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.

Core Functions

PEX12 activates the E3 ubiquitin-protein ligase activity of PEX10 within the PEX2-PEX10-PEX12 complex. PEX12's degenerate RING domain does not have intrinsic E3 activity but enhances PEX10-mediated monoubiquitination of PEX5, enabling PEX5 receptor recycling. PEX12 also contributes five transmembrane segments to the retrotranslocation channel (PMID:24662292, PMID:35768507).

Molecular Function:

ubiquitin ligase activator activity

Directly Involved In:

protein import into peroxisome matrix, receptor recycling

Cellular Locations:

peroxisomal membrane

In Complex:

peroxisomal importomer complex

Substrates:

PEX5

Supporting Evidence:

PMID:24662292
The E3 activity of Pex10p is essential for its peroxisome-restoring activity, being enhanced by another RING peroxin, Pex12p.

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

Molecular Function:

protein transmembrane transporter activity

Directly Involved In:

protein import into peroxisome matrix

Cellular Locations:

peroxisomal membrane

In Complex:

peroxisomal importomer complex

Supporting Evidence:

PMID:35768507
Each subunit of the complex contributes five transmembrane segments that co-assemble into an open channel.

References

GO_REF:0000002

Gene Ontology annotation through association of InterPro records with GO terms

GO_REF:0000033

Annotation inferences using phylogenetic trees

GO_REF:0000041

Gene Ontology annotation based on UniPathway vocabulary mapping

GO_REF:0000043

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

GO_REF:0000117

Electronic Gene Ontology annotations created by ARBA machine learning models

GO_REF:0000120

Combined Automated Annotation using Multiple IEA Methods

PMID:10562279

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

PEX12 zinc-binding domain binds PEX5 and PEX10

"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."
S320F mutation reduces PEX12-PEX5 and PEX12-PEX10 interactions

"we identified a patient with a missense mutation in the PEX12 zinc-binding domain, S320F, and observed that this mutation reduces the binding of PEX12 to PEX5 and PEX10."
PEX12 and PEX10 act downstream of receptor docking in import

"PEX12 and PEX10 play direct roles in peroxisomal matrix protein import downstream of the receptor docking event."

PMID:10704444

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

PEX19 binds PEX12 for membrane targeting

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

PMID:10837480

Molecular anatomy of the peroxin Pex12p: ring finger domain is essential for Pex12p function and interacts with the peroxisome-targeting signal type 1-receptor Pex5p and a ring peroxin, Pex10p.

RING finger of PEX12 binds PEX5 and PEX10

"The RING finger of Pex12p bound to Pex10p and the PTS1-receptor Pex5p."
RING finger is essential for PEX12 function but not peroxisomal targeting

"RING finger is essential for peroxisome-restoring activity of Pex12p but not necessary for targeting to peroxisomes."
PEX12 co-immunoprecipitates with PEX10

"Pex12p was co-immunoprecipitated with Pex10p from CHO-K1 cells"

PMID:12096124

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

PEX12 RING domain interacts with PEX5

"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."
PEX12 RING domain does not alter PEX5-PTS1 binding

"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."

PMID:12456682

PEX5 binds the PTS1 independently of Hsp70 and the peroxin PEX12.

PEX12 zinc RING domain has no effect on PEX5-PTS1 binding kinetics

"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."

PMID:12751901

The peroxisomal membrane targeting elements of human peroxin 2 (PEX2).

PEX12 used as peroxisomal membrane marker

PMID:17534573

A novel PEX12 mutation identified as the cause of a peroxisomal biogenesis disorder with mild clinical phenotype, mild biochemical abnormalities in fibroblasts and a mosaic catalase immunofluorescence pattern, even at 40 degrees C.

R34S mutation causes mild PBD

"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."

PMID:21525035

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

PEX12 identified as constituent of PEX14 complexes at the peroxisomal membrane

"Using mass spectrometric analysis, almost all known human peroxins involved in protein import were identified as constituents of the PEX14 complexes."

PMID:24662292

Distinct modes of ubiquitination of peroxisome-targeting signal type 1 (PTS1) receptor Pex5p regulate PTS1 protein import.

PEX10 has intrinsic E3 activity enhanced by PEX12

"The E3 activity of Pex10p is essential for its peroxisome-restoring activity, being enhanced by another RING peroxin, Pex12p."
PEX12 does not have intrinsic E3 ubiquitin ligase activity

"RING finger Pex10p functions as an E3 with an E2, UbcH5C."
PEX10-PEX12 complex monoubiquitinates PEX5 at lysine residues

"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."
RING peroxins required for both mono- and polyubiquitination of PEX5

"RING peroxins are required for both modes of Pex5p ubiquitination, thus playing a pivotal role in Pex5p shuttling."
C304W mutation abolishes PEX12 ability to activate PEX10 E3 activity

"The E3 activity of Pex10p is essential for its peroxisome-restoring activity, being enhanced by another RING peroxin, Pex12p."

PMID:26344566

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

PEX2/10/12 E3 ligase participates in ROS-induced PEX5 ubiquitination for pexophagy

"The RING peroxins PEX2, PEX10 and PEX12 are part of a peroxisome-localized E3 ligase responsible for polyubiquitination of PEX5"

PMID:32296183

A reference map of the human binary protein interactome.

High-throughput binary interactome data

PMID:35768507

A peroxisomal ubiquitin ligase complex forms a retrotranslocation channel.

Cryo-EM structure of fungal PEX2-PEX10-PEX12 complex

"Each subunit of the complex contributes five transmembrane segments that co-assemble into an open channel."
Each subunit contributes 5 TM segments forming a retrotranslocation channel

"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."
RF2 (PEX2) positioned above channel pore for monoubiquitination

"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."
RF10 and RF12 cooperate for polyubiquitination in RADAR pathway

"If recycling is compromised, receptors are polyubiquitylated by the concerted action of RF10 and RF12 and degraded."

PMID:9090384

Isolation of the human PEX12 gene, mutated in group 3 of the peroxisome biogenesis disorders.

PEX12 identified as the gene mutated in CG3 PBD

"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."
PEX12 localizes to peroxisome membrane

"PEX12 shared the same subcellular distribution as yeast Pex12p and localized to the peroxisome membrane."
PEX12 is essential for matrix protein import

"PEX12 expression restored peroxisomal protein import in fibroblasts from PBD patients of complement group 3 (CG3)"

PMID:9354782

PEX12 encodes an integral membrane protein of peroxisomes.

