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.

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.

Molecular Function:

protein-macromolecule adaptor activity

Directly Involved In:

protein import into peroxisome matrix

Cellular Locations:

peroxisomal membrane

In Complex:

peroxisomal importomer complex

Supporting Evidence:

PMID:9653144
This peroxin interacts with Pex5p and Pex13p(SH3) and is directly required for peroxisomal protein import.
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

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

Molecular Function:

beta-tubulin binding

Directly Involved In:

peroxisome transport along microtubule

Cellular Locations:

peroxisomal membrane

Supporting Evidence:

PMID:10562279
PEX14 binds tubulin directly via a domain that overlaps with the PEX5-binding site

References

GO_REF:0000024

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

GO_REF:0000033

Annotation inferences using phylogenetic trees

GO_REF:0000043

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

GO_REF:0000052

Gene Ontology annotation based on curation of immunofluorescence data

GO_REF:0000107

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

GO_REF:0000120

Combined Automated Annotation using Multiple IEA Methods

PMID:10022913

Identification and characterization of the human orthologue of yeast Pex14p.

HsPex14p identified as a carbonate-resistant peroxisomal membrane protein that binds PEX5 and is required for peroxisomal matrix protein import.

"HsPex14p is a carbonate-resistant peroxisomal membrane protein with its C terminus exposed to the cytosol"

PMID:10562279

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

PMID:10704444

PEX19 binds multiple peroxisomal membrane proteins, is predominantly cytoplasmic, and is required for peroxisome membrane synthesis.

PEX19 binds PEX14 as part of its broad PMP-binding activity.

"PEX19 binds a broad spectrum of PMPs, displays saturable PMP binding, and interacts with regions of PMPs required for their targeting to peroxisomes"

PMID:11438541

The di-aromatic pentapeptide repeats of the human peroxisome import receptor PEX5 are separate high affinity binding sites for the peroxisomal membrane protein PEX14.

Each of the seven WxxxF/Y motifs in PEX5 binds PEX14 N-terminal domain with nanomolar affinity, establishing PEX14 as the primary docking factor.

"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:11669066

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

PMID:11863372

NAPP2, a peroxisomal membrane protein, is also a transcriptional corepressor.

PEX14 (NAPP2) reported to interact with HDAC1 and inhibit p45/NF-E2 transcription. Single study; physiological relevance for a peroxisomal membrane protein is uncertain.

"ectopically expressed NAPP2 inhibited p45-directed transcriptional activation. Furthermore, NAPP2 functions as a corepressor and interacts specifically with histone deacetylase l (HDAC1)"

PMID:12096124

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

PEX14 interacts with PEX5, PEX13, PEX19, and itself (predominantly as a dimer). The PEX5-PEX13 interaction is bridged by PEX14.

"the Pex5p-Pex13p interaction is bridged by Pex14p and that the latter molecule exists predominantly as a dimer in vivo"

PMID:12488033

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

PEX14 N-terminal ~130 residues are protected by the peroxisomal membrane. PEX14 forms homo-oligomers of variable stoichiometry via aa 147-278.

"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 of this peroxin"

PMID:15146459

Identification of a new complementation group of the peroxisome biogenesis disorders and PEX14 as the mutated gene.

PEX14 p.Q185X nonsense mutation causes Zellweger syndrome (new complementation group). PEX14 is essential for both PTS1 and PTS2 import in humans.

"PEX14 is a key component of the peroxisomal import machinery and may be the initial docking site for the two import receptors PEX5 and PEX7"

PMID:16449325

Failure of microtubule-mediated peroxisome division and trafficking in disorders with reduced peroxisome abundance.

PMID:17881773

Peroxisomes in human and mouse testis: differential expression of peroxisomal proteins in germ cells and distinct somatic cell types of the testis.

PMID:18346465

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

PMID:19197237

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

NMR structure of PEX14 N-terminal domain in complex with PEX5 and PEX19. PEX5 and PEX19 bind competitively to the same surface with opposite directionality.

"Pex5 and Pex19 ligand helices bind competitively to the same surface in Pex14(N) albeit with opposite directionality"

PMID:19584060

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

1:6 stoichiometry for PEX5:PEX14 complex determined by SAXS.

"Titration studies yielded a 1:6 stoichiometry for the Pex5p.Pex14p complex"

PMID:19946888

Defining the membrane proteome of NK cells.

PMID:21375735

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

PMID:21525035

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

PEX14 directly binds tubulin through its N-terminal domain. PEX14-deficient cells lose microtubule-based peroxisome motility. PEX14 is a multi-tasking protein serving both import and motility functions.

"tubulin was discovered to be the major PEX14-associated protein, and direct binding of the proteins was demonstrated"

PMID:21976670

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

PEX14 N-terminal domain disrupts PEX5-catalase interaction, demonstrating PEX14's role in cargo release at the DTM.

"the PEX5-catalase interaction is disrupted by the N-terminal domain of PEX14, a component of the docking/translocation machinery"

PMID:24235149

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

Novel LVXEF motif in PEX5 binds PEX14 N-terminal domain with faster dissociation kinetics than WxxxF/Y motifs. May represent initial tethering site.

"The novel motif composes the sequence LVAEF with the evolutionarily conserved consensus sequence LVXEF"

PMID:25538232

Mechanistic insights into PTS2-mediated peroxisomal protein import: the co-receptor PEX5L drastically increases the interaction strength between the cargo protein and the receptor PEX7.

PMID:26344566

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

PEX14 protein levels decrease during ROS-induced pexophagy. PEX14 used as a marker of peroxisome degradation, not an active participant in ROS sensing.

"ATM signalling activates ULK1 and inhibits mTORC1 to induce autophagy. Specificity for autophagy of peroxisomes (pexophagy) is provided by ATM phosphorylation of PEX5 at Ser 141"

PMID:28765278

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

DTM is a large cavity-forming assembly. PEX14 is a major component. PEX5-PEX14 interaction is stable at pH 11.5. Multiple PEX5 domains interact with DTM in a 'fuzzy' manner.

"the interaction between PEX5 and PEX14, a major DTM component, is stable at pH 11.5"

PMID:29997244

LuTHy: a double-readout bioluminescence-based two-hybrid technology for quantitative mapping of protein-protein interactions in mammalian cells.

PMID:31467278

Maximizing binary interactome mapping with a minimal number of assays.

PMID:32296183

A reference map of the human binary protein interactome.

PMID:37165185

Peroxisome biogenesis initiated by protein phase separation.

Pex14 forms foci during cargo import events, consistent with transient channel formation through liquid-liquid phase separation with Pex5-cargo.

"cargo import correlates with transient focusing of GFP-Pex13 and GFP-Pex14 on the peroxisome membrane"

PMID:37398436

AI-guided pipeline for protein-protein interaction drug discovery identifies a SARS-CoV-2 inhibitor.

PMID:9653144

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

First identification of human PEX14 as a peroxisomal membrane protein that binds PEX5 and PEX13, directly required for peroxisomal protein import.

"Recombinant Pex14p was specifically recognized by the "import inhibiting" ab-MF3 and bound Pex5p and the Src homology 3 (SH3) domain of Pex13p in ligand blots"

Reactome:R-HSA-8953917

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

Reactome:R-HSA-8953946

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

Reactome:R-HSA-9033235

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

Reactome:R-HSA-9033236

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

Reactome:R-HSA-9033485

PEX2:PEX10:PEX12 monoubiquitinates PEX5L at cysteine-11

Reactome:R-HSA-9033499

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

Reactome:R-HSA-9033514

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

Reactome:R-HSA-9033516

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

Reactome:R-HSA-9033527

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

Reactome:R-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

(PEX14-deep-research-falcon.md)

Research Report: Human **PEX14** (UniProt **O75381**) — Functional Annotation and Current Understanding Falcon Edison Scientific Literature 33 citations 2026-03-05T00:41:10.011318

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 PEX14 (UniProt O75381) — Functional Annotation and Current Understanding

0) Target verification (mandatory)

Verified target: Human PEX14 (peroxisomal membrane protein; “PTS1 receptor-docking protein”; peroxin-14 family), corresponding to UniProt O75381.

Evidence for correct identity and UniProt mapping: A 2023 peer‑reviewed review of the peroxisomal docking complex explicitly references the AlphaFold2 model AF‑O75381‑F1 for human PEX14, directly tying the protein discussed in the mechanistic literature to UniProt accession O75381. The same review and multiple other sources consistently describe PEX14 as a peroxisomal membrane peroxin and core component of the docking/translocation module for PEX5-dependent matrix protein import, matching the UniProt description provided. (ruttermann2023goodthingscome pages 4-6)

1) Key concepts and definitions (current understanding)

1.1 Peroxisomal matrix protein import and the docking/translocation module (DTM)

Peroxisomes are single‑membrane organelles that rely on post‑translational import of nuclear‑encoded proteins. Matrix proteins carry targeting signals (PTS1 or PTS2) that are recognized in the cytosol by receptors PEX5 (PTS1) and PEX7 (PTS2, typically with PEX5 as co‑receptor), after which cargo‑loaded receptors engage a peroxisomal membrane docking/translocation machinery. (kumar2024theperoxisomean pages 1-3, pandey2024molecularinteractionsof pages 16-20)

A central concept for PEX14 annotation is the Docking/Translocation Module (DTM). In the current consensus model, PEX13 and PEX14 form a conserved membrane module that recruits cargo‑bound PEX5 and supports translocation into the peroxisomal matrix. (skowyra2024towardssolvingthe pages 1-3)

1.2 What PEX14 is (functional definition)

Human PEX14 is best defined as a peroxisomal membrane docking/translocon factor that binds the import receptor PEX5 via short linear motifs (notably WxxxF/Y motifs in PEX5), thereby enabling receptor engagement with the peroxisomal membrane import machinery and contributing to early steps of matrix protein import. (skowyra2024towardssolvingthe pages 1-3, ruttermann2023goodthingscome pages 4-6)

2) Molecular function and mechanism (primary function)

2.1 Primary function: receptor docking and coordination of import

Stepwise view of PEX14’s role in import (high‑level):
1. Cargo‑bound PEX5 is recruited to the peroxisome by a complex including PEX13 and PEX14.
2. Translocation is proposed to involve a conduit formed primarily by PEX13, while a lumenal domain of PEX14 engages motifs within PEX5’s N‑terminal disordered region to drive receptor movement into the matrix.
3. After cargo release, PEX5 is recycled by monoubiquitination and ATP‑dependent extraction via PEX1/PEX6.

