PEX12

Existing Annotations Review

GO Term	Evidence	Action	Reason
GO:0004842 ubiquitin-protein transferase activity	IBA GO_REF:0000033	ACCEPT	Summary: PEX12 is a subunit of the PEX2-PEX10-PEX12 E3 ubiquitin ligase complex that ubiquitinates PEX5. However, PEX12 itself has a degenerate RING domain and does NOT possess intrinsic E3 ubiquitin ligase activity (PMID:24662292). Instead, PEX12 activates PEX10's E3 activity. The IBA annotation of ubiquitin-protein transferase activity is appropriate at the complex level but may be misleading for PEX12 specifically. However, as part of the complex, PEX12 contributes to the overall ubiquitin transferase activity, and the IBA reflects a phylogenetically supported annotation. Reason: PEX12 is a core component of the PEX2-PEX10-PEX12 E3 ubiquitin ligase complex. While PEX12's RING domain is degenerate and lacks intrinsic E3 activity, it enhances PEX10's E3 activity and the complex as a whole functions as a ubiquitin-protein transferase. The IBA annotation captures the complex-level function appropriately. Supporting Evidence: PMID:24662292 The E3 activity of Pex10p is essential for its peroxisome-restoring activity, being enhanced by another RING peroxin, Pex12p. PMID:35768507 Both monoubiquitylation and polyubiquitylation of the receptors are catalysed by a conserved membrane-embedded ubiquitin ligase (E3) complex, consisting of Pex2, Pex10 and Pex12 (refs. 5,6).
GO:0005778 peroxisomal membrane	IBA GO_REF:0000033	ACCEPT	Summary: PEX12 is an integral peroxisomal membrane protein with five transmembrane segments (by homology to the cryo-EM structure of the fungal complex, PMID:35768507). Multiple experimental studies have confirmed peroxisomal membrane localization of PEX12 (PMID:9090384, PMID:9354782, PMID:9922452). Reason: Peroxisomal membrane localization is the established primary localization for PEX12, supported by multiple independent experimental studies and phylogenetic inference. Supporting Evidence: PMID:9354782 PEX12 encodes an integral membrane protein of peroxisomes. PMID:9090384 PEX12 shared the same subcellular distribution as yeast Pex12p and localized to the peroxisome membrane.
GO:0016558 protein import into peroxisome matrix	IBA GO_REF:0000033	ACCEPT	Summary: PEX12 is essential for peroxisomal matrix protein import, functioning as part of the PEX2-PEX10-PEX12 complex that ubiquitinates PEX5 for receptor recycling. Loss of PEX12 causes defects in both PTS1 and PTS2 protein import (PMID:9090384, PMID:10562279). Reason: This is a core function of PEX12, well-supported by phylogenetic inference and extensive experimental evidence showing PEX12 is required for peroxisomal matrix protein import. Supporting Evidence: PMID:9090384 PEX12 expression restored peroxisomal protein import in fibroblasts from PBD patients of complement group 3 (CG3) and frameshift mutations in PEX12 were detected in two unrelated CG3 patients. PMID:10562279 PEX12 and PEX10 play direct roles in peroxisomal matrix protein import downstream of the receptor docking event.
GO:0006513 protein monoubiquitination	IBA GO_REF:0000033	ACCEPT	Summary: The PEX2-PEX10-PEX12 complex catalyzes monoubiquitination of PEX5 at Cys11 in mammals, which is required for PEX5 receptor recycling (PMID:24662292, PMID:35768507). PEX12 enhances PEX10's E3 activity for this monoubiquitination event. Reason: Protein monoubiquitination is the primary enzymatic output of the PEX2-PEX10-PEX12 complex during normal peroxisomal import, and PEX12 is essential for this activity. Supporting Evidence: PMID:24662292 The Pex10p·Pex12p complex catalyzes monoubiquitination of Pex5p at one of multiple lysine residues in vitro, following the dissociation of Pex5p from Pex14p and the PTS1 cargo. PMID:35768507 We propose that the N terminus of a recycling receptor is inserted from the peroxisomal lumen into the pore and monoubiquitylated by RF2 to enable extraction into the cytosol.