PEX12 is an integral peroxisomal membrane protein

"PEX12 encodes an integral membrane protein of peroxisomes."
C-terminal region exposed to cytoplasm

PMID:9922452

Peroxisome synthesis in the absence of preexisting peroxisomes.

PEX12myc used as peroxisomal membrane protein marker

"The CG3 cell line, PBD097, is a compound heterozygote for two inactivating frameshift mutations in PEX12 (Chang et al., 1997)."

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

file:human/PEX12/PEX12-deep-research-falcon.md

Deep research review of PEX12 function and biology

PEX12 is a core subunit of the PEX2-PEX10-PEX12 RING finger E3 ubiquitin ligase complex functioning as an activator of PEX10 E3 activity for PEX5 ubiquitination in the peroxisomal matrix protein import pathway

Deep Research

Falcon

(PEX12-deep-research-falcon.md)

Research Report: Human **PEX12** (UniProt **O00623**) — Functional Annotation, Mechanisms, and Clinical Relevance Falcon Edison Scientific Literature 39 citations 2026-03-05T03:53:42.522066

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 PEX12 (UniProt O00623) — Functional Annotation, Mechanisms, and Clinical Relevance

Executive summary

Human PEX12 encodes a multi-pass peroxisomal membrane peroxin that is a core subunit of the PEX2–PEX10–PEX12 RING E3 ubiquitin ligase complex required for peroxisomal matrix protein import. Its primary functional role is in the ubiquitination-dependent recycling (retrotranslocation) of the import receptor PEX5, a step essential for sustained import cycles. A major recent advance (2022–2024) is the demonstration that the PEX2–PEX10–PEX12 complex forms a membrane-spanning pore/channel that serves as the retrotranslocation conduit for PEX5, linking ubiquitination to extraction by the PEX1–PEX6 AAA ATPase. Defects in this machinery cause peroxisome biogenesis disorders (PBD) in the Zellweger spectrum, and modern clinical workflows detect PEX-gene ZSD using newborn screening biomarkers (e.g., C26:0-LPC) and confirmatory biochemical and genetic testing. (feng2022structureandfunction pages 1-3, skowyra2024towardssolvingthe pages 21-27, feng2022aperoxisomalubiquitin pages 1-2, beltran2024newbornscreeningfor pages 2-4)

Aspect	Key Points	Best Supporting Sources	Source Details
Identity & Domains	Human PEX12 is an integral peroxisomal membrane protein containing a conserved C-terminal RING-finger domain. It forms an obligate heterotrimeric complex with PEX2 and PEX10 in the peroxisomal membrane.	(feng2022structureandfunction pages 1-3, feng2022structureandfunction pages 3-5)	Biochem. Soc. Trans. (Nov 2022) https://doi.org/10.1042/bst20221393; Nature (Jun 2022) https://doi.org/10.1038/s41586-022-04903-x
Molecular Function	Functions as a subunit of the peroxisomal E3 ubiquitin ligase complex. The complex catalyzes monoubiquitination of the PEX5 import receptor at a conserved cysteine (C11), a mandatory step for PEX5 recycling to the cytosol. It also polyubiquitinates receptors for degradation when recycling fails (RADAR pathway).	(platta2009pex2andpex12 pages 1-2, liu2012recentadvancesin pages 9-10, feng2022structureandfunction pages 1-3, li2021mechanismsandfunctions pages 2-4)	Mol. Cell. Biol. (Oct 2009) https://doi.org/10.1128/mcb.00388-09; Cells (May 2021) https://doi.org/10.3390/cells10051094
Mechanism & Structure	2022-2024 Breakthrough: Cryo-EM structures reveal the PEX2–PEX10–PEX12 complex forms a conductive membrane pore (retrotranslocation channel). PEX5 inserts its N-terminus into this pore to be ubiquitinated and is subsequently pulled out by the PEX1–PEX6 AAA+ ATPase.	(skowyra2024towardssolvingthe pages 21-27, feng2022aperoxisomalubiquitin pages 1-2, feng2022structureandfunction pages 5-6, skowyra2024towardssolvingthe pages 6-8)	Trends Cell Biol. (May 2024) https://doi.org/10.1016/j.tcb.2023.08.005; Nature (Jun 2022) https://doi.org/10.1038/s41586-022-04903-x
Quality Control & Pexophagy	PEX12 and the RING complex regulate peroxisome homeostasis. Accumulation of ubiquitinated PEX5 or other PMPs on the membrane (often due to recycling failure) recruits autophagy adaptors like NBR1/p62, triggering pexophagy (selective peroxisome degradation).	(li2021mechanismsandfunctions pages 2-4, zientararytter2016autophagicdegradationof pages 4-5, li2021mechanismsandfunctions pages 4-5)	Cells (May 2021) https://doi.org/10.3390/cells10051094; Biochem. Soc. Trans. (Apr 2016) https://doi.org/10.1042/bst20150268
Disease & Diagnostics	Defects in PEX12 cause Peroxisome Biogenesis Disorders (Zellweger Spectrum). Recent studies (2024) highlight detection via newborn screening for elevated C26:0-LPC and confirmation with novel serum bile acid (C27) mass spectrometry assays and sequencing.	(beltran2024newbornscreeningfor pages 2-4, beltran2024newbornscreeningfor pages 1-2, zhang2024tandemmassspectrometry pages 1-2, zhang2024tandemmassspectrometry pages 7-8)	Genes (Jun 2024) https://doi.org/10.3390/genes15070838; J. Mass Spectrom. Adv. Clin. Lab (Nov 2024) https://doi.org/10.1016/j.jmsacl.2024.10.005

Table: Overview of PEX12 identity, molecular mechanism as a retrotranslocation channel, and clinical relevance in 2023-2024 literature.