This mechanistic framing is explicitly described in a 2024 Trends in Cell Biology review and illustrated in its Figure 1 (retrieved as image evidence). (skowyra2024towardssolvingthe pages 1-3, skowyra2024towardssolvingthe media 6dadeff0)

2.2 Key interaction motifs (PEX14 ↔ PEX5)

Canonical docking interface: PEX14 binds the N‑terminal region of PEX5 through WxxxF/Y motifs in PEX5. This motif‑based recognition is emphasized across recent mechanistic models of matrix import and remains central to functional annotation. (skowyra2024towardssolvingthe pages 1-3, ruttermann2023goodthingscome pages 4-6)

Newer (2023) interface linking import and recycling: A 2023 mechanistic study (preprint) reports an additional interface in which a conserved PEX14 C‑terminal peptide motif IPSWQI binds the TPR cargo‑binding domain of PEX5 at a site distinct from PTS1 binding. Mutations in this interface cause partial import defects and reduce steady‑state PEX5 levels, consistent with a functional connection between docking/import and receptor recycling. (emmanouilidis2023anovelpex14pex5 pages 1-4, ghosh2024molecularcharacterizationof pages 60-63)

2.3 Pore formation: what is known vs debated

Peroxisomes can import folded or oligomeric proteins, implying a transient, adaptable translocation mechanism. Mechanistic discussions include models where receptor–membrane complexes yield a translocation pore; some reconstitution literature summarized in a 2024 dissertation‑style source argues that PEX5 and PEX14 can be minimal components supporting channel activity that expands upon cargo binding, while also noting lack of definitive structural proof for a stable PEX14-only aqueous pore and highlighting alternative models emphasizing PEX13 as the major conduit. This remains an active area of investigation. (ghosh2024molecularcharacterizationof pages 25-28, ghosh2024molecularcharacterizationof pages 60-63, lipinski2025earlystagesofa pages 16-19)

3) Protein features: localization, topology, domains

3.1 Subcellular localization

PEX14 is a peroxisomal membrane protein and a core component of the peroxisomal docking complex in mammals (mainly PEX13 + PEX14). (ruttermann2023goodthingscome pages 2-4, skowyra2024towardssolvingthe pages 1-3)

3.2 Domain organization and residue ranges (human)

A 2023 peer‑reviewed review provides a concrete domain/topology summary for human PEX14, including approximate residue ranges:
- Conserved N‑terminal domain (reported for human around ~25–70) mediating receptor interactions.
- Single transmembrane helix around ~110–138.
- Coiled‑coil region (example given around ~158–197), contributing to oligomerization/scaffold function.
- Extended unstructured/flexible C‑terminal region implicated in regulatory interactions and additional binding sites.

The same review references AlphaFold2 model AF‑O75381‑F1 for human PEX14. (ruttermann2023goodthingscome pages 4-6)

3.3 Oligomerization and structural role

PEX14 can oligomerize (e.g., coiled‑coil‑mediated assemblies), and docking complex organization differs across species; nonetheless, PEX14 is consistently described as the conserved core component. Structural models include rod‑like Pex14 oligomers (described particularly in yeast), and in mammals PEX14 acts as a scaffold for receptor engagement and possibly dynamic remodeling during import. (ruttermann2023goodthingscome pages 6-7, ruttermann2023goodthingscome pages 4-6)

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

4.1 2024: Updated mechanistic model for matrix import highlights PEX13/PEX14 division of labor

A 2024 Trends in Cell Biology review synthesizes emerging evidence and argues that cargo‑bound PEX5 is recruited by PEX13/PEX14, that PEX13 provides a principal conduit across the membrane, and that a PEX14 lumenal interaction with PEX5 motifs can drive receptor movement into the matrix. This clarifies PEX14’s role as part of a coordinated DTM rather than a standalone pore. (skowyra2024towardssolvingthe pages 1-3)

4.2 2023: A novel PEX14–PEX5 interface suggests coupling between import and recycling

The 2023 preprint identifying the IPSWQI motif interaction between PEX14 and the PEX5 TPR domain reframes PEX14 from purely a “docking factor” to a coordinator of receptor conformational states relevant to downstream steps, including receptor stability/recycling phenotypes. (emmanouilidis2023anovelpex14pex5 pages 1-4)

4.3 2024: PEX14 as a pexophagy platform in human cells (emerging function)

A 2024 bioRxiv report proposes that PEX14 also functions as a molecular bridge to recruit optineurin (OPTN) to the peroxisomal membrane, enabling OPTN-mediated pexophagy. Proximity labeling and biochemical pulldown support OPTN–PEX14 interaction, with mapping implicating the PEX14 coiled‑coil region. This is a notable expansion of PEX14’s functional footprint beyond import, linking peroxisome maintenance/turnover to a specific membrane anchor. (li2024pex14functionsas pages 1-5, li2024pex14functionsas pages 5-7)

5) Current applications and real‑world implementations

5.1 Diagnostic/live-cell imaging of peroxisomes (2024 Nature Communications)

While not PEX14-specific as a reagent target, peroxisome biology in clinical and research workflows frequently uses immunostaining for peroxisomal membrane proteins (including PEX14) as markers, and recent work has expanded live‑cell diagnostic options.

A 2024 Nature Communications study reports PeroxiSPY650/555 and related fluorescent fatty‑acid conjugates for rapid live‑cell peroxisome imaging, including use in PBD CRISPR/Cas9 models and patient-derived cell lines. The authors report that PeroxiSPY enabled “immediate differentiation” between WT and patient-derived fibroblasts by quantifying dye incorporation into peroxisomes, supporting real‑world utility in diagnosing peroxisome abnormalities in vitro. (korotkova2024fluorescentfattyacid pages 1-2, korotkova2024fluorescentfattyacid pages 6-7)

5.2 PEX14 in pexophagy as an actionable node (conceptual application)

The emerging model where PEX14 recruits OPTN and interacts with LC3/ATG9A-related machinery suggests a mechanistic basis to modulate peroxisome turnover, with potential downstream relevance to disease contexts where peroxisome quality control is dysregulated. (li2024pex14functionsas pages 1-5, li2024pex14functionsas pages 5-7)

6) Disease relevance (human genetics) and supporting data

6.1 Peroxisome biogenesis disorders (Zellweger spectrum)

Peroxisome biogenesis disorders (PBDs), including Zellweger spectrum disorders (ZSDs), arise from mutations in PEX genes that disrupt peroxisome assembly or protein import. Reviews summarize that these disorders show hallmark metabolic abnormalities (e.g., accumulation of very‑long‑chain fatty acids and branched-chain fatty acids; plasmalogen deficiency) and multi‑system disease. (kumar2024theperoxisomean pages 1-3, jiang2025modellingperoxisomaldisorders pages 3-5)

6.2 Open Targets (database) association for PEX14

An Open Targets query links PEX14 (ENSG00000142655) to “peroxisome biogenesis disorder” and “Peroxisome biogenesis disorder–Zellweger syndrome spectrum,” with evidence consistent with biallelic autosomal inheritance and citing genetic literature (including PMID 27604308 in the Open Targets evidence list). This supports PEX14’s validated disease association at the human genetics level, although the snippet does not include prevalence figures. (OpenTargets Search: Peroxisome biogenesis disorder,Zellweger spectrum disorder-PEX14)

6.3 Specific reported patient variants (PEX14 truncations; pexophagy phenotype)

A 2024 bioRxiv study cites two patients with autosomal dominant Zellweger spectrum disorder carrying C‑terminally truncated PEX14 frameshift variants (p.A196Lfs*34 and p.A196Vfs*34) and reports increased pexophagy in patient cells that was only partially rescued by NBR1 knockdown, implicating a dysregulated PEX14–OPTN axis as a contributor to phenotype. (li2024pex14functionsas pages 10-13)

7) Expert opinions and analysis (authoritative synthesis)

7.1 Converging expert view: PEX14 is a core docking factor, but mechanism is nuanced

Recent authoritative syntheses emphasize that PEX14 is conserved and essential for docking/translocation in many organisms, but that:
- mechanistic division of labor may place PEX13 as the principal conduit,
- PEX14 provides high-affinity receptor interactions via motif recognition,
- and PEX14’s additional interfaces (e.g., C-terminal IPSWQI) may couple import to receptor cycling.