GO:1990429 peroxisomal importomer complex	IBA GO_REF:0000033	ACCEPT	Summary: PEX12 is a component of the peroxisomal importomer complex, specifically the RING finger E3 ligase subcomplex (PEX2-PEX10-PEX12) that together with the docking complex (PEX13-PEX14) forms the importomer. This is well-supported by structural and biochemical evidence (PMID:35768507, PMID:10562279). Reason: PEX12 is a bona fide component of the peroxisomal importomer complex, supported by phylogenetic inference and extensive biochemical and structural data. Supporting Evidence: PMID:35768507 Each subunit of the complex contributes five transmembrane segments that co-assemble into an open channel.
GO:0005778 peroxisomal membrane	IEA GO_REF:0000120	ACCEPT	Summary: IEA annotation of peroxisomal membrane localization, consistent with all experimental evidence and other annotations. Reason: Peroxisomal membrane localization is well-established for PEX12 and this IEA is consistent with the experimentally supported annotations.
GO:0007031 peroxisome organization	IEA GO_REF:0000117	ACCEPT	Summary: PEX12 is involved in peroxisome organization through its role in matrix protein import and receptor recycling. Loss of PEX12 leads to peroxisome biogenesis defects (PMID:9090384, PMID:17534573). Reason: PEX12 is required for normal peroxisome biogenesis and organization. This is a broader term than the more specific import function, but is accurate.
GO:0008270 zinc ion binding	IEA GO_REF:0000120	ACCEPT	Summary: PEX12 contains a degenerate RING-type zinc finger domain (aa 304-343) that coordinates one zinc ion. UniProt annotates zinc binding at Cys304, Cys307, Cys325, Cys328 based on homology to the fungal structure (PMID:35768507). Mutagenesis of Cys304 abolishes PEX12 function (PMID:24662292). Reason: Zinc ion binding is structurally supported by the degenerate RING domain that coordinates at least one zinc ion, confirmed by mutagenesis studies. Supporting Evidence: PMID:10562279 Mutations in human PEX12 result in Zellweger syndrome, a lethal neurological disorder, and implicate the zinc ring domain in PEX12 function.
GO:0015031 protein transport	IEA GO_REF:0000043	ACCEPT	Summary: PEX12 is involved in protein transport, specifically peroxisomal matrix protein import. This is a very broad parent term. Reason: While overly general, protein transport is technically correct for PEX12. More specific child terms (protein import into peroxisome matrix) are also annotated.
GO:0016558 protein import into peroxisome matrix	IEA GO_REF:0000002	ACCEPT	Summary: IEA annotation from InterPro mapping, consistent with PEX12's established role in peroxisomal matrix protein import. Reason: This is a core function annotation consistent with all other evidence.
GO:0046872 metal ion binding	IEA GO_REF:0000043	ACCEPT	Summary: PEX12 binds zinc through its degenerate RING finger domain. Metal ion binding is a broad parent of zinc ion binding. Reason: Correct but overly broad. The more specific zinc ion binding annotation also exists.
GO:0005515 protein binding	IPI PMID:10562279 PEX12 interacts with PEX5 and PEX10 and acts downstream of r...	MODIFY	Summary: PMID:10562279 demonstrated that PEX12 interacts with PEX5 and PEX10 via its C-terminal zinc-binding domain using two-hybrid, blot overlay, and coimmunoprecipitation experiments. These are specific, functionally relevant interactions within the peroxisomal import machinery. Reason: Generic protein binding is uninformative. PEX12 interacts specifically with PEX5 and PEX10 in the context of the peroxisomal import machinery. A more specific term should be used. Proposed replacements: ubiquitin ligase activator activity Supporting Evidence: PMID:10562279 the zinc-binding domain of PEX12 binds both PEX5, the PTS1 receptor, and PEX10, another integral peroxisomal membrane protein required for peroxisomal matrix protein import.