1) Key concepts and definitions (current understanding)

1.1 Peroxins, peroxisomal matrix protein import, and the receptor cycle

Peroxisome biogenesis and matrix protein import require peroxins (PEX proteins). Matrix proteins synthesized in the cytosol are targeted to peroxisomes primarily by PEX5, which binds cargos and delivers them to the peroxisomal membrane; after cargo delivery, PEX5 must be recycled to enable repeated rounds of import. Ubiquitination of membrane-associated PEX5 is a key signal controlling whether PEX5 is recycled (mono-ubiquitination) or routed to degradation (poly-ubiquitination) in quality control pathways. (thoms2006peroxisomalmatrixprotein pages 1-2, liu2012recentadvancesin pages 9-10)

1.2 The RING peroxins and PEX12’s molecular identity

PEX12 is part of a conserved triad of RING-finger peroxins (PEX2, PEX10, PEX12) that form a membrane-embedded E3 ubiquitin ligase complex at the peroxisomal membrane. Reviews and mechanistic studies describe PEX12 as an integral membrane peroxin required for receptor ubiquitination and recycling, and as physically/functional integrated with PEX2 and PEX10 in the “RING subcomplex” of the import machinery. (liu2012recentadvancesin pages 9-10, thoms2006peroxisomalmatrixprotein pages 9-9)

1.3 What PEX12 does not do

PEX12 is not an enzyme that catalyzes a metabolic reaction (peroxisomal metabolism is carried out by matrix enzymes). Instead, its primary “biochemical activity” is as a membrane E3 ligase subunit in a multi-protein complex that coordinates ubiquitin transfer to receptors and provides a protein-conducting pathway for receptor retrotranslocation. (feng2022structureandfunction pages 1-3, feng2022aperoxisomalubiquitin pages 1-2)

2) Primary function and mechanism of action of PEX12

2.1 PEX12 in the ubiquitination machinery controlling PEX5 recycling

Foundational work established that the RING peroxins function as E3s in the matrix import pathway, with PEX12 implicated in PEX5 monoubiquitination (a recycling signal) and PEX2 implicated in PEX5 polyubiquitination (a degradation/quality-control signal) in yeast models, with conservation to mammals suggested by E2 usage differences in humans. (platta2009pex2andpex12 pages 1-2, liu2012recentadvancesin pages 9-10)

Mechanistically, mono-ubiquitination occurs on a conserved N-terminal cysteine of PEX5 (reviewed as C6 in yeast and as C11 in mammals in later summaries). This modification is essential for recognition/extraction by the PEX1–PEX6 AAA ATPase complex that dislocates PEX5 from the membrane back to the cytosol, after which deubiquitination resets PEX5. (liu2012recentadvancesin pages 9-10, li2021mechanismsandfunctions pages 2-4)

2.2 PEX12 as part of a membrane channel for receptor retrotranslocation (conceptual shift)

A central recent advance is that the PEX2–PEX10–PEX12 ligase complex is not merely a peripheral E3 ligase but forms the retrotranslocation channel for receptor recycling.

Structure/function insight (cryo-EM): Each subunit (PEX2/PEX10/PEX12) contributes five transmembrane segments that assemble into an open pore (~10 Å), while the RING fingers form a cytosolic tower positioned above the pore. This provides a physical basis for how a luminal/matrix-exposed segment of PEX5 can be moved back across the membrane to the cytosol. (feng2022structureandfunction pages 3-5)

Proposed sequence: The N-terminus of PEX5 inserts into the pore from the lumenal side and is monoubiquitinated by a RING finger positioned above the pore; extraction is then driven by the PEX1–PEX6 AAA ATPase. If recycling is compromised, receptors are polyubiquitinated by the other RING fingers and degraded (RADAR-like quality control). (feng2022structureandfunction pages 1-3, feng2022aperoxisomalubiquitin pages 1-2)

2.3 Experimental signatures used to study this step

A 2024 synthesis highlights a retrotranslocation intermediate in which PEX5 adopts a transmembrane orientation with ~20–30 N-terminal residues exposed to the cytosol, and this intermediate is enriched when the conserved cysteine required for recycling is mutated; immunoprecipitation identifies the PEX2–PEX10–PEX12 complex as major interactors, supporting its assignment as the retrotranslocon. (skowyra2024towardssolvingthe pages 6-8)

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

3.1 2024 expert synthesis: “towards solving the mystery” of import

A 2024 Trends in Cell Biology review integrates structural and biochemical work into a model in which PEX5 can fully enter the peroxisomal lumen/matrix and then be returned to the cytosol through the PEX2–PEX10–PEX12 pore, with ubiquitination at a conserved cysteine licensing extraction by PEX1–PEX6. This consolidates PEX12’s role as essential for sustained matrix import through receptor recycling. (skowyra2024towardssolvingthe pages 21-27)

Publication details: Skowyra ML, Feng P, Rapoport TA. Trends in Cell Biology (May 2024). URL: https://doi.org/10.1016/j.tcb.2023.08.005 (skowyra2024towardssolvingthe pages 21-27)

3.2 2024 updates in peroxisome quality control (pexophagy) context

PEX5 ubiquitination is increasingly viewed as part of a broader “organelle quality control” logic where persistent ubiquitin signals on peroxisomal membranes can recruit ubiquitin-binding autophagy adaptors (e.g., NBR1/p62) to trigger pexophagy. While some pathways emphasize PEX2 as a key E3 in starvation-induced pexophagy, the core import-associated RING complex (including PEX12) is mechanistically linked to the ubiquitination states that can generate pexophagy signals when recycling is blocked. (li2021mechanismsandfunctions pages 4-5, wang2017roleofpex5 pages 5-6)

3.3 Visual/structural evidence (high-impact primary literature)

The cryo-EM structure and pore model of the Pex2–Pex10–Pex12 complex—foundational to the “channel” concept—are shown in figure panels depicting the transmembrane pore and cytosolic RING tower. These visuals directly support mechanistic claims about pore formation and RING-domain positioning. (feng2022aperoxisomalubiquitin media d4311c14, feng2022aperoxisomalubiquitin media 27c6b8ba)

Publication details: Feng P et al. Nature (June 2022). URL: https://doi.org/10.1038/s41586-022-04903-x (feng2022aperoxisomalubiquitin pages 1-2)

4) Current applications and real-world implementations

4.1 Clinical genetics and newborn screening workflows relevant to PEX12/ZSD

Although newborn screening programs are typically designed for X-linked adrenoleukodystrophy (X-ALD), they can incidentally detect Zellweger spectrum disorder (ZSD) caused by biallelic PEX gene variants (potentially including PEX12) because both can elevate C26:0-lysophosphatidylcholine (C26:0-LPC).