This reflects a shift from simplistic “PEX14 forms the pore” models toward a more modular DTM model. (skowyra2024towardssolvingthe pages 1-3, emmanouilidis2023anovelpex14pex5 pages 1-4, ruttermann2023goodthingscome pages 4-6)

7.2 Emerging consensus: PEX14 is also a peroxisome quality-control hub

The OPTN/pexophagy literature argues that PEX14 is not merely an import factor but can be repurposed as an autophagy docking platform, potentially integrating peroxisome biogenesis/import with turnover under stress or remodeling cues. This is still developing and requires continued validation across cell types and physiological contexts. (li2024pex14functionsas pages 5-7, li2024pex14functionsas pages 1-5)

8) Key quantitative/statistical data from recent studies

Two patients with autosomal dominant ZSD and PEX14 frameshift truncations (p.A196Lfs34; p.A196Vfs34) were reported to show increased pexophagy, supporting a specific, countable human observation linking PEX14 to disease and peroxisome turnover. (li2024pex14functionsas pages 10-13)
PeroxiSPY imaging work reports quantitative imaging metrics (e.g., peroxisome-to-cytoplasm fluorescence ratios, pooled measurements from >300 peroxisomes per replicate in some analyses) and claims fast, non-cytotoxic staining suitable for diagnostic differentiation of patient fibroblasts. (korotkova2024fluorescentfattyacid pages 9-10, korotkova2024fluorescentfattyacid pages 6-7)

Visual evidence (mechanistic schematic)

Figure evidence showing the recruitment of cargo-bound PEX5 by PEX13/PEX14 and subsequent translocation steps is available from Skowyra et al. 2024 (Figure 1). (skowyra2024towardssolvingthe media 6dadeff0)

Summary table (high-level functional annotation)

Functional Role	Mechanism / Key Interactions	Key Evidence / Motifs	Representative Source
PEX5 Docking & Import	N-terminal domain (NTD) forms a hydrophobic cavity that binds WxxxF/Y motifs in the disordered N-terminus of the import receptor PEX5. Forms the Docking/Translocation Module (DTM) with PEX13.	Core component of the peroxisomal translocon; NTD (approx. residues 25–70) essential for PEX5 recruitment; 1:1 PEX5:PEX14 stoichiometry observed in pore models.	Trends Cell Biol. (May 2024) Skowyra et al. (skowyra2024towardssolvingthe pages 1-3)
Receptor Recycling Link	C-terminal intrinsically disordered region interacts with the PEX5 TPR (cargo-binding) domain, modulating receptor conformation for recycling.	Identification of conserved IPSWQI motif in PEX14 C-terminus; binds PEX5 TPR hinge to induce "open" state. Mutations cause PEX5 instability (recycling defect phenotype).	bioRxiv (Aug 2023) Emmanouilidis et al. (emmanouilidis2023anovelpex14pex5 pages 19-20, emmanouilidis2023anovelpex14pex5 pages 1-4)
Pexophagy Recruitment	Acts as a molecular bridge to recruit the autophagy receptor Optineurin (OPTN) to peroxisomes. Interaction via PEX14 Coiled-Coil (CC) domain binding OPTN UBD.	Proximity labeling (BioID) places PEX14 in OPTN interactome; PEX14 overexpression drives OPTN recruitment, peroxisome clustering, and degradation.	J. Cell Biol. (Oct 2025) Li et al. (li2025pex14actsas pages 7-8, li2025pex14actsas pages 1-2)
Structural Scaffold	Membrane anchoring and oligomerization to form rod-like structures/pores.	Single TM helix (approx. aa 110–138); Coiled-coil (approx. aa 158–197) mediates homotrimerization; Structure predicted by AlphaFold AF-O75381-F1.	Biol. Chem. (Sep 2023) Rüttermann & Gatsogiannis (ruttermann2023goodthingscome pages 4-6)

Table: Summary of the primary biological functions, mechanistic interactions, and structural features of the human PEX14 protein, with citations from 2023–2025 literature.

Key cited sources (with dates and URLs)

Rüttermann M, Gatsogiannis C. “Good things come to those who bait: the peroxisomal docking complex.” Biological Chemistry (Sep 2023). https://doi.org/10.1515/hsz-2022-0161 (ruttermann2023goodthingscome pages 4-6)
Skowyra ML, Feng P, Rapoport TA. “Towards solving the mystery of peroxisomal matrix protein import.” Trends in Cell Biology (May 2024). https://doi.org/10.1016/j.tcb.2023.08.005 (skowyra2024towardssolvingthe pages 1-3, skowyra2024towardssolvingthe media 6dadeff0)
Emmanouilidis L et al. “A novel PEX14/PEX5 interface links peroxisomal protein import and receptor recycling.” bioRxiv (Aug 2023). https://doi.org/10.1101/2023.08.08.552478 (emmanouilidis2023anovelpex14pex5 pages 1-4)
Li H et al. “PEX14 functions as a molecular link between optineurin and pexophagy in human cells.” bioRxiv (May 31 2024 posting; listed Nov 2024 in metadata). https://doi.org/10.1101/2024.05.31.596776 (li2024pex14functionsas pages 5-7, li2024pex14functionsas pages 10-13)
Korotkova D et al. “Fluorescent fatty acid conjugates for live cell imaging of peroxisomes.” Nature Communications (May 2024). https://doi.org/10.1038/s41467-024-48679-2 (korotkova2024fluorescentfattyacid pages 1-2, korotkova2024fluorescentfattyacid pages 6-7)
Open Targets Platform disease–target association: PEX14 ↔ peroxisome biogenesis disorder / ZSD (accessed via tool; platform described in Nucleic Acids Research). (OpenTargets Search: Peroxisome biogenesis disorder,Zellweger spectrum disorder-PEX14)