GO:0005515 protein binding	IPI PMID:10704444 PEX19 binds multiple peroxisomal membrane proteins, is predo...	MODIFY	Summary: PMID:10704444 showed that PEX19 binds multiple peroxisomal membrane proteins including PEX12. PEX19 is the chaperone/receptor for PMP targeting to the peroxisomal membrane. The interaction is biologically relevant for PEX12 membrane insertion. Reason: Generic protein binding is uninformative. The interaction with PEX19 represents PEX12 being a client of the PMP import pathway. This is better captured by the peroxisomal membrane localization annotation. Proposed replacements: peroxisomal membrane Supporting Evidence: PMID:10704444 PEX19 binds a broad spectrum of PMPs, displays saturable PMP binding, and interacts with regions of PMPs required for their targeting to peroxisomes.
GO:0005515 protein binding	IPI PMID:12096124 Analysis of mammalian peroxin interactions using a non-trans...	MODIFY	Summary: PMID:12096124 used a bacterial two-hybrid system to map mammalian peroxin interactions, showing PEX12 interacts with PEX5 via its RING finger domain. This is a specific interaction within the peroxisomal import pathway. Reason: Generic protein binding is uninformative. The PEX12-PEX5 interaction is part of PEX12's role in the ubiquitination/import machinery. Better captured by more specific MF terms. Proposed replacements: ubiquitin ligase activator activity Supporting Evidence: PMID:12096124 the C(3)HC(4) RING (really interesting new gene) finger domain of Pex12p does not alter the binding properties of Pex5p for the C-terminal peroxisome-targeting signal PTS1.
GO:0005515 protein binding	IPI PMID:32296183 A reference map of the human binary protein interactome.	MARK AS OVER ANNOTATED	Summary: PMID:32296183 is a large-scale binary protein interactome mapping study (HuRI). The interactions detected are high-throughput and not specific to PEX12's known biology. Reason: High-throughput interactome study. Generic protein binding from HuRI does not provide informative functional annotation for PEX12. The specific interactions (PEX5, PEX10, PEX19) are already captured by other annotations.
GO:0016558 protein import into peroxisome matrix	NAS PMID:24662292 Distinct modes of ubiquitination of peroxisome-targeting sig...	ACCEPT	Summary: PMID:24662292 demonstrated that PEX12 enhances PEX10's E3 ubiquitin ligase activity and that the complex is required for PEX5 ubiquitination, which is essential for peroxisomal matrix protein import. This NAS is well-supported. Reason: This is a core function of PEX12 with strong supporting evidence from PMID:24662292. Supporting Evidence: PMID:24662292 RING peroxins are required for both modes of Pex5p ubiquitination, thus playing a pivotal role in Pex5p shuttling.
GO:0016567 protein ubiquitination	IEA GO_REF:0000041	ACCEPT	Summary: IEA from UniPathway mapping. PEX12 is involved in protein ubiquitination as part of the PEX2-PEX10-PEX12 E3 ligase complex. Reason: Correct annotation. PEX12 participates in ubiquitination of PEX5, both monoubiquitination (for recycling) and polyubiquitination (for degradation).
GO:0000209 protein polyubiquitination	IDA PMID:24662292 Distinct modes of ubiquitination of peroxisome-targeting sig...	ACCEPT	Summary: PMID:24662292 demonstrated that RING peroxins (including PEX12) are required for polyubiquitination of PEX5 when recycling is compromised, leading to proteasomal degradation (RADAR pathway). The cryo-EM structure study (PMID:35768507) confirmed that RF10 and RF12 cooperate in polyubiquitination. Reason: PEX12 participates in PEX5 polyubiquitination as part of the RADAR pathway when normal receptor recycling is blocked. This is a secondary but well-documented function. Supporting Evidence: PMID:24662292 RING peroxins are required for both modes of Pex5p ubiquitination, thus playing a pivotal role in Pex5p shuttling. PMID:35768507 If recycling is compromised, receptors are polyubiquitylated by the concerted action of RF10 and RF12 and degraded.
GO:0005778 peroxisomal membrane	IDA PMID:12751901 The peroxisomal membrane targeting elements of human peroxin...	ACCEPT	Summary: PMID:12751901 is primarily about PEX2 membrane targeting elements, not PEX12 directly. However, PEX12 was used as a control/comparison in the study, confirming peroxisomal membrane localization. Reason: Peroxisomal membrane localization of PEX12 is well-established and supported by this study.