A 2024 California case series (2016–2022) describes a two-tier approach (tier 1 FIA-MS/MS; tier 2 LC-MS/MS) for C26:0-LPC, followed by ABCD1 sequencing; among nine infants ultimately diagnosed with non–X-ALD conditions, 7/9 had ZSD due to biallelic PEX variants, confirmed by targeted ZSD gene panels or whole-exome sequencing and confirmatory biochemical markers. (beltran2024newbornscreeningfor pages 1-2)

Publication details: Beltran CFM et al. Genes (June 2024). URL: https://doi.org/10.3390/genes15070838 (beltran2024newbornscreeningfor pages 1-2)

4.2 Quantitative biomarkers used in diagnostic confirmation

A 2024 clinical-lab mass spectrometry study reports a serum assay for C27 cholestanoic bile acids (DHCA/THCA and conjugates) with clear separation between controls and peroxisomal-disorder patients.

Adult controls (n=20): mean total C27 ≈ 0.007 ± 0.004 μmol/L
Peroxisomal disorder cohort (reported as genetically confirmed; n≈49): mean total C27 ≈ 14.06 ± 2.59 μmol/L, with wide range 0.05–86.76 μmol/L (zhang2024tandemmassspectrometry pages 1-2, zhang2024tandemmassspectrometry pages 7-8)

Publication details: Zhang W et al. Journal of Mass Spectrometry and Advances in the Clinical Lab (Nov 2024). URL: https://doi.org/10.1016/j.jmsacl.2024.10.005 (zhang2024tandemmassspectrometry pages 1-2)

4.3 Translational/therapeutic example (supportive management)

In the California NBS ZSD series, 4 infants received cholic acid therapy initiated between 2–8 months, illustrating that earlier molecular diagnosis via screening can accelerate initiation of supportive/interventional management (though responses were mixed and genotype-specific conclusions were limited). (beltran2024newbornscreeningfor pages 2-4)

5) Expert opinions and analysis (authoritative perspectives)

5.1 “Channel + ligase” model as a unifying framework

Recent expert reviews interpret the PEX2–PEX10–PEX12 complex as a peroxisome analog of retrotranslocation/ubiquitin systems (conceptually similar to ERAD, but adapted for peroxisomal receptor cycling). In this view, ubiquitination is not merely a tag but is physically and temporally coupled to receptor movement through a dedicated pore formed by the ligase complex. (feng2022structureandfunction pages 5-6, skowyra2024towardssolvingthe pages 21-27)

5.2 E3 division of labor remains nuanced

Earlier mechanistic assignments implicated PEX12 in monoubiquitination (recycling) and PEX2 in polyubiquitination (degradation) in yeast, whereas structural/review syntheses emphasize that RF2 (PEX2) is positioned above the pore and may catalyze monoubiquitination in the channel model; the conceptual consensus is that the complex is required as a whole, while catalytic contributions may be organism- and context-dependent and remain an active area of refinement. (platta2009pex2andpex12 pages 1-2, feng2022structureandfunction pages 3-5)

6) Data and statistics from recent studies

6.1 Newborn screening quantitative values (ZSD detection via X-ALD screening)

In the 2024 California study of nine infants with elevated C26:0-LPC who were not X-ALD:

First-tier C26:0-LPC: mean 1.68 μmol/L (cutoff ≤0.42), median 2.20, range 0.44–3.01
Second-tier C26:0-LPC: mean 1.00 μmol/L (cutoff ≤0.22), median 1.18, range 0.224–1.475
Clinical outcomes: 6 survivors, 3 deaths before age 1 year (2, 4, 7 months)

These values quantify the screening signal strength and outcomes for infants in whom downstream workup identified ZSD due to biallelic PEX variants. (beltran2024newbornscreeningfor pages 2-4)

6.2 Diagnostic assay performance (C27 bile acids)

The 2024 serum C27 assay reports linear quantification range 20–2,500 ng/mL and intra-/inter-assay imprecision <20% CV, supporting feasibility for clinical lab workflows, and provides disease vs control distributions (above). (zhang2024tandemmassspectrometry pages 1-2)

7) Subcellular localization and pathway placement

7.1 Localization

PEX12 is a peroxisomal membrane component of the import machinery, functioning as part of the membrane-embedded ubiquitin ligase/retrotranslocon that acts at the cytosolic face (RING tower) and across the membrane (pore). (feng2022structureandfunction pages 3-5, feng2022aperoxisomalubiquitin pages 1-2)

7.2 Pathway placement: importomer/export module coupling

PEX12 is positioned at the critical interface between:

Import/docking (PEX13/PEX14; receptor engagement) and cargo delivery (contextual)
Receptor recycling/export requiring ubiquitination by the PEX2–PEX10–PEX12 complex and extraction by PEX1–PEX6 AAA ATPase

This coupling provides a mechanistic explanation for why loss-of-function in PEX12 disrupts peroxisomal matrix protein import globally. (liu2012recentadvancesin pages 9-10, skowyra2024towardssolvingthe pages 21-27)

8) Disease relevance: PEX12 and Zellweger spectrum disorders (ZSD)

Mutations in components of the PEX2–PEX10–PEX12 ligase/channel cause peroxisome biogenesis disorders; structural reviews explicitly connect disease-causing point mutations to transmembrane segments and RING domains, linking protein architecture to pathology. (feng2022structureandfunction pages 3-5, feng2022aperoxisomalubiquitin pages 1-2)

Recent clinical implementation papers (newborn screening and biomarker assays) support a modern diagnostic pipeline for PEX-gene ZSD that would include PEX12 as a candidate gene in sequencing panels/WES follow-up and biochemical confirmation. (beltran2024newbornscreeningfor pages 1-2, zhang2024tandemmassspectrometry pages 1-2)

Limitations of the current evidence base for PEX12 specifically

The most detailed mechanistic and structural sources focus on the PEX2–PEX10–PEX12 complex rather than isolating PEX12-only functions, and recent (2023–2024) human-PEX12-specific patient variant series were not directly retrieved in the available full texts. Thus, ZSD statistics are presented for PEX-gene ZSD broadly, with PEX12 placed mechanistically in the causal pathway. (beltran2024newbornscreeningfor pages 2-4, feng2022structureandfunction pages 3-5)

Key cited sources (with dates and URLs)