References

(ruttermann2023goodthingscome pages 4-6): Maximilian Rüttermann and Christos Gatsogiannis. Good things come to those who bait: the peroxisomal docking complex. Biological Chemistry, 404:107-119, Sep 2023. URL: https://doi.org/10.1515/hsz-2022-0161, doi:10.1515/hsz-2022-0161. This article has 9 citations and is from a peer-reviewed journal.
(kumar2024theperoxisomean pages 1-3): 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.
(pandey2024molecularinteractionsof pages 16-20): Saroj Pandey. Molecular interactions of the human pex1/pex6 aaa+ atpase complex and in vivo mrna editing of the pex1-g843d mutation. May 2024. URL: https://doi.org/10.15496/publikation-94953, doi:10.15496/publikation-94953. This article has 0 citations.
(skowyra2024towardssolvingthe pages 1-3): Michael L. Skowyra, Peiqiang Feng, and Tom A. Rapoport. Towards solving the mystery of peroxisomal matrix protein import. Trends in Cell Biology, 34:388-405, May 2024. URL: https://doi.org/10.1016/j.tcb.2023.08.005, doi:10.1016/j.tcb.2023.08.005. This article has 27 citations and is from a domain leading peer-reviewed journal.
(skowyra2024towardssolvingthe media 6dadeff0): Michael L. Skowyra, Peiqiang Feng, and Tom A. Rapoport. Towards solving the mystery of peroxisomal matrix protein import. Trends in Cell Biology, 34:388-405, May 2024. URL: https://doi.org/10.1016/j.tcb.2023.08.005, doi:10.1016/j.tcb.2023.08.005. This article has 27 citations and is from a domain leading peer-reviewed journal.
(emmanouilidis2023anovelpex14pex5 pages 1-4): Leonidas Emmanouilidis, Jessica Sehr, Katharina Reglinski, Stefan Gaussmann, David Goricanec, Jonathan Kordon, Filipe Menezes, Dominic Waithe, Philip Hublitz, Verian Bader, Konstanze F. Winklhofer, Martin Jung, Wolfgang Schliebs, Christian Eggeling, Ralf Erdmann, and Michael Sattler. A novel pex14/pex5 interface links peroxisomal protein import and receptor recycling. bioRxiv, Aug 2023. URL: https://doi.org/10.1101/2023.08.08.552478, doi:10.1101/2023.08.08.552478. This article has 0 citations.
(ghosh2024molecularcharacterizationof pages 60-63): Mausumi Ghosh. Molecular characterization of protein translocation pores. ArXiv, 2024. URL: https://doi.org/10.53846/goediss-10355, doi:10.53846/goediss-10355. This article has 0 citations.
(ghosh2024molecularcharacterizationof pages 25-28): Mausumi Ghosh. Molecular characterization of protein translocation pores. ArXiv, 2024. URL: https://doi.org/10.53846/goediss-10355, doi:10.53846/goediss-10355. This article has 0 citations.
(lipinski2025earlystagesofa pages 16-19): O Lipiński. Early stages of peroxisomal protein import. Unknown journal, 2025.
(ruttermann2023goodthingscome pages 2-4): Maximilian Rüttermann and Christos Gatsogiannis. Good things come to those who bait: the peroxisomal docking complex. Biological Chemistry, 404:107-119, Sep 2023. URL: https://doi.org/10.1515/hsz-2022-0161, doi:10.1515/hsz-2022-0161. This article has 9 citations and is from a peer-reviewed journal.
(ruttermann2023goodthingscome pages 6-7): Maximilian Rüttermann and Christos Gatsogiannis. Good things come to those who bait: the peroxisomal docking complex. Biological Chemistry, 404:107-119, Sep 2023. URL: https://doi.org/10.1515/hsz-2022-0161, doi:10.1515/hsz-2022-0161. This article has 9 citations and is from a peer-reviewed journal.
(li2024pex14functionsas pages 1-5): Hongli Li, Suyuan Chen, Celien Lismont, Bram Vandewinkel, Mohamed A. F. Hussein, Cláudio F. Costa, Dorien Imberechts, Yiyang Liu, Jorge E Azevedo, Wim Vandenberghe, Steven Verhelst, Myriam Baes, and Marc Fransen. Pex14 functions as a molecular link between optineurin and pexophagy in human cells. bioRxiv, Nov 2024. URL: https://doi.org/10.1101/2024.05.31.596776, doi:10.1101/2024.05.31.596776. This article has 0 citations.
(li2024pex14functionsas pages 5-7): Hongli Li, Suyuan Chen, Celien Lismont, Bram Vandewinkel, Mohamed A. F. Hussein, Cláudio F. Costa, Dorien Imberechts, Yiyang Liu, Jorge E Azevedo, Wim Vandenberghe, Steven Verhelst, Myriam Baes, and Marc Fransen. Pex14 functions as a molecular link between optineurin and pexophagy in human cells. bioRxiv, Nov 2024. URL: https://doi.org/10.1101/2024.05.31.596776, doi:10.1101/2024.05.31.596776. This article has 0 citations.
(korotkova2024fluorescentfattyacid pages 1-2): Daria Korotkova, Anya Borisyuk, Anthony Guihur, Manon Bardyn, Fabien Kuttler, Luc Reymond, Milena Schuhmacher, and Triana Amen. Fluorescent fatty acid conjugates for live cell imaging of peroxisomes. Nature Communications, May 2024. URL: https://doi.org/10.1038/s41467-024-48679-2, doi:10.1038/s41467-024-48679-2. This article has 22 citations and is from a highest quality peer-reviewed journal.
(korotkova2024fluorescentfattyacid pages 6-7): Daria Korotkova, Anya Borisyuk, Anthony Guihur, Manon Bardyn, Fabien Kuttler, Luc Reymond, Milena Schuhmacher, and Triana Amen. Fluorescent fatty acid conjugates for live cell imaging of peroxisomes. Nature Communications, May 2024. URL: https://doi.org/10.1038/s41467-024-48679-2, doi:10.1038/s41467-024-48679-2. This article has 22 citations and is from a highest quality peer-reviewed journal.
(jiang2025modellingperoxisomaldisorders pages 3-5): Chenxing S. Jiang and Michael Schrader. Modelling peroxisomal disorders in zebrafish. Cells, 14:147, Jan 2025. URL: https://doi.org/10.3390/cells14020147, doi:10.3390/cells14020147. This article has 2 citations.
(OpenTargets Search: Peroxisome biogenesis disorder,Zellweger spectrum disorder-PEX14): Open Targets Query (Peroxisome biogenesis disorder,Zellweger spectrum disorder-PEX14, 5 results). Buniello, A. et al. (2025). Open Targets Platform: facilitating therapeutic hypotheses building in drug discovery. Nucleic Acids Research.
(li2024pex14functionsas pages 10-13): Hongli Li, Suyuan Chen, Celien Lismont, Bram Vandewinkel, Mohamed A. F. Hussein, Cláudio F. Costa, Dorien Imberechts, Yiyang Liu, Jorge E Azevedo, Wim Vandenberghe, Steven Verhelst, Myriam Baes, and Marc Fransen. Pex14 functions as a molecular link between optineurin and pexophagy in human cells. bioRxiv, Nov 2024. URL: https://doi.org/10.1101/2024.05.31.596776, doi:10.1101/2024.05.31.596776. This article has 0 citations.
(korotkova2024fluorescentfattyacid pages 9-10): Daria Korotkova, Anya Borisyuk, Anthony Guihur, Manon Bardyn, Fabien Kuttler, Luc Reymond, Milena Schuhmacher, and Triana Amen. Fluorescent fatty acid conjugates for live cell imaging of peroxisomes. Nature Communications, May 2024. URL: https://doi.org/10.1038/s41467-024-48679-2, doi:10.1038/s41467-024-48679-2. This article has 22 citations and is from a highest quality peer-reviewed journal.
(emmanouilidis2023anovelpex14pex5 pages 19-20): Leonidas Emmanouilidis, Jessica Sehr, Katharina Reglinski, Stefan Gaussmann, David Goricanec, Jonathan Kordon, Filipe Menezes, Dominic Waithe, Philip Hublitz, Verian Bader, Konstanze F. Winklhofer, Martin Jung, Wolfgang Schliebs, Christian Eggeling, Ralf Erdmann, and Michael Sattler. A novel pex14/pex5 interface links peroxisomal protein import and receptor recycling. bioRxiv, Aug 2023. URL: https://doi.org/10.1101/2023.08.08.552478, doi:10.1101/2023.08.08.552478. This article has 0 citations.
(li2025pex14actsas pages 7-8): Hongli Li, Suyuan Chen, Celien Lismont, Bram Vandewinkel, Mohamed A.F. Hussein, Cláudio F. Costa, Dorien Imberechts, Yiyang Liu, Jorge E. Azevedo, Wim Vandenberghe, Steven Verhelst, Hans R. Waterham, Pieter Vanden Berghe, Myriam Baes, and Marc Fransen. Pex14 acts as a molecular link between optineurin and the autophagic machinery to induce pexophagy. Journal of Cell Biology, Oct 2025. URL: https://doi.org/10.1083/jcb.202411184, doi:10.1083/jcb.202411184. This article has 4 citations and is from a highest quality peer-reviewed journal.
(li2025pex14actsas pages 1-2): Hongli Li, Suyuan Chen, Celien Lismont, Bram Vandewinkel, Mohamed A.F. Hussein, Cláudio F. Costa, Dorien Imberechts, Yiyang Liu, Jorge E. Azevedo, Wim Vandenberghe, Steven Verhelst, Hans R. Waterham, Pieter Vanden Berghe, Myriam Baes, and Marc Fransen. Pex14 acts as a molecular link between optineurin and the autophagic machinery to induce pexophagy. Journal of Cell Biology, Oct 2025. URL: https://doi.org/10.1083/jcb.202411184, doi:10.1083/jcb.202411184. This article has 4 citations and is from a highest quality peer-reviewed journal.

Citations

ruttermann2023goodthingscome pages 4-6
skowyra2024towardssolvingthe pages 1-3
kumar2024theperoxisomean pages 1-3
pandey2024molecularinteractionsof pages 16-20
ghosh2024molecularcharacterizationof pages 60-63
ghosh2024molecularcharacterizationof pages 25-28
lipinski2025earlystagesofa pages 16-19
ruttermann2023goodthingscome pages 2-4
ruttermann2023goodthingscome pages 6-7
korotkova2024fluorescentfattyacid pages 1-2
korotkova2024fluorescentfattyacid pages 6-7
jiang2025modellingperoxisomaldisorders pages 3-5
korotkova2024fluorescentfattyacid pages 9-10
Skowyra et al.
Emmanouilidis et al.
Li et al.
Rüttermann & Gatsogiannis
https://doi.org/10.1016/j.tcb.2023.08.005
https://doi.org/10.1101/2023.08.08.552478
https://doi.org/10.1083/jcb.202411184
https://doi.org/10.1515/hsz-2022-0161
https://doi.org/10.1101/2024.05.31.596776
https://doi.org/10.1038/s41467-024-48679-2
https://doi.org/10.1515/hsz-2022-0161,
https://doi.org/10.1007/s00418-023-02259-5,
https://doi.org/10.15496/publikation-94953,
https://doi.org/10.1016/j.tcb.2023.08.005,
https://doi.org/10.1101/2023.08.08.552478,
https://doi.org/10.53846/goediss-10355,
https://doi.org/10.1101/2024.05.31.596776,
https://doi.org/10.1038/s41467-024-48679-2,
https://doi.org/10.3390/cells14020147,
https://doi.org/10.1083/jcb.202411184,