GO:0006515 protein quality control for misfolded or incompletely synthesized proteins	ISS PMID:35768507 A peroxisomal ubiquitin ligase complex forms a retrotransloc...	KEEP AS NON CORE	Summary: PMID:35768507 describes the cryo-EM structure of the fungal PEX2-PEX10-PEX12 complex and shows it functions as a retrotranslocation channel. When PEX5 recycling fails, polyubiquitination leads to proteasomal degradation (RADAR pathway), analogous to ERAD quality control. The ISS annotation extends this to human PEX12. Reason: The RADAR pathway is a quality control mechanism where PEX5 that fails to recycle is polyubiquitinated and degraded by the proteasome. This is a secondary function of the PEX2-PEX10-PEX12 complex, not the primary function of PEX12. The annotation is reasonable by sequence similarity to the structurally characterized fungal complex. Supporting Evidence: PMID:35768507 the receptors are instead polyubiquitylated on Lys residues and subsequently degraded by the proteasome. This alternative pathway has been termed 'receptor accumulation and degradation in the absence of recycling (RADAR)'
GO:0008320 protein transmembrane transporter activity	ISS PMID:35768507 A peroxisomal ubiquitin ligase complex forms a retrotransloc...	ACCEPT	Summary: PMID:35768507 determined the cryo-EM structure of the fungal PEX2-PEX10-PEX12 complex and showed it forms a retrotranslocation channel through which PEX5 is transported across the peroxisomal membrane. This ISS extends the finding to human PEX12. Reason: The PEX2-PEX10-PEX12 complex forms a retrotranslocation channel for PEX5 receptor export. PEX12 contributes five transmembrane segments to this channel. This is a direct structural/functional role of PEX12. Supporting Evidence: PMID:35768507 Each subunit of the complex contributes five transmembrane segments that co-assemble into an open channel. The three ring finger domains form a cytosolic tower, with ring finger 2 (RF2) positioned above the channel pore.
GO:0034614 cellular response to reactive oxygen species	IDA PMID:26344566 ATM functions at the peroxisome to induce pexophagy in respo...	KEEP AS NON CORE	Summary: PMID:26344566 showed that the PEX2/PEX10/PEX12 E3 ligase complex participates in ROS-induced pexophagy by ubiquitinating PEX5. ATM phosphorylates PEX5 at Ser141 in response to ROS, promoting PEX5 monoubiquitination at Lys209 by the RING peroxin E3 ligase, which targets peroxisomes for p62-mediated pexophagy. The annotation for PEX12 specifically is indirect -- the study showed knockdown of PEX2/10/12 collectively reduced PEX5 ubiquitination in response to ROS. Reason: PEX12 participates in ROS-responsive pexophagy as part of the PEX2-PEX10-PEX12 E3 ligase complex that ubiquitinates PEX5. However, this is a downstream consequence of its ubiquitin ligase activity rather than a direct ROS-sensing function. The study knocked down PEX2/10/12 together, making the specific contribution of PEX12 unclear. Supporting Evidence: PMID:26344566 The RING peroxins PEX2, PEX10 and PEX12 are part of a peroxisome-localized E3 ligase responsible for polyubiquitination of PEX5
GO:0043161 proteasome-mediated ubiquitin-dependent protein catabolic process	ISS PMID:35768507 A peroxisomal ubiquitin ligase complex forms a retrotransloc...	KEEP AS NON CORE	Summary: PMID:35768507 demonstrated that when receptor recycling is blocked, the PEX2-PEX10-PEX12 complex polyubiquitinates PEX5 for proteasomal degradation (RADAR pathway). This ISS extends the finding from the fungal system to human PEX12. Reason: Proteasome-mediated degradation of PEX5 via the RADAR pathway is a secondary function that occurs when normal recycling fails. It is not the primary function of PEX12. Supporting Evidence: PMID:35768507 If recycling is compromised, receptors are polyubiquitylated by the concerted action of RF10 and RF12 and degraded.
GO:0044721 protein import into peroxisome matrix, substrate release	ISS PMID:35768507 A peroxisomal ubiquitin ligase complex forms a retrotransloc...	ACCEPT	Summary: PMID:35768507 describes the PEX2-PEX10-PEX12 complex as a retrotranslocation channel. The structural model suggests cargo release occurs before receptor ubiquitination and extraction. The ISS extends this to human PEX12. Reason: The retrotranslocation channel model implies PEX12 contributes to the substrate release step by forming part of the channel through which the receptor traverses after cargo delivery. This is consistent with PEX12's core role in the import cycle. Supporting Evidence: PMID:35768507 We propose that the N terminus of a recycling receptor is inserted from the peroxisomal lumen into the pore and monoubiquitylated by RF2 to enable extraction into the cytosol.