Feng P, Skowyra ML, Rapoport TA. Structure and function of the peroxisomal ubiquitin ligase complex. Biochemical Society Transactions. Nov 2022. https://doi.org/10.1042/bst20221393 (feng2022structureandfunction pages 1-3)
Feng P et al. A peroxisomal ubiquitin ligase complex forms a retrotranslocation channel. Nature. Jun 2022. https://doi.org/10.1038/s41586-022-04903-x (feng2022aperoxisomalubiquitin pages 1-2)
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 21-27)
Beltran CFM et al. Newborn screening for X-ALD… other genetic conditions. Genes. Jun 2024. https://doi.org/10.3390/genes15070838 (beltran2024newbornscreeningfor pages 1-2)
Zhang W, Rivas MN, Setchell KDR. Tandem MS of serum cholestanoic (C27) acids…. JMS Adv Clin Lab. Nov 2024. https://doi.org/10.1016/j.jmsacl.2024.10.005 (zhang2024tandemmassspectrometry pages 1-2)

References

(feng2022structureandfunction pages 1-3): Peiqiang Feng, Michael L. Skowyra, and Tom A. Rapoport. Structure and function of the peroxisomal ubiquitin ligase complex. Biochemical Society Transactions, 50:1921-1930, Nov 2022. URL: https://doi.org/10.1042/bst20221393, doi:10.1042/bst20221393. This article has 14 citations and is from a peer-reviewed journal.
(skowyra2024towardssolvingthe pages 21-27): 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.
(feng2022aperoxisomalubiquitin pages 1-2): Peiqiang Feng, Xudong Wu, Satchal K. Erramilli, Joao A. Paulo, Pawel Knejski, Steven P. Gygi, Anthony A. Kossiakoff, and Tom A. Rapoport. A peroxisomal ubiquitin ligase complex forms a retrotranslocation channel. Nature, 607:374-380, Jun 2022. URL: https://doi.org/10.1038/s41586-022-04903-x, doi:10.1038/s41586-022-04903-x. This article has 65 citations and is from a highest quality peer-reviewed journal.
(beltran2024newbornscreeningfor pages 2-4): Carlos F. Mares Beltran, Christina G. Tise, Rebekah Barrick, Annie D. Niehaus, Rebecca Sponberg, Richard Chang, Gregory M. Enns, and Jose E. Abdenur. Newborn screening for x-linked adrenoleukodystrophy (x-ald): biochemical, molecular, and clinical characteristics of other genetic conditions. Genes, 15:838, Jun 2024. URL: https://doi.org/10.3390/genes15070838, doi:10.3390/genes15070838. This article has 6 citations.
(feng2022structureandfunction pages 3-5): Peiqiang Feng, Michael L. Skowyra, and Tom A. Rapoport. Structure and function of the peroxisomal ubiquitin ligase complex. Biochemical Society Transactions, 50:1921-1930, Nov 2022. URL: https://doi.org/10.1042/bst20221393, doi:10.1042/bst20221393. This article has 14 citations and is from a peer-reviewed journal.
(platta2009pex2andpex12 pages 1-2): Harald W. Platta, Fouzi El Magraoui, Bastian E. Bäumer, Daniel Schlee, Wolfgang Girzalsky, and Ralf Erdmann. Pex2 and pex12 function as protein-ubiquitin ligases in peroxisomal protein import. Oct 2009. URL: https://doi.org/10.1128/mcb.00388-09, doi:10.1128/mcb.00388-09. This article has 263 citations and is from a domain leading peer-reviewed journal.
(liu2012recentadvancesin pages 9-10): Xueqian Liu, Changle Ma, and Suresh Subramani. Recent advances in peroxisomal matrix protein import. Current opinion in cell biology, 24 4:484-9, Aug 2012. URL: https://doi.org/10.1016/j.ceb.2012.05.003, doi:10.1016/j.ceb.2012.05.003. This article has 80 citations and is from a peer-reviewed journal.
(li2021mechanismsandfunctions pages 2-4): Jing Li and Wei Wang. Mechanisms and functions of pexophagy in mammalian cells. Cells, 10:1094, May 2021. URL: https://doi.org/10.3390/cells10051094, doi:10.3390/cells10051094. This article has 36 citations.
(feng2022structureandfunction pages 5-6): Peiqiang Feng, Michael L. Skowyra, and Tom A. Rapoport. Structure and function of the peroxisomal ubiquitin ligase complex. Biochemical Society Transactions, 50:1921-1930, Nov 2022. URL: https://doi.org/10.1042/bst20221393, doi:10.1042/bst20221393. This article has 14 citations and is from a peer-reviewed journal.
(skowyra2024towardssolvingthe pages 6-8): 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.
(zientararytter2016autophagicdegradationof pages 4-5): Katarzyna Zientara-Rytter and Suresh Subramani. Autophagic degradation of peroxisomes in mammals. Biochemical Society transactions, 44 2:431-40, Apr 2016. URL: https://doi.org/10.1042/bst20150268, doi:10.1042/bst20150268. This article has 78 citations and is from a peer-reviewed journal.
(li2021mechanismsandfunctions pages 4-5): Jing Li and Wei Wang. Mechanisms and functions of pexophagy in mammalian cells. Cells, 10:1094, May 2021. URL: https://doi.org/10.3390/cells10051094, doi:10.3390/cells10051094. This article has 36 citations.
(beltran2024newbornscreeningfor pages 1-2): Carlos F. Mares Beltran, Christina G. Tise, Rebekah Barrick, Annie D. Niehaus, Rebecca Sponberg, Richard Chang, Gregory M. Enns, and Jose E. Abdenur. Newborn screening for x-linked adrenoleukodystrophy (x-ald): biochemical, molecular, and clinical characteristics of other genetic conditions. Genes, 15:838, Jun 2024. URL: https://doi.org/10.3390/genes15070838, doi:10.3390/genes15070838. This article has 6 citations.
(zhang2024tandemmassspectrometry pages 1-2): Wujuan Zhang, Monica Narvaez Rivas, and Kenneth D.R. Setchell. Tandem mass spectrometry of serum cholestanoic (c27) acids – typical concentration ranges and application to the study of peroxisomal biogenesis disorders. Journal of Mass Spectrometry and Advances in the Clinical Lab, 34:34-43, Nov 2024. URL: https://doi.org/10.1016/j.jmsacl.2024.10.005, doi:10.1016/j.jmsacl.2024.10.005. This article has 3 citations.
(zhang2024tandemmassspectrometry pages 7-8): Wujuan Zhang, Monica Narvaez Rivas, and Kenneth D.R. Setchell. Tandem mass spectrometry of serum cholestanoic (c27) acids – typical concentration ranges and application to the study of peroxisomal biogenesis disorders. Journal of Mass Spectrometry and Advances in the Clinical Lab, 34:34-43, Nov 2024. URL: https://doi.org/10.1016/j.jmsacl.2024.10.005, doi:10.1016/j.jmsacl.2024.10.005. This article has 3 citations.
(thoms2006peroxisomalmatrixprotein pages 1-2): Sven Thoms and Ralf Erdmann. Peroxisomal matrix protein receptor ubiquitination and recycling. Biochimica et biophysica acta, 1763 12:1620-8, Dec 2006. URL: https://doi.org/10.1016/j.bbamcr.2006.08.046, doi:10.1016/j.bbamcr.2006.08.046. This article has 66 citations.
(thoms2006peroxisomalmatrixprotein pages 9-9): Sven Thoms and Ralf Erdmann. Peroxisomal matrix protein receptor ubiquitination and recycling. Biochimica et biophysica acta, 1763 12:1620-8, Dec 2006. URL: https://doi.org/10.1016/j.bbamcr.2006.08.046, doi:10.1016/j.bbamcr.2006.08.046. This article has 66 citations.
(wang2017roleofpex5 pages 5-6): Wei Wang and Suresh Subramani. Role of pex5 ubiquitination in maintaining peroxisome dynamics and homeostasis. Cell Cycle, 16:2037-2045, Sep 2017. URL: https://doi.org/10.1080/15384101.2017.1376149, doi:10.1080/15384101.2017.1376149. This article has 69 citations and is from a peer-reviewed journal.
(feng2022aperoxisomalubiquitin media d4311c14): Peiqiang Feng, Xudong Wu, Satchal K. Erramilli, Joao A. Paulo, Pawel Knejski, Steven P. Gygi, Anthony A. Kossiakoff, and Tom A. Rapoport. A peroxisomal ubiquitin ligase complex forms a retrotranslocation channel. Nature, 607:374-380, Jun 2022. URL: https://doi.org/10.1038/s41586-022-04903-x, doi:10.1038/s41586-022-04903-x. This article has 65 citations and is from a highest quality peer-reviewed journal.
(feng2022aperoxisomalubiquitin media 27c6b8ba): Peiqiang Feng, Xudong Wu, Satchal K. Erramilli, Joao A. Paulo, Pawel Knejski, Steven P. Gygi, Anthony A. Kossiakoff, and Tom A. Rapoport. A peroxisomal ubiquitin ligase complex forms a retrotranslocation channel. Nature, 607:374-380, Jun 2022. URL: https://doi.org/10.1038/s41586-022-04903-x, doi:10.1038/s41586-022-04903-x. This article has 65 citations and is from a highest quality peer-reviewed journal.