📄 View Raw YAML

id: O75381
gene_symbol: PEX14
product_type: PROTEIN
status: IN_PROGRESS
taxon:
  id: NCBITaxon:9606
  label: Homo sapiens
description: Peroxisomal membrane protein PEX14 (peroxin-14) is a central component of the peroxisomal docking/translocation module (DTM) for matrix protein import. PEX14 is an integral peroxisomal membrane protein with a single transmembrane helix, an N-terminal PEX5-binding domain exposed to the lumen/membrane, and a large cytoplasmic C-terminal domain including a coiled-coil region. It serves as the primary high-affinity docking site for the PTS1 import receptor PEX5 via WxxxF/Y motifs and also interacts with the PMP receptor PEX19 and the docking partner PEX13. PEX14 forms homo-oligomeric assemblies and contributes to the architecture of the translocation pore. Beyond import, PEX14 binds tubulin directly to mediate microtubule-based peroxisome motility. Mutations in PEX14 cause a severe form of Zellweger spectrum disorder (PBD complementation group K). Recent work also implicates PEX14 in pexophagy via recruitment of the autophagy receptor optineurin (OPTN).
alternative_products:
- name: '1'
  id: O75381-1
- name: '2'
  id: O75381-2
  sequence_note: VSP_037021
existing_annotations:
- term:
    id: GO:0005778
    label: peroxisomal membrane
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  review:
    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.
    action: ACCEPT
    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.
    supported_by:
    - reference_id: PMID:10022913
      supporting_text: HsPex14p is a carbonate-resistant peroxisomal membrane protein with its C terminus exposed to the cytosol.
    - reference_id: PMID:9653144
      supporting_text: Immunoblot analysis of rat liver subcellular fractions demonstrated that this protein was present exclusively in peroxisomal membranes.
- term:
    id: GO:0016560
    label: protein import into peroxisome matrix, docking
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  review:
    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.
    action: ACCEPT
    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.
    supported_by:
    - reference_id: PMID:11438541
      supporting_text: 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
    - reference_id: PMID:9653144
      supporting_text: this peroxin interacts with Pex5p and Pex13p(SH3) and is directly required for peroxisomal protein import
- term:
    id: GO:0005102
    label: signaling receptor binding
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  review:
    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.
    action: MODIFY
    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_replacement_terms:
    - id: GO:0030674
      label: protein-macromolecule adaptor activity
- term:
    id: GO:1990429
    label: peroxisomal importomer complex
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  review:
    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.
    action: ACCEPT
    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.
    supported_by:
    - reference_id: PMID:28765278
      supporting_text: the peroxisomal membrane docking/translocation module (DTM) comprising PEX13, PEX14
- term:
    id: GO:0005778
    label: peroxisomal membrane
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  review:
    summary: IEA annotation for peroxisomal membrane localization, consistent with extensive experimental evidence. Redundant with IBA and IDA annotations but not incorrect.
    action: ACCEPT
    reason: Correct annotation, consistent with all other evidence for peroxisomal membrane localization. IEA is broader but not wrong.
- term:
    id: GO:0015031
    label: protein transport
  evidence_type: IEA
  original_reference_id: GO_REF:0000043
  review:
    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.
    action: ACCEPT
    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.
- term:
    id: GO:0016558
    label: protein import into peroxisome matrix
  evidence_type: IPI
  original_reference_id: PMID:10022913
  review:
    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.
    action: ACCEPT
    reason: Core function. The paper demonstrates PEX14 binds PEX5 and overexpression disrupts matrix protein import, supporting PEX14's role in this process.
    supported_by:
    - reference_id: PMID:10022913
      supporting_text: HsPex14p overexpression leads to the decoration of tubular structures and mislocalization of peroxisomal catalase to the cytosol
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:10704444
  review:
    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.
    action: MARK_AS_OVER_ANNOTATED
    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.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:12096124
  review:
    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.
    action: MARK_AS_OVER_ANNOTATED
    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).
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:19197237
  review:
    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.
    action: MARK_AS_OVER_ANNOTATED
    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).
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:21525035
  review:
    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.
    action: MARK_AS_OVER_ANNOTATED
    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.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:29997244
  review:
    summary: LuTHy is a high-throughput binary interactome mapping technology. The specific interactions detected are not detailed in the context of PEX14 biology.
    action: MARK_AS_OVER_ANNOTATED
    reason: High-throughput protein-protein interaction study. GO:0005515 is uninformative and does not tell us which proteins PEX14 interacts with.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:31467278
  review:
    summary: High-throughput interactome mapping study. Protein binding is uninformative.
    action: MARK_AS_OVER_ANNOTATED
    reason: High-throughput study. GO:0005515 is too vague to be useful.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:32296183
  review:
    summary: Reference map of the human binary protein interactome. Protein binding is uninformative.
    action: MARK_AS_OVER_ANNOTATED
    reason: High-throughput study. GO:0005515 is too vague to be useful.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:37398436
  review:
    summary: AI-guided pipeline study for PPI drug discovery focused on SARS-CoV-2. Not directly relevant to PEX14 core function.
    action: MARK_AS_OVER_ANNOTATED
    reason: High-throughput study not specific to PEX14 biology. GO:0005515 is uninformative.
- term:
    id: GO:0042802
    label: identical protein binding
  evidence_type: IPI
  original_reference_id: PMID:12096124
  review:
    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."
    action: ACCEPT
    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.
    supported_by:
    - reference_id: PMID:12096124
      supporting_text: the latter molecule exists predominantly as a dimer in vivo
    - reference_id: PMID:12488033
      supporting_text: Heterologous expressed Pex14p was found to be a homopolymer of variable stoichiometry
- term:
    id: GO:0005777
    label: peroxisome
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  review:
    summary: IEA annotation for peroxisome localization, consistent with the more specific peroxisomal membrane annotation. PEX14 is a peroxisomal protein.
    action: ACCEPT
    reason: Correct parent term. PEX14 is a peroxisomal membrane protein and thus is correctly annotated to the parent term peroxisome as well.
- term:
    id: GO:0030674
    label: protein-macromolecule adaptor activity
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  review:
    summary: IEA annotation from Ensembl Compara transfer. PEX14 functions as an adaptor bridging PEX5 (cytosolic receptor) to the peroxisomal membrane import machinery.
    action: ACCEPT
    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).
- term:
    id: GO:0032991
    label: protein-containing complex
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  review:
    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.
    action: ACCEPT
    reason: Correct but very generic parent term. More specific complex annotations exist (peroxisomal importomer complex). Acceptable as a broad IEA annotation.
- term:
    id: GO:0005777
    label: peroxisome
  evidence_type: IDA
  original_reference_id: GO_REF:0000052
  review:
    summary: IDA based on curation of immunofluorescence data showing peroxisomal localization.
    action: ACCEPT
    reason: Correct localization. PEX14 is a peroxisomal membrane protein confirmed by immunofluorescence and subcellular fractionation.
- term:
    id: GO:0005778
    label: peroxisomal membrane
  evidence_type: IDA
  original_reference_id: PMID:37165185
  review:
    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.
    action: ACCEPT
    reason: Peroxisomal membrane localization of PEX14 is extensively documented.
    supported_by:
    - reference_id: PMID:37165185
      supporting_text: imaging fluorescence cross-correlation spectroscopy shows that cargo import correlates with transient focusing of GFP-Pex13 and GFP-Pex14 on the peroxisome membrane
- term:
    id: GO:0016560
    label: protein import into peroxisome matrix, docking
  evidence_type: NAS
  original_reference_id: PMID:37165185
  review:
    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.
    action: ACCEPT
    reason: Consistent with PEX14's core function as part of the docking machinery.
- term:
    id: GO:0005778
    label: peroxisomal membrane
  evidence_type: IDA
  original_reference_id: PMID:28765278
  review:
    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.
    action: ACCEPT
    reason: Core localization confirmed by biochemical studies.
    supported_by:
    - reference_id: PMID:28765278
      supporting_text: the interaction between PEX5 and PEX14, a major DTM component, is stable at pH 11.5
- term:
    id: GO:0008320
    label: protein transmembrane transporter activity
  evidence_type: IDA
  original_reference_id: PMID:28765278
  review:
    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.
    action: MODIFY
    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_replacement_terms:
    - id: GO:0030674
      label: protein-macromolecule adaptor activity
    supported_by:
    - reference_id: PMID:28765278
      supporting_text: 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
- term:
    id: GO:0016560
    label: protein import into peroxisome matrix, docking
  evidence_type: IDA
  original_reference_id: PMID:28765278
  review:
    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.
    action: ACCEPT
    reason: Core function of PEX14, well-supported by this and many other studies.
    supported_by:
    - reference_id: PMID:28765278
      supporting_text: 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
- term:
    id: GO:0016561
    label: protein import into peroxisome matrix, translocation
  evidence_type: IDA
  original_reference_id: PMID:28765278
  review:
    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.
    action: ACCEPT
    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.
    supported_by:
    - reference_id: PMID:28765278
      supporting_text: the DTM is best described as a large cavity-forming protein assembly into which cytosolic PEX5 can enter to release its cargo
- term:
    id: GO:0030674
    label: protein-macromolecule adaptor activity
  evidence_type: IDA
  original_reference_id: PMID:28765278
  review:
    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.
    action: ACCEPT
    reason: Accurate description of PEX14's molecular function as an adaptor that bridges PEX5 (receptor) to the membrane import machinery.
- term:
    id: GO:0016560
    label: protein import into peroxisome matrix, docking
  evidence_type: IDA
  original_reference_id: PMID:25538232
  review:
    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.
    action: ACCEPT
    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.
- term:
    id: GO:0030674
    label: protein-macromolecule adaptor activity
  evidence_type: IDA
  original_reference_id: PMID:24235149
  review:
    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.
    action: ACCEPT
    reason: Directly demonstrates PEX14's adaptor function, showing it binds PEX5 through multiple motifs (WxxxF/Y and LVXEF) to mediate receptor docking.
    supported_by:
    - reference_id: PMID:24235149
      supporting_text: Receptor-cargo docking occurs at the membrane-associated protein Pex14. In human cells, this interaction is mediated by seven conserved diaromatic penta-peptide motifs
- term:
    id: GO:0030674
    label: protein-macromolecule adaptor activity
  evidence_type: IDA
  original_reference_id: PMID:11438541
  review:
    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.
    action: ACCEPT
    reason: Key study establishing PEX14 as the high-affinity docking factor for PEX5. The adaptor function is directly demonstrated.
    supported_by:
    - reference_id: PMID:11438541
      supporting_text: 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
- term:
    id: GO:0034614
    label: cellular response to reactive oxygen species
  evidence_type: IDA
  original_reference_id: PMID:26344566
  review:
    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.
    action: MARK_AS_OVER_ANNOTATED
    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.
    supported_by:
    - reference_id: PMID:26344566
      supporting_text: a concomitant decrease in peroxisomal proteins PEX1 and PEX14
- term:
    id: GO:0005778
    label: peroxisomal membrane
  evidence_type: IDA
  original_reference_id: PMID:19197237
  review:
    summary: Neufeld et al. (2009) demonstrated PEX14 peroxisomal membrane localization by immunofluorescence and showed mutations in the N-terminal domain impair membrane targeting.
    action: ACCEPT
    reason: Direct experimental demonstration of peroxisomal membrane localization.
    supported_by:
    - reference_id: PMID:19197237
      supporting_text: The corresponding full-length Pex14 variants are impaired in peroxisomal membrane localisation in vivo
- term:
    id: GO:0016560
    label: protein import into peroxisome matrix, docking
  evidence_type: IDA
  original_reference_id: PMID:11438541
  review:
    summary: Saidowsky et al. (2001) characterized the PEX5-PEX14 interaction at the molecular level, establishing PEX14 as the docking site for PEX5.
    action: ACCEPT
    reason: Core function of PEX14 as the docking site for PEX5 import receptor.
    supported_by:
    - reference_id: PMID:11438541
      supporting_text: 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
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:24235149