GO:0005778 peroxisomal membrane	IDA PMID:9922452 Peroxisome synthesis in the absence of preexisting peroxisom...	ACCEPT	Summary: PMID:9922452 (South & Gould 1999) studied peroxisome synthesis in the absence of preexisting peroxisomes. PEX12myc was used as a peroxisomal membrane protein marker, confirming its peroxisomal membrane localization. Reason: Well-established peroxisomal membrane localization confirmed by immunofluorescence. Supporting Evidence: PMID:9922452 The CG3 cell line, PBD097, is a compound heterozygote for two inactivating frameshift mutations in PEX12 (Chang et al., 1997).
GO:0016562 protein import into peroxisome matrix, receptor recycling	IDA PMID:24662292 Distinct modes of ubiquitination of peroxisome-targeting sig...	ACCEPT	Summary: PMID:24662292 demonstrated that PEX12 activates PEX10's E3 ubiquitin ligase activity, and the PEX10-PEX12 complex monoubiquitinates PEX5, which is required for PEX5 recycling from the peroxisome membrane back to the cytosol. This is the primary molecular function of PEX12 in the import cycle. Reason: Receptor recycling is the most specific and accurate description of PEX12's primary function in the import cycle. PEX12 activates PEX10 E3 activity for PEX5 monoubiquitination, which is the prerequisite for PEX5 extraction by PEX1-PEX6. Supporting Evidence: PMID:24662292 The E3 activity of Pex10p is essential for its peroxisome-restoring activity, being enhanced by another RING peroxin, Pex12p.
GO:0061630 ubiquitin protein ligase activity	IDA NOT PMID:24662292 Distinct modes of ubiquitination of peroxisome-targeting sig...	ACCEPT	Summary: PMID:24662292 demonstrated that PEX12 does NOT possess intrinsic E3 ubiquitin-protein ligase activity. The RING domain of PEX12 is degenerate and coordinates only one zinc ion. Instead, PEX12 activates the E3 activity of PEX10. This is an important negated annotation distinguishing PEX12 from PEX10. Reason: This negated annotation is critical for understanding PEX12's role. The UniProt entry states the RING-type zinc-finger is degenerated and only coordinates one zinc ion, preventing E3 ubiquitin-protein ligase activity. PEX12 instead functions as an E3 ligase activator. Supporting Evidence: PMID:24662292 RING finger Pex10p functions as an E3 with an E2, UbcH5C. The E3 activity of Pex10p is essential for its peroxisome-restoring activity, being enhanced by another RING peroxin, Pex12p.
GO:1990757 ubiquitin ligase activator activity	IDA PMID:24662292 Distinct modes of ubiquitination of peroxisome-targeting sig...	ACCEPT	Summary: PMID:24662292 directly demonstrated that PEX12 enhances (activates) the E3 ubiquitin ligase activity of PEX10. The Pex10p-Pex12p complex shows dramatically augmented E3 activity compared to PEX10 alone. Mutation of PEX12's RING domain (C304W) abolishes its ability to activate PEX10 E3 activity. Reason: This is the most precise molecular function annotation for PEX12. PEX12 does not have intrinsic E3 activity but activates PEX10's E3 activity, making ubiquitin ligase activator activity the correct MF term. Supporting Evidence: PMID:24662292 The E3 activity of Pex10p is essential for its peroxisome-restoring activity, being enhanced by another RING peroxin, Pex12p. file:human/PEX12/PEX12-deep-research-falcon.md PEX12 contains a degenerate RING domain that coordinates only one zinc ion and lacks intrinsic E3 activity, instead functioning as an activator of PEX10 E3 activity.