Citations

feng2022structureandfunction pages 3-5
skowyra2024towardssolvingthe pages 6-8
skowyra2024towardssolvingthe pages 21-27
feng2022aperoxisomalubiquitin pages 1-2
beltran2024newbornscreeningfor pages 1-2
zhang2024tandemmassspectrometry pages 1-2
beltran2024newbornscreeningfor pages 2-4
feng2022structureandfunction pages 1-3
liu2012recentadvancesin pages 9-10
li2021mechanismsandfunctions pages 2-4
feng2022structureandfunction pages 5-6
zientararytter2016autophagicdegradationof pages 4-5
li2021mechanismsandfunctions pages 4-5
zhang2024tandemmassspectrometry pages 7-8
thoms2006peroxisomalmatrixprotein pages 1-2
thoms2006peroxisomalmatrixprotein pages 9-9
https://doi.org/10.1042/bst20221393;
https://doi.org/10.1038/s41586-022-04903-x
https://doi.org/10.1128/mcb.00388-09;
https://doi.org/10.3390/cells10051094
https://doi.org/10.1016/j.tcb.2023.08.005;
https://doi.org/10.3390/cells10051094;
https://doi.org/10.1042/bst20150268
https://doi.org/10.3390/genes15070838;
https://doi.org/10.1016/j.jmsacl.2024.10.005
https://doi.org/10.1016/j.tcb.2023.08.005
https://doi.org/10.3390/genes15070838
https://doi.org/10.1042/bst20221393
https://doi.org/10.1042/bst20221393,
https://doi.org/10.1016/j.tcb.2023.08.005,
https://doi.org/10.1038/s41586-022-04903-x,
https://doi.org/10.3390/genes15070838,
https://doi.org/10.1128/mcb.00388-09,
https://doi.org/10.1016/j.ceb.2012.05.003,
https://doi.org/10.3390/cells10051094,
https://doi.org/10.1042/bst20150268,
https://doi.org/10.1016/j.jmsacl.2024.10.005,
https://doi.org/10.1016/j.bbamcr.2006.08.046,
https://doi.org/10.1080/15384101.2017.1376149,