  review:
    summary: Neuhaus et al. (2014) demonstrate PEX14 binds PEX5 through a novel LVXEF motif. Protein binding is uninformative for this specific interaction.
    action: MARK_AS_OVER_ANNOTATED
    reason: GO:0005515 is too vague. The PEX14-PEX5 interaction is better captured by the adaptor activity annotation.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:12488033
  review:
    summary: Oliveira et al. (2002) characterized PEX14-PEX14 homo-oligomerization and PEX14-PEX5 interaction. Protein binding is uninformative.
    action: MARK_AS_OVER_ANNOTATED
    reason: GO:0005515 is too vague. The self-interaction is captured by identical protein binding (GO:0042802) and PEX5 interaction by adaptor activity.
- term:
    id: GO:0042802
    label: identical protein binding
  evidence_type: IPI
  original_reference_id: PMID:12488033
  review:
    summary: Oliveira et al. (2002) demonstrated PEX14 forms homo-oligomers of variable stoichiometry through aa 147-278 (coiled-coil region).
    action: ACCEPT
    reason: Well-established self-interaction through the coiled-coil domain, important for DTM architecture.
    supported_by:
    - reference_id: PMID:12488033
      supporting_text: 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
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:21976670
  review:
    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.
    action: MARK_AS_OVER_ANNOTATED
    reason: GO:0005515 is uninformative. The study demonstrates PEX14's role in cargo release, better captured by the substrate release annotation (GO:0044721).
    supported_by:
    - reference_id: PMID:21976670
      supporting_text: the PEX5-catalase interaction is disrupted by the N-terminal domain of PEX14, a component of the docking/translocation machinery
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-9603775
  review:
    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).
    action: KEEP_AS_NON_CORE
    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.
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-9603784
  review:
    summary: Reactome annotation for PEX19:class I PMP binding to PEX3. PEX14 is transiently cytosolic as a PEX19 cargo.
    action: KEEP_AS_NON_CORE
    reason: Same as above - transient cytosolic presence during PMP biogenesis, not the primary localization.
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-9603804
  review:
    summary: Reactome annotation for PEX19 binding class I PMPs. PEX14 is transiently cytosolic when bound to PEX19.
    action: KEEP_AS_NON_CORE
    reason: Transient cytosolic presence during PMP biogenesis.
- term:
    id: GO:0005778
    label: peroxisomal membrane
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-8953917
  review:
    summary: Reactome annotation for PEX2:PEX10:PEX12 binding PEX5 in PEX5:PEX13:PEX14 complex. Confirms PEX14 at the peroxisomal membrane in the import complex.
    action: ACCEPT
    reason: Correct localization, consistent with PEX14's role in the DTM complex at the peroxisomal membrane.
- term:
    id: GO:0005778
    label: peroxisomal membrane
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-8953946
  review:
    summary: Reactome annotation for ubiquitination of PEX5 at the DTM.
    action: ACCEPT
    reason: Correct localization.
- term:
    id: GO:0005778
    label: peroxisomal membrane
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-9033235
  review:
    summary: Reactome annotation for cargo translocation to peroxisomal matrix. PEX14 is at the peroxisomal membrane as part of the DTM.
    action: ACCEPT
    reason: Correct localization.
- term:
    id: GO:0005778
    label: peroxisomal membrane
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-9033236
  review:
    summary: Reactome annotation for PEX5:Cargo binding DTM.
    action: ACCEPT
    reason: Correct localization.
- term:
    id: GO:0005778
    label: peroxisomal membrane
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-9033485
  review:
    summary: Reactome annotation for PEX5L ubiquitination at DTM.
    action: ACCEPT
    reason: Correct localization.
- term:
    id: GO:0005778
    label: peroxisomal membrane
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-9033499
  review:
    summary: Reactome annotation for PEX1:PEX6 dissociating PEX5 from PEX14:PEX13 complex.
    action: ACCEPT
    reason: Correct localization.
- term:
    id: GO:0005778
    label: peroxisomal membrane
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-9033514
  review:
    summary: Reactome annotation for PTS2 cargo translocation.
    action: ACCEPT
    reason: Correct localization.
- term:
    id: GO:0005778
    label: peroxisomal membrane
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-9033516
  review:
    summary: Reactome annotation for PEX1:PEX6:PEX26 binding DTM complex.
    action: ACCEPT
    reason: Correct localization.
- term:
    id: GO:0005778
    label: peroxisomal membrane
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-9033527
  review:
    summary: Reactome annotation for PEX2:PEX10:PEX12 binding PEX5L in DTM context.
    action: ACCEPT
    reason: Correct localization.
- term:
    id: GO:0005778
    label: peroxisomal membrane
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-9033533
  review:
    summary: Reactome annotation for PEX1:PEX6:PEX26 binding to ubiquitinated PEX5:PEX13:PEX14.
    action: ACCEPT
    reason: Correct localization.
- term:
    id: GO:0005778
    label: peroxisomal membrane
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-9603775
  review:
    summary: Reactome annotation for PEX3:PEX19:PMP dissociation at the peroxisomal membrane.
    action: ACCEPT
    reason: Correct localization.
- term:
    id: GO:0016020
    label: membrane
  evidence_type: HDA
  original_reference_id: PMID:19946888
  review:
    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.
    action: ACCEPT
    reason: Correct but very generic. PEX14 is a membrane protein (specifically peroxisomal membrane). Acceptable as a broad HDA annotation.
- term:
    id: GO:0044721
    label: protein import into peroxisome matrix, substrate release
  evidence_type: IDA
  original_reference_id: PMID:21976670
  review:
    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.
    action: ACCEPT
    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.
    supported_by:
    - reference_id: PMID:21976670
      supporting_text: the PEX5-catalase interaction is disrupted by the N-terminal domain of PEX14, a component of the docking/translocation machinery
- term:
    id: GO:0036250
    label: peroxisome transport along microtubule
  evidence_type: IDA
  original_reference_id: PMID:21525035
  review:
    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.
    action: ACCEPT
    reason: Well-established secondary function of PEX14. Direct experimental evidence showing PEX14 is required for peroxisome motility along microtubules.
    supported_by:
    - reference_id: PMID:21525035
      supporting_text: peroxisomal remnants in PEX14-deficient cells have lost their ability to move along microtubules
- term:
    id: GO:0032991
    label: protein-containing complex
  evidence_type: IDA
  original_reference_id: PMID:19584060
  review:
    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.
    action: ACCEPT
    reason: Correct annotation. PEX14 forms a defined complex with PEX5 (1:6 stoichiometry). Though generic, the more specific importomer complex annotation exists elsewhere.
    supported_by:
    - reference_id: PMID:19584060
      supporting_text: Titration studies yielded a 1:6 stoichiometry for the Pex5p.Pex14p complex
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:19584060
  review:
    summary: Shiozawa et al. (2009) demonstrate PEX14-PEX5 interaction by SAXS. Protein binding is uninformative.
    action: MARK_AS_OVER_ANNOTATED
    reason: GO:0005515 is too vague. The PEX5-PEX14 complex is captured by other annotations.
- term:
    id: GO:0005777
    label: peroxisome
  evidence_type: IDA
  original_reference_id: PMID:21375735
  review:
    summary: Danpure et al. (2011) studied PTS1 recognition in the context of sterol carrier protein 2. PEX14 peroxisomal localization confirmed.
    action: ACCEPT
    reason: Correct localization.
- term:
    id: GO:0005778
    label: peroxisomal membrane
  evidence_type: IDA
  original_reference_id: PMID:11669066
  review:
    summary: Amery et al. (2001) used phage display to identify peroxisomal proteins and confirmed PEX14 at the peroxisomal membrane.
    action: ACCEPT
    reason: Correct localization.
- term:
    id: GO:0005778
    label: peroxisomal membrane
  evidence_type: IDA
  original_reference_id: PMID:18346465
  review:
    summary: Study comparing PTS1 and Rab8b binding of Pex5p and Pex5Rp/TRIP8b. PEX14 peroxisomal membrane localization confirmed in the context of PEX5 binding studies.
    action: ACCEPT
    reason: Correct localization.
- term:
    id: GO:0005778
    label: peroxisomal membrane
  evidence_type: HDA
  original_reference_id: PMID:21525035
  review:
    summary: Bharti et al. (2011) performed mass spectrometric analysis of PEX14 complexes purified from peroxisomal membranes.
    action: ACCEPT
    reason: Correct localization confirmed by proteomics.
- term:
    id: GO:0008017
    label: microtubule binding
  evidence_type: IDA
  original_reference_id: PMID:21525035
  review:
    summary: Bharti et al. (2011) demonstrated direct binding of PEX14 to tubulin and that PEX14 serves as a membrane anchor for microtubules at peroxisomes.
    action: ACCEPT
    reason: Well-documented secondary function. PEX14 directly binds tubulin through its N-terminal domain, mediating peroxisome-microtubule attachment.
    supported_by:
    - reference_id: PMID:21525035
      supporting_text: tubulin was discovered to be the major PEX14-associated protein, and direct binding of the proteins was demonstrated
- term:
    id: GO:0005102
    label: signaling receptor binding
  evidence_type: IPI
  original_reference_id: PMID:21525035
  review:
    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.
    action: MODIFY
    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_replacement_terms:
    - id: GO:0008017
      label: microtubule binding
- term:
    id: GO:0016561
    label: protein import into peroxisome matrix, translocation
  evidence_type: IDA
  original_reference_id: PMID:21525035
  review:
    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.
    action: ACCEPT
    reason: PEX14 is part of the translocation machinery (DTM). The study confirmed PEX14 complexes contain import machinery components.
    supported_by:
    - reference_id: PMID:21525035
      supporting_text: almost all known human peroxins involved in protein import were identified as constituents of the PEX14 complexes
- term:
    id: GO:0034453
    label: microtubule anchoring
  evidence_type: IDA
  original_reference_id: PMID:21525035
  review:
    summary: Bharti et al. (2011) demonstrated PEX14 serves as a membrane anchor for microtubules at peroxisomes, directly binding tubulin through its N-terminal domain.
    action: ACCEPT
    reason: Well-supported secondary function. PEX14 anchors microtubules to peroxisomes through direct tubulin binding.
    supported_by:
    - reference_id: PMID:21525035
      supporting_text: 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
- term:
    id: GO:0048487
    label: beta-tubulin binding
  evidence_type: IPI
  original_reference_id: PMID:21525035
  review:
    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.
    action: ACCEPT
    reason: Well-supported specific molecular function. PEX14 binds tubulin directly through its N-terminal domain to mediate peroxisome motility.
    supported_by:
    - reference_id: PMID:21525035
      supporting_text: 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
- term:
    id: GO:0065003
    label: protein-containing complex assembly
  evidence_type: IDA
  original_reference_id: PMID:21525035
  review:
    summary: Bharti et al. (2011) established a procedure for isolating native PEX14 complexes and showed distinct multimeric PEX14 assemblies at the peroxisomal membrane.
    action: KEEP_AS_NON_CORE
    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.
    supported_by:
    - reference_id: PMID:21525035
      supporting_text: Size-exclusion chromatography revealed the existence of distinct multimeric PEX14 assemblies at the peroxisomal membrane
- term:
    id: GO:0005778
    label: peroxisomal membrane
  evidence_type: IDA
  original_reference_id: PMID:10022913
  review:
    summary: Will et al. (1999) identified human PEX14 as a carbonate-resistant peroxisomal membrane protein.
    action: ACCEPT
    reason: Core localization.
    supported_by:
    - reference_id: PMID:10022913
      supporting_text: HsPex14p is a carbonate-resistant peroxisomal membrane protein with its C terminus exposed to the cytosol
- term:
    id: GO:0005777
    label: peroxisome
  evidence_type: IDA
  original_reference_id: PMID:17881773
  review:
    summary: Study on peroxisomal protein expression in testis. PEX14 peroxisomal localization confirmed by immunostaining.
    action: ACCEPT
    reason: Correct localization.
- term:
    id: GO:0005777
    label: peroxisome
  evidence_type: IDA
  original_reference_id: PMID:19197237
  review:
    summary: Neufeld et al. (2009) confirm PEX14 peroxisomal localization by immunofluorescence.
    action: ACCEPT
    reason: Correct localization.
- term:
    id: GO:0005778
    label: peroxisomal membrane
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  review:
    summary: ISS annotation transferred from orthologs. Consistent with extensive direct experimental evidence for human PEX14.
    action: ACCEPT
    reason: Correct localization, supported by direct evidence in human.
- term:
    id: GO:0007031
    label: peroxisome organization
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  review:
    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].
    action: ACCEPT
    reason: PEX14 is essential for peroxisome organization/biogenesis. PEX14 deficiency results in peroxisome biogenesis disorders (PMID:15146459). Correct annotation at an appropriate level.
    supported_by:
    - reference_id: PMID:15146459
      supporting_text: the role of PEX14 is also essential in humans
- term:
    id: GO:0016020
    label: membrane
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  review:
    summary: Very generic ISS annotation. PEX14 is a membrane protein.
    action: ACCEPT
    reason: Correct but extremely generic. More specific terms exist.
- term:
    id: GO:0032991
    label: protein-containing complex
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  review:
    summary: ISS annotation indicating PEX14 is part of a protein complex. Very generic.
    action: ACCEPT
    reason: Correct. PEX14 is part of the DTM complex. More specific terms exist (peroxisomal importomer complex).
