlapping its PEX5-binding domain, linking peroxisomes to microtubules for microtubule-dependent organelle motility and distribution.

References

Deep Research

Falcon

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