📄 View Raw YAML

id: O00623
gene_symbol: PEX12
product_type: PROTEIN
status: IN_PROGRESS
taxon:
  id: NCBITaxon:9606
  label: Homo sapiens
description: >-
  PEX12 (Peroxin-12) is an integral peroxisomal membrane protein and a core subunit of the
  PEX2-PEX10-PEX12 RING finger E3 ubiquitin ligase complex. This complex catalyzes the
  monoubiquitination of the PTS1 receptor PEX5 at Cys11, which is required for PEX5 recycling
  back to the cytosol by the PEX1-PEX6 AAA ATPase. PEX12 contains a degenerate RING domain
  that coordinates only one zinc ion; it does not possess intrinsic E3 ligase activity but instead
  activates the E3 activity of PEX10. The PEX2-PEX10-PEX12 complex also forms a retrotranslocation
  channel with each subunit contributing five transmembrane segments. When PEX5 recycling is
  compromised, the complex polyubiquitinates PEX5 for proteasomal degradation (RADAR pathway).
  Mutations in PEX12 cause Zellweger spectrum disorders (complementation group 3).
existing_annotations:
- term:
    id: GO:0004842
    label: ubiquitin-protein transferase activity
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  review:
    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.
    action: ACCEPT
    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.
    supported_by:
      - reference_id: PMID:24662292
        supporting_text: >-
          The E3 activity of Pex10p is essential for its peroxisome-restoring activity, being enhanced
          by another RING peroxin, Pex12p.
      - reference_id: PMID:35768507
        supporting_text: >-
          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).
- term:
    id: GO:0005778
    label: peroxisomal membrane
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  review:
    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).
    action: ACCEPT
    reason: >-
      Peroxisomal membrane localization is the established primary localization for PEX12, supported
      by multiple independent experimental studies and phylogenetic inference.
    supported_by:
      - reference_id: PMID:9354782
        supporting_text: >-
          PEX12 encodes an integral membrane protein of peroxisomes.
      - reference_id: PMID:9090384
        supporting_text: >-
          PEX12 shared the same subcellular distribution as yeast Pex12p and localized to the
          peroxisome membrane.
- term:
    id: GO:0016558
    label: protein import into peroxisome matrix
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  review:
    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).
    action: ACCEPT
    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.
    supported_by:
      - reference_id: PMID:9090384
        supporting_text: >-
          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.
      - reference_id: PMID:10562279
        supporting_text: >-
          PEX12 and PEX10 play direct roles in peroxisomal matrix protein import downstream
          of the receptor docking event.
- term:
    id: GO:0006513
    label: protein monoubiquitination
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  review:
    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.
    action: ACCEPT
    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.
    supported_by:
      - reference_id: PMID:24662292
        supporting_text: >-
          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.
      - reference_id: PMID:35768507
        supporting_text: >-
          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.
- term:
    id: GO:1990429
    label: peroxisomal importomer complex
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  review:
    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).
    action: ACCEPT
    reason: >-
      PEX12 is a bona fide component of the peroxisomal importomer complex, supported by
      phylogenetic inference and extensive biochemical and structural data.
    supported_by:
      - reference_id: PMID:35768507
        supporting_text: >-
          Each subunit of the complex contributes five transmembrane segments that co-assemble
          into an open channel.
- term:
    id: GO:0005778
    label: peroxisomal membrane
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  review:
    summary: >-
      IEA annotation of peroxisomal membrane localization, consistent with all experimental
      evidence and other annotations.
    action: ACCEPT
    reason: >-
      Peroxisomal membrane localization is well-established for PEX12 and this IEA is consistent
      with the experimentally supported annotations.
- term:
    id: GO:0007031
    label: peroxisome organization
  evidence_type: IEA
  original_reference_id: GO_REF:0000117
  review:
    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).
    action: ACCEPT
    reason: >-
      PEX12 is required for normal peroxisome biogenesis and organization. This is a broader
      term than the more specific import function, but is accurate.
- term:
    id: GO:0008270
    label: zinc ion binding
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  review:
    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).
    action: ACCEPT
    reason: >-
      Zinc ion binding is structurally supported by the degenerate RING domain that coordinates
      at least one zinc ion, confirmed by mutagenesis studies.
    supported_by:
      - reference_id: PMID:10562279
        supporting_text: >-
          Mutations in human PEX12 result in Zellweger syndrome, a lethal neurological disorder,
          and implicate the zinc ring domain in PEX12 function.
- term:
    id: GO:0015031
    label: protein transport
  evidence_type: IEA
  original_reference_id: GO_REF:0000043
  review:
    summary: >-
      PEX12 is involved in protein transport, specifically peroxisomal matrix protein import.
      This is a very broad parent term.
    action: ACCEPT
    reason: >-
      While overly general, protein transport is technically correct for PEX12. More specific
      child terms (protein import into peroxisome matrix) are also annotated.
- term:
    id: GO:0016558
    label: protein import into peroxisome matrix
  evidence_type: IEA
  original_reference_id: GO_REF:0000002
  review:
    summary: >-
      IEA annotation from InterPro mapping, consistent with PEX12's established role in
      peroxisomal matrix protein import.
    action: ACCEPT
    reason: >-
      This is a core function annotation consistent with all other evidence.
- term:
    id: GO:0046872
    label: metal ion binding
  evidence_type: IEA
  original_reference_id: GO_REF:0000043
  review:
    summary: >-
      PEX12 binds zinc through its degenerate RING finger domain. Metal ion binding is a
      broad parent of zinc ion binding.
    action: ACCEPT
    reason: >-
      Correct but overly broad. The more specific zinc ion binding annotation also exists.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:10562279
  review:
    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.
    action: MODIFY
    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_replacement_terms:
      - id: GO:1990757
        label: ubiquitin ligase activator activity
    supported_by:
      - reference_id: PMID:10562279
        supporting_text: >-
          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.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:10704444
  review:
    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.
    action: MODIFY
    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_replacement_terms:
      - id: GO:0005778
        label: peroxisomal membrane
    supported_by:
      - reference_id: PMID:10704444
        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.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:12096124
  review:
    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.
    action: MODIFY
    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_replacement_terms:
      - id: GO:1990757
        label: ubiquitin ligase activator activity
    supported_by:
      - reference_id: PMID:12096124
        supporting_text: >-
          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.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:32296183
  review:
    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.
    action: MARK_AS_OVER_ANNOTATED
    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.
- term:
    id: GO:0016558
    label: protein import into peroxisome matrix
  evidence_type: NAS
  original_reference_id: PMID:24662292
  review:
    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.
    action: ACCEPT
    reason: >-
      This is a core function of PEX12 with strong supporting evidence from PMID:24662292.
    supported_by:
      - reference_id: PMID:24662292
        supporting_text: >-
          RING peroxins are required for both modes of Pex5p ubiquitination, thus playing
          a pivotal role in Pex5p shuttling.
- term:
    id: GO:0016567
    label: protein ubiquitination
  evidence_type: IEA
  original_reference_id: GO_REF:0000041
  review:
    summary: >-
      IEA from UniPathway mapping. PEX12 is involved in protein ubiquitination as part of
      the PEX2-PEX10-PEX12 E3 ligase complex.