- term:
    id: GO:0045892
    label: negative regulation of DNA-templated transcription
  evidence_type: IDA
  original_reference_id: PMID:11863372
  review:
    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.
    action: MARK_AS_OVER_ANNOTATED
    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.
    supported_by:
    - reference_id: PMID:11863372
      supporting_text: In mammalian cell culture, ectopically expressed NAPP2 inhibited p45-directed transcriptional activation
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:11863372
  review:
    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.
    action: MARK_AS_OVER_ANNOTATED
    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.
- term:
    id: GO:0005634
    label: nucleus
  evidence_type: NAS
  original_reference_id: PMID:11863372
  review:
    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.
    action: REMOVE
    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.
- term:
    id: GO:0016558
    label: protein import into peroxisome matrix
  evidence_type: IMP
  original_reference_id: PMID:15146459
  review:
    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.
    action: ACCEPT
    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.
    supported_by:
    - reference_id: PMID:15146459
      supporting_text: 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
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:10562279
  review:
    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.
    action: MARK_AS_OVER_ANNOTATED
    reason: GO:0005515 is uninformative. The PEX14-PEX5 docking interaction is better captured by other annotations.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:9653144
  review:
    summary: Fransen et al. (1998) demonstrated PEX14 binds PEX5 and PEX13 in the original characterization of human PEX14. Protein binding is uninformative.
    action: MARK_AS_OVER_ANNOTATED
    reason: GO:0005515 is too vague. The PEX5 and PEX13 interactions are captured by more specific annotations (adaptor activity, docking).
- term:
    id: GO:0005777
    label: peroxisome
  evidence_type: IDA
  original_reference_id: PMID:16449325
  review:
    summary: Study on microtubule-mediated peroxisome division and trafficking in disorders with reduced peroxisome abundance. PEX14 peroxisomal localization confirmed.
    action: ACCEPT
    reason: Correct localization.
- term:
    id: GO:0005778
    label: peroxisomal membrane
  evidence_type: IDA
  original_reference_id: PMID:16449325
  review:
    summary: PEX14 peroxisomal membrane localization confirmed by immunofluorescence.
    action: ACCEPT
    reason: Correct localization.
references:
- id: GO_REF:0000024
  title: Manual transfer of experimentally-verified manual GO annotation data to orthologs by curator judgment of sequence similarity
  findings: []
- id: GO_REF:0000033
  title: Annotation inferences using phylogenetic trees
  findings: []
- id: GO_REF:0000043
  title: Gene Ontology annotation based on UniProtKB/Swiss-Prot keyword mapping
  findings: []
- id: GO_REF:0000052
  title: Gene Ontology annotation based on curation of immunofluorescence data
  findings: []
- id: GO_REF:0000107
  title: Automatic transfer of experimentally verified manual GO annotation data to orthologs using Ensembl Compara
  findings: []
- id: GO_REF:0000120
  title: Combined Automated Annotation using Multiple IEA Methods
  findings: []
- id: PMID:10022913
  title: Identification and characterization of the human orthologue of yeast Pex14p.
  findings:
  - statement: HsPex14p identified as a carbonate-resistant peroxisomal membrane protein that binds PEX5 and is required for peroxisomal matrix protein import.
    supporting_text: HsPex14p is a carbonate-resistant peroxisomal membrane protein with its C terminus exposed to the cytosol
- id: PMID:10562279
  title: PEX12 interacts with PEX5 and PEX10 and acts downstream of receptor docking in peroxisomal matrix protein import.
  findings: []
- id: PMID:10704444
  title: PEX19 binds multiple peroxisomal membrane proteins, is predominantly cytoplasmic, and is required for peroxisome membrane synthesis.
  findings:
  - statement: PEX19 binds PEX14 as part of its broad PMP-binding activity.
    supporting_text: PEX19 binds a broad spectrum of PMPs, displays saturable PMP binding, and interacts with regions of PMPs required for their targeting to peroxisomes
- id: PMID:11438541
  title: The di-aromatic pentapeptide repeats of the human peroxisome import receptor PEX5 are separate high affinity binding sites for the peroxisomal membrane protein PEX14.
  findings:
  - statement: Each of the seven WxxxF/Y motifs in PEX5 binds PEX14 N-terminal domain with nanomolar affinity, establishing PEX14 as the primary docking factor.
    supporting_text: 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
- id: PMID:11669066
  title: Identification of a novel human peroxisomal 2,4-dienoyl-CoA reductase related protein using the M13 phage protein VI phage display technology.
  findings: []
- id: PMID:11863372
  title: NAPP2, a peroxisomal membrane protein, is also a transcriptional corepressor.
  findings:
  - statement: PEX14 (NAPP2) reported to interact with HDAC1 and inhibit p45/NF-E2 transcription. Single study; physiological relevance for a peroxisomal membrane protein is uncertain.
    supporting_text: ectopically expressed NAPP2 inhibited p45-directed transcriptional activation. Furthermore, NAPP2 functions as a corepressor and interacts specifically with histone deacetylase l (HDAC1)
- id: PMID:12096124
  title: Analysis of mammalian peroxin interactions using a non-transcription-based bacterial two-hybrid assay.
  findings:
  - statement: PEX14 interacts with PEX5, PEX13, PEX19, and itself (predominantly as a dimer). The PEX5-PEX13 interaction is bridged by PEX14.
    supporting_text: the Pex5p-Pex13p interaction is bridged by Pex14p and that the latter molecule exists predominantly as a dimer in vivo
- id: PMID:12488033
  title: 'Mammalian Pex14p: membrane topology and characterisation of the Pex14p-Pex14p interaction.'
  findings:
  - statement: PEX14 N-terminal ~130 residues are protected by the peroxisomal membrane. PEX14 forms homo-oligomers of variable stoichiometry via aa 147-278.
    supporting_text: 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 of this peroxin
- id: PMID:15146459
  title: Identification of a new complementation group of the peroxisome biogenesis disorders and PEX14 as the mutated gene.
  findings:
  - statement: PEX14 p.Q185X nonsense mutation causes Zellweger syndrome (new complementation group). PEX14 is essential for both PTS1 and PTS2 import in humans.
    supporting_text: PEX14 is a key component of the peroxisomal import machinery and may be the initial docking site for the two import receptors PEX5 and PEX7
- id: PMID:16449325
  title: Failure of microtubule-mediated peroxisome division and trafficking in disorders with reduced peroxisome abundance.
  findings: []
- id: PMID:17881773
  title: 'Peroxisomes in human and mouse testis: differential expression of peroxisomal proteins in germ cells and distinct somatic cell types of the testis.'
  findings: []
- id: PMID:18346465
  title: Comparison of the PTS1- and Rab8b-binding properties of Pex5p and Pex5Rp/TRIP8b.
  findings: []
- id: PMID:19197237
  title: Structural basis for competitive interactions of Pex14 with the import receptors Pex5 and Pex19.
  findings:
  - statement: NMR structure of PEX14 N-terminal domain in complex with PEX5 and PEX19. PEX5 and PEX19 bind competitively to the same surface with opposite directionality.
    supporting_text: Pex5 and Pex19 ligand helices bind competitively to the same surface in Pex14(N) albeit with opposite directionality
- id: PMID:19584060
  title: Solution structure of human Pex5.Pex14.PTS1 protein complexes obtained by small angle X-ray scattering.
  findings:
  - statement: 1:6 stoichiometry for PEX5:PEX14 complex determined by SAXS.
    supporting_text: Titration studies yielded a 1:6 stoichiometry for the Pex5p.Pex14p complex
- id: PMID:19946888
  title: Defining the membrane proteome of NK cells.
  findings: []
- id: PMID:21375735
  title: The Peroxisomal Targeting Signal 1 in sterol carrier protein 2 is autonomous and essential for receptor recognition.
  findings: []
- id: PMID:21525035
  title: PEX14 is required for microtubule-based peroxisome motility in human cells.
  findings:
  - statement: PEX14 directly binds tubulin through its N-terminal domain. PEX14-deficient cells lose microtubule-based peroxisome motility. PEX14 is a multi-tasking protein serving both import and motility functions.
    supporting_text: tubulin was discovered to be the major PEX14-associated protein, and direct binding of the proteins was demonstrated
- id: PMID:21976670
  title: PEX5 protein binds monomeric catalase blocking its tetramerization and releases it upon binding the N-terminal domain of PEX14.
  findings:
  - statement: PEX14 N-terminal domain disrupts PEX5-catalase interaction, demonstrating PEX14's role in cargo release at the DTM.
    supporting_text: the PEX5-catalase interaction is disrupted by the N-terminal domain of PEX14, a component of the docking/translocation machinery
- id: PMID:24235149
  title: A novel Pex14 protein-interacting site of human Pex5 is critical for matrix protein import into peroxisomes.
  findings:
  - statement: Novel LVXEF motif in PEX5 binds PEX14 N-terminal domain with faster dissociation kinetics than WxxxF/Y motifs. May represent initial tethering site.
    supporting_text: The novel motif composes the sequence LVAEF with the evolutionarily conserved consensus sequence LVXEF
- id: PMID:25538232
  title: 'Mechanistic insights into PTS2-mediated peroxisomal protein import: the co-receptor PEX5L drastically increases the interaction strength between the cargo protein and the receptor PEX7.'
  findings: []
- id: PMID:26344566
  title: ATM functions at the peroxisome to induce pexophagy in response to ROS.
  findings:
  - statement: PEX14 protein levels decrease during ROS-induced pexophagy. PEX14 used as a marker of peroxisome degradation, not an active participant in ROS sensing.
    supporting_text: ATM signalling activates ULK1 and inhibits mTORC1 to induce autophagy. Specificity for autophagy of peroxisomes (pexophagy) is provided by ATM phosphorylation of PEX5 at Ser 141
- id: PMID:28765278
  title: The peroxisomal matrix protein translocon is a large cavity-forming protein assembly into which PEX5 protein enters to release its cargo.
  findings:
  - statement: DTM is a large cavity-forming assembly. PEX14 is a major component. PEX5-PEX14 interaction is stable at pH 11.5. Multiple PEX5 domains interact with DTM in a 'fuzzy' manner.
    supporting_text: the interaction between PEX5 and PEX14, a major DTM component, is stable at pH 11.5
- id: PMID:29997244
  title: 'LuTHy: a double-readout bioluminescence-based two-hybrid technology for quantitative mapping of protein-protein interactions in mammalian cells.'
  findings: []
- id: PMID:31467278
  title: Maximizing binary interactome mapping with a minimal number of assays.
  findings: []
- id: PMID:32296183
  title: A reference map of the human binary protein interactome.
  findings: []
- id: PMID:37165185
  title: Peroxisome biogenesis initiated by protein phase separation.
  findings:
  - statement: Pex14 forms foci during cargo import events, consistent with transient channel formation through liquid-liquid phase separation with Pex5-cargo.
    supporting_text: cargo import correlates with transient focusing of GFP-Pex13 and GFP-Pex14 on the peroxisome membrane
- id: PMID:37398436
  title: AI-guided pipeline for protein-protein interaction drug discovery identifies a SARS-CoV-2 inhibitor.
  findings: []
- id: PMID:9653144
  title: Identification of a human PTS1 receptor docking protein directly required for peroxisomal protein import.
  findings:
  - statement: First identification of human PEX14 as a peroxisomal membrane protein that binds PEX5 and PEX13, directly required for peroxisomal protein import.
    supporting_text: Recombinant Pex14p was specifically recognized by the "import inhibiting" ab-MF3 and bound Pex5p and the Src homology 3 (SH3) domain of Pex13p in ligand blots
- id: Reactome:R-HSA-8953917
  title: PEX2:PEX10:PEX12 binds PEX5S,L (in PEX5S:PEX13:PEX14) and Ub:UBE2D1,2,3
  findings: []
- id: Reactome:R-HSA-8953946
  title: PEX2:PEX10:PEX12 monoubiquitinates PEX5S,L at cysteine-11
  findings: []
- id: Reactome:R-HSA-9033235
  title: Cargo of PEX5S,L translocates from the cytosol to the peroxisomal matrix
  findings: []
- id: Reactome:R-HSA-9033236
  title: PEX5S,L:Cargo binds PEX13:PEX14:PEX2:PEX10:PEX12 (Docking and Translocation Module)
  findings: []
- id: Reactome:R-HSA-9033485
  title: PEX2:PEX10:PEX12 monoubiquitinates PEX5L at cysteine-11
  findings: []
- id: Reactome:R-HSA-9033499
  title: PEX1:PEX6:PEX26:ZFAND6 dissociates Ub:PEX5L and PEX7 from PEX14:PEX13:PEX2:PEX10:PEX12 and translocates PEX5L and PEX7 from the peroxisomal membrane to the cytosol
  findings: []
- id: Reactome:R-HSA-9033514
  title: Cargo of PEX5L:PEX7 translocates from the cytosol to the peroxisomal matrix
  findings: []
- id: Reactome:R-HSA-9033516
  title: PEX2:PEX10:PEX12:Ub:PEX5L:PEX7:PEX13:PEX14 binds PEX1:PEX6:PEX26 and ZFAND6
  findings: []
- id: Reactome:R-HSA-9033527
  title: PEX2:PEX10:PEX12 binds PEX5L (in PEX5L:PEX7:PEX13:PEX14:PEX2:PEX10:PEX12) and Ub:UBE2D1,2,3
  findings: []
- id: Reactome:R-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: []
core_functions:
- description: 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.
  molecular_function:
    id: GO:0030674
    label: protein-macromolecule adaptor activity
  directly_involved_in:
  - id: GO:0016558
    label: protein import into peroxisome matrix
  locations:
  - id: GO:0005778
    label: peroxisomal membrane
  in_complex:
    id: GO:1990429
    label: peroxisomal importomer complex
  supported_by:
  - reference_id: PMID:9653144
    supporting_text: This peroxin interacts with Pex5p and Pex13p(SH3) and is directly required for peroxisomal protein import.
  - reference_id: PMID:11438541
    supporting_text: 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
- description: PEX14 directly binds tubulin via a region overlapping its PEX5-binding domain, linking peroxisomes to microtubules for microtubule-dependent organelle motility and distribution.
  molecular_function:
    id: GO:0048487
    label: beta-tubulin binding
  directly_involved_in:
  - id: GO:0036250
    label: peroxisome transport along microtubule
  locations:
  - id: GO:0005778
    label: peroxisomal membrane
  supported_by:
  - reference_id: PMID:10562279
    supporting_text: PEX14 binds tubulin directly via a domain that overlaps with the PEX5-binding site
    full_text_unavailable: true