GO:0007031 peroxisome organization	IDA PMID:9354782 PEX12 encodes an integral membrane protein of peroxisomes.	ACCEPT	Summary: PMID:9354782 (Okumoto & Fujiki 1997) characterized PEX12 as an integral membrane protein of peroxisomes and demonstrated its role in peroxisome biogenesis/organization through complementation of CG3 patient fibroblasts. Reason: PEX12 is essential for peroxisome organization, as demonstrated by the peroxisome biogenesis defects in PEX12-deficient cells. Supporting Evidence: PMID:9354782 PEX12 encodes an integral membrane protein of peroxisomes.
GO:0005829 cytosol	TAS Reactome:R-HSA-9603775	KEEP AS NON CORE	Summary: Reactome annotation from the PEX3-PEX19-PMP dissociation pathway. PEX12 is synthesized in the cytosol before being targeted to the peroxisomal membrane via PEX19-PEX3 pathway. The cytosolic localization represents a transient biosynthetic intermediate. Reason: PEX12 transiently resides in the cytosol as a newly synthesized protein before membrane insertion via the PEX19-PEX3 pathway. This is not its functional localization but reflects its biosynthetic pathway.
GO:0005829 cytosol	TAS Reactome:R-HSA-9603784	KEEP AS NON CORE	Summary: Duplicate cytosol annotation from Reactome PEX19-PEX3 pathway. Same rationale as above. Reason: Transient cytosolic localization during PMP biogenesis, not the functional site.
GO:0005829 cytosol	TAS Reactome:R-HSA-9603804	KEEP AS NON CORE	Summary: Duplicate cytosol annotation from Reactome PEX19 binding pathway. Same rationale as above. Reason: Transient cytosolic localization during PMP biogenesis, not the functional site.
GO:0005778 peroxisomal membrane	TAS Reactome:R-HSA-8953917	ACCEPT	Summary: Reactome annotation for PEX2:PEX10:PEX12 binding PEX5 and Ub:UBE2D at the peroxisomal membrane. Consistent with PEX12's established localization. Reason: Well-established peroxisomal membrane localization of PEX12 as part of the E3 ligase complex.
GO:0005778 peroxisomal membrane	TAS Reactome:R-HSA-8953946	ACCEPT	Summary: Reactome annotation for PEX2:PEX10:PEX12 monoubiquitination of PEX5 at peroxisomal membrane. Reason: Consistent with PEX12's established peroxisomal membrane localization.
GO:0005778 peroxisomal membrane	TAS Reactome:R-HSA-9033235	ACCEPT	Summary: Reactome annotation for cargo translocation step at peroxisomal membrane. Reason: Consistent with PEX12's peroxisomal membrane localization.
GO:0005778 peroxisomal membrane	TAS Reactome:R-HSA-9033236	ACCEPT	Summary: Reactome annotation for PEX5:Cargo binding to the docking and translocation module at the peroxisomal membrane. Reason: Consistent with PEX12's peroxisomal membrane localization.
GO:0005778 peroxisomal membrane	TAS Reactome:R-HSA-9033485	ACCEPT	Summary: Reactome annotation for PEX5L monoubiquitination at peroxisomal membrane. Reason: Consistent with PEX12's peroxisomal membrane localization.
GO:0005778 peroxisomal membrane	TAS Reactome:R-HSA-9033499	ACCEPT	Summary: Reactome annotation for PEX1:PEX6 mediated receptor extraction at peroxisomal membrane. Reason: Consistent with PEX12's peroxisomal membrane localization.
GO:0005778 peroxisomal membrane	TAS Reactome:R-HSA-9033514	ACCEPT	Summary: Reactome annotation for PTS2 pathway cargo translocation at peroxisomal membrane. Reason: Consistent with PEX12's peroxisomal membrane localization.
GO:0005778 peroxisomal membrane	TAS Reactome:R-HSA-9033516	ACCEPT	Summary: Reactome annotation for PEX1:PEX6:PEX26 binding at peroxisomal membrane. Reason: Consistent with PEX12's peroxisomal membrane localization.
GO:0005778 peroxisomal membrane	TAS Reactome:R-HSA-9033527	ACCEPT	Summary: Reactome annotation for E2 binding at peroxisomal membrane. Reason: Consistent with PEX12's peroxisomal membrane localization.