PEX14

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

Research Report: Human PEX14 (UniProt O75381) — Functional Annotation and Current Understanding

0) Target verification (mandatory)

1) Key concepts and definitions (current understanding)

1.1 Peroxisomal matrix protein import and the docking/translocation module (DTM)

1.2 What PEX14 is (functional definition)

2) Molecular function and mechanism (primary function)

2.1 Primary function: receptor docking and coordination of import

2.2 Key interaction motifs (PEX14 ↔ PEX5)

2.3 Pore formation: what is known vs debated

3) Protein features: localization, topology, domains

3.1 Subcellular localization

3.2 Domain organization and residue ranges (human)

3.3 Oligomerization and structural role

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

4.1 2024: Updated mechanistic model for matrix import highlights PEX13/PEX14 division of labor

4.2 2023: A novel PEX14–PEX5 interface suggests coupling between import and recycling

4.3 2024: PEX14 as a pexophagy platform in human cells (emerging function)

5) Current applications and real‑world implementations

5.1 Diagnostic/live-cell imaging of peroxisomes (2024 Nature Communications)

5.2 PEX14 in pexophagy as an actionable node (conceptual application)

6) Disease relevance (human genetics) and supporting data

6.1 Peroxisome biogenesis disorders (Zellweger spectrum)

6.2 Open Targets (database) association for PEX14

6.3 Specific reported patient variants (PEX14 truncations; pexophagy phenotype)

7) Expert opinions and analysis (authoritative synthesis)

7.1 Converging expert view: PEX14 is a core docking factor, but mechanism is nuanced

7.2 Emerging consensus: PEX14 is also a peroxisome quality-control hub

8) Key quantitative/statistical data from recent studies

Visual evidence (mechanistic schematic)

Summary table (high-level functional annotation)

Key cited sources (with dates and URLs)

Citations

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