GO:0005778 peroxisomal membrane	TAS Reactome:R-HSA-9033533	ACCEPT	Summary: Reactome annotation for PEX1:PEX6:PEX26 complex binding at peroxisomal membrane. Reason: Consistent with PEX12's peroxisomal membrane localization.
GO:0005778 peroxisomal membrane	TAS Reactome:R-HSA-9603775	ACCEPT	Summary: Reactome annotation for PEX3:PEX19:PMP dissociation at peroxisomal membrane. Reason: Consistent with PEX12's peroxisomal membrane localization.
GO:0005778 peroxisomal membrane	HDA PMID:21525035 PEX14 is required for microtubule-based peroxisome motility ...	ACCEPT	Summary: PMID:21525035 identified PEX12 as a constituent of PEX14 complexes at the peroxisomal membrane by mass spectrometry. PEX14 purification from digitonin-solubilized membranes co-purified nearly all known peroxins involved in protein import, including PEX12. Reason: High-throughput data confirming PEX12's well-established peroxisomal membrane localization. Supporting Evidence: PMID:21525035 Using mass spectrometric analysis, almost all known human peroxins involved in protein import were identified as constituents of the PEX14 complexes.
GO:0005778 peroxisomal membrane	IDA PMID:9090384 Isolation of the human PEX12 gene, mutated in group 3 of the...	ACCEPT	Summary: PMID:9090384 (Chang et al. 1997) identified human PEX12 and showed it localizes to the peroxisome membrane, sharing subcellular distribution with yeast Pex12p. Reason: Original identification paper establishing PEX12's peroxisomal membrane localization. Supporting Evidence: PMID:9090384 PEX12 shared the same subcellular distribution as yeast Pex12p and localized to the peroxisome membrane.
GO:0005778 peroxisomal membrane	IDA PMID:9354782 PEX12 encodes an integral membrane protein of peroxisomes.	ACCEPT	Summary: PMID:9354782 (Okumoto & Fujiki 1997) characterized PEX12 as an integral membrane protein of peroxisomes, establishing its topology with cytoplasmic N- and C-termini. Reason: Key paper establishing PEX12 as an integral peroxisomal membrane protein. Supporting Evidence: PMID:9354782 PEX12 encodes an integral membrane protein of peroxisomes.
GO:0016558 protein import into peroxisome matrix	IMP PMID:9090384 Isolation of the human PEX12 gene, mutated in group 3 of the...	ACCEPT	Summary: PMID:9090384 demonstrated that PEX12 expression restored peroxisomal protein import in CG3 patient fibroblasts, establishing PEX12's essential role in matrix protein import. Reason: Mutant phenotype complementation directly demonstrates PEX12's requirement for peroxisomal matrix protein import. Supporting Evidence: PMID:9090384 PEX12 expression restored peroxisomal protein import in fibroblasts from PBD patients of complement group 3 (CG3) and frameshift mutations in PEX12 were detected in two unrelated CG3 patients.
GO:0007031 peroxisome organization	IMP PMID:17534573 A novel PEX12 mutation identified as the cause of a peroxiso...	ACCEPT	Summary: PMID:17534573 identified a novel PEX12 mutation (R34S) causing mild peroxisome biogenesis disorder with mosaic catalase immunofluorescence, demonstrating PEX12's role in peroxisome organization. Reason: Patient mutation study confirms PEX12 is required for normal peroxisome organization. Supporting Evidence: PMID:17534573 PEX12 sequencing revealed homozygosity for a novel c.102A>T (p.R34S) missense mutation affecting a partially conserved residue in the N-terminal region important for localization to peroxisomes.
GO:0016558 protein import into peroxisome matrix	IMP PMID:10562279 PEX12 interacts with PEX5 and PEX10 and acts downstream of r...	ACCEPT	Summary: PMID:10562279 demonstrated that PEX12 acts downstream of receptor docking in peroxisomal matrix protein import. The S320F mutation in PEX12's zinc-binding domain decreases peroxisomal protein import. Reason: Direct demonstration of PEX12's requirement for peroxisomal matrix protein import through analysis of patient mutations and protein interactions. Supporting Evidence: PMID:10562279 PEX12 and PEX10 play direct roles in peroxisomal matrix protein import downstream of the receptor docking event.
GO:0005777 peroxisome	IDA PMID:9922452 Peroxisome synthesis in the absence of preexisting peroxisom...	ACCEPT	Summary: PMID:9922452 used PEX12myc as a peroxisomal membrane protein marker, confirming its localization to peroxisomes. The more specific term peroxisomal membrane is also annotated. Reason: Correct but less specific than peroxisomal membrane. Both annotations are acceptable. Supporting Evidence: PMID:9922452 The CG3 cell line, PBD097, is a compound heterozygote for two inactivating frameshift mutations in PEX12 (Chang et al., 1997).
GO:0005515 protein binding	IPI PMID:10837480 Molecular anatomy of the peroxin Pex12p: ring finger domain ...	MODIFY	Summary: PMID:10837480 demonstrated that the RING finger domain of PEX12 binds PEX5 and PEX10 using yeast two-hybrid and in vitro binding assays. PEX12 was co-immunoprecipitated with PEX10 from CHO-K1 cells. Reason: Generic protein binding is uninformative. The interactions with PEX5 and PEX10 are functionally relevant and specific to PEX12's role as a ubiquitin ligase activator. Proposed replacements: ubiquitin ligase activator activity Supporting Evidence: PMID:10837480 The RING finger of Pex12p bound to Pex10p and the PTS1-receptor Pex5p.
GO:0006625 protein targeting to peroxisome	NAS PMID:12096124 Analysis of mammalian peroxin interactions using a non-trans...	ACCEPT	Summary: PMID:12096124 mapped peroxin-peroxin interactions using bacterial two-hybrid, confirming PEX12 interactions within the import machinery. Protein targeting to peroxisome is a valid broader annotation. Reason: Protein targeting to peroxisome is a broader term encompassing PEX12's role in the import pathway. While less specific than protein import into peroxisome matrix, it is not incorrect.
GO:0016558 protein import into peroxisome matrix	NAS PMID:12456682 PEX5 binds the PTS1 independently of Hsp70 and the peroxin P...	ACCEPT	Summary: PMID:12456682 tested whether PEX12's zinc RING domain affects PEX5-PTS1 binding kinetics and found no effect, clarifying that PEX12 acts at a step other than cargo recognition. This supports PEX12's role in import at a downstream step. Reason: The study confirms PEX12's involvement in peroxisomal matrix protein import by clarifying its role is not in cargo recognition but in a downstream step. Supporting Evidence: PMID:12456682 Another protein known to interact with the PTS1-binding domain of PEX5, the PEX12 zinc RING domain, also had no discernable effect on PEX5-PTS1 binding kinetics.
GO:0005778 peroxisomal membrane	TAS PMID:10562279 PEX12 interacts with PEX5 and PEX10 and acts downstream of r...	ACCEPT	Summary: PMID:10562279 confirmed PEX12 as an integral peroxisomal membrane protein with a zinc ring domain at its carboxy terminus. Reason: Well-established peroxisomal membrane localization. Supporting Evidence: PMID:10562279 Peroxisomal matrix protein import requires PEX12, an integral peroxisomal membrane protein with a zinc ring domain at its carboxy terminus.
GO:0008270 zinc ion binding	IMP PMID:10562279 PEX12 interacts with PEX5 and PEX10 and acts downstream of r...	ACCEPT	Summary: PMID:10562279 showed that the S320F mutation in PEX12's zinc-binding domain reduces binding to PEX5 and PEX10, and decreases peroxisomal protein import. This demonstrates the functional importance of the zinc-binding domain. The IMP evidence code is appropriate as the mutation in the zinc-binding domain causes a phenotype. Reason: The zinc-binding RING domain is essential for PEX12 function. Mutations in zinc-coordinating residues abolish PEX12's ability to activate PEX10 E3 activity. Supporting Evidence: PMID:10562279 Mutations in human PEX12 result in Zellweger syndrome, a lethal neurological disorder, and implicate the zinc ring domain in PEX12 function.

Gene Description

Existing Annotations Review

Core Functions

PEX12 contributes five transmembrane segments to the PEX2-PEX10-PEX12 retrotranslocation channel that facilitates PEX5 receptor export across the peroxisomal membrane (PMID:35768507).

References

Deep Research

Falcon

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