    action: ACCEPT
    reason: >-
      Correct annotation. PEX12 participates in ubiquitination of PEX5, both monoubiquitination
      (for recycling) and polyubiquitination (for degradation).
- term:
    id: GO:0000209
    label: protein polyubiquitination
  evidence_type: IDA
  original_reference_id: PMID:24662292
  review:
    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.
    action: ACCEPT
    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.
    supported_by:
      - reference_id: PMID:24662292
        supporting_text: >-
          RING peroxins are required for both modes of Pex5p ubiquitination, thus playing
          a pivotal role in Pex5p shuttling.
      - reference_id: PMID:35768507
        supporting_text: >-
          If recycling is compromised, receptors are polyubiquitylated by the concerted action
          of RF10 and RF12 and degraded.
- term:
    id: GO:0005778
    label: peroxisomal membrane
  evidence_type: IDA
  original_reference_id: PMID:12751901
  review:
    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.
    action: ACCEPT
    reason: >-
      Peroxisomal membrane localization of PEX12 is well-established and supported by this study.
- term:
    id: GO:0006515
    label: protein quality control for misfolded or incompletely synthesized proteins
  evidence_type: ISS
  original_reference_id: PMID:35768507
  review:
    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.
    action: KEEP_AS_NON_CORE
    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.
    supported_by:
      - reference_id: PMID:35768507
        supporting_text: >-
          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)'
- term:
    id: GO:0008320
    label: protein transmembrane transporter activity
  evidence_type: ISS
  original_reference_id: PMID:35768507
  review:
    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.
    action: ACCEPT
    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.
    supported_by:
      - reference_id: PMID:35768507
        supporting_text: >-
          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.
- term:
    id: GO:0034614
    label: cellular response to reactive oxygen species
  evidence_type: IDA
  original_reference_id: PMID:26344566
  review:
    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.
    action: KEEP_AS_NON_CORE
    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.
    supported_by:
      - reference_id: PMID:26344566
        supporting_text: >-
          The RING peroxins PEX2, PEX10 and PEX12 are part of a peroxisome-localized E3 ligase
          responsible for polyubiquitination of PEX5
- term:
    id: GO:0043161
    label: proteasome-mediated ubiquitin-dependent protein catabolic process
  evidence_type: ISS
  original_reference_id: PMID:35768507
  review:
    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.
    action: KEEP_AS_NON_CORE
    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.
    supported_by:
      - reference_id: PMID:35768507
        supporting_text: >-
          If recycling is compromised, receptors are polyubiquitylated by the concerted action
          of RF10 and RF12 and degraded.
- term:
    id: GO:0044721
    label: protein import into peroxisome matrix, substrate release
  evidence_type: ISS
  original_reference_id: PMID:35768507
  review:
    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.
    action: ACCEPT
    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.
    supported_by:
      - reference_id: PMID:35768507
        supporting_text: >-
          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.
- term:
    id: GO:0005778
    label: peroxisomal membrane
  evidence_type: IDA
  original_reference_id: PMID:9922452
  review:
    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.
    action: ACCEPT
    reason: >-
      Well-established peroxisomal membrane localization confirmed by immunofluorescence.
    supported_by:
      - reference_id: PMID:9922452
        supporting_text: >-
          The CG3 cell line, PBD097, is a compound heterozygote for two inactivating frameshift
          mutations in PEX12 (Chang et al., 1997).
- term:
    id: GO:0016562
    label: protein import into peroxisome matrix, receptor recycling
  evidence_type: IDA
  original_reference_id: PMID:24662292
  review:
    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.
    action: ACCEPT
    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.
    supported_by:
      - reference_id: PMID:24662292
        supporting_text: >-
          The E3 activity of Pex10p is essential for its peroxisome-restoring activity, being enhanced
          by another RING peroxin, Pex12p.
- term:
    id: GO:0061630
    label: ubiquitin protein ligase activity
  evidence_type: IDA
  original_reference_id: PMID:24662292
  negated: true
  review:
    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.
    action: ACCEPT
    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.
    supported_by:
      - reference_id: PMID:24662292
        supporting_text: >-
          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.
- term:
    id: GO:1990757
    label: ubiquitin ligase activator activity
  evidence_type: IDA
  original_reference_id: PMID:24662292
  review:
    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.
    action: ACCEPT
    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.
    supported_by:
      - reference_id: PMID:24662292
        supporting_text: >-
          The E3 activity of Pex10p is essential for its peroxisome-restoring activity, being
          enhanced by another RING peroxin, Pex12p.
      - reference_id: file:human/PEX12/PEX12-deep-research-falcon.md
        supporting_text: >-
          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.
- term:
    id: GO:0007031
    label: peroxisome organization
  evidence_type: IDA
  original_reference_id: PMID:9354782
  review:
    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.
    action: ACCEPT
    reason: >-
      PEX12 is essential for peroxisome organization, as demonstrated by the peroxisome
      biogenesis defects in PEX12-deficient cells.
    supported_by:
      - reference_id: PMID:9354782
        supporting_text: >-
          PEX12 encodes an integral membrane protein of peroxisomes.
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-9603775
  review:
    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.
    action: KEEP_AS_NON_CORE
    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.
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-9603784
  review:
    summary: >-
      Duplicate cytosol annotation from Reactome PEX19-PEX3 pathway. Same rationale as above.
    action: KEEP_AS_NON_CORE
    reason: >-
      Transient cytosolic localization during PMP biogenesis, not the functional site.
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-9603804
  review:
    summary: >-
      Duplicate cytosol annotation from Reactome PEX19 binding pathway. Same rationale as above.
    action: KEEP_AS_NON_CORE
    reason: >-
      Transient cytosolic localization during PMP biogenesis, not the functional site.
- 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 and Ub:UBE2D at the peroxisomal
      membrane. Consistent with PEX12's established localization.
    action: ACCEPT
    reason: >-
      Well-established peroxisomal membrane localization of PEX12 as part of the E3 ligase complex.
- term:
    id: GO:0005778
    label: peroxisomal membrane
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-8953946
  review:
    summary: >-
      Reactome annotation for PEX2:PEX10:PEX12 monoubiquitination of PEX5 at peroxisomal membrane.
    action: ACCEPT
    reason: >-
      Consistent with PEX12's established peroxisomal membrane 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 step at peroxisomal membrane.
    action: ACCEPT
    reason: >-
      Consistent with PEX12's peroxisomal membrane 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 to the docking and translocation module at
      the peroxisomal membrane.
    action: ACCEPT
    reason: >-
      Consistent with PEX12's peroxisomal membrane localization.
- term:
    id: GO:0005778
    label: peroxisomal membrane
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-9033485
  review:
    summary: >-
      Reactome annotation for PEX5L monoubiquitination at peroxisomal membrane.
    action: ACCEPT
    reason: >-
      Consistent with PEX12's peroxisomal membrane 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 mediated receptor extraction at peroxisomal membrane.
    action: ACCEPT
    reason: >-
      Consistent with PEX12's peroxisomal membrane localization.
- term:
    id: GO:0005778
    label: peroxisomal membrane
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-9033514
  review:
    summary: >-
      Reactome annotation for PTS2 pathway cargo translocation at peroxisomal membrane.
    action: ACCEPT
    reason: >-
      Consistent with PEX12's peroxisomal membrane 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 at peroxisomal membrane.
    action: ACCEPT
    reason: >-
      Consistent with PEX12's peroxisomal membrane localization.
- term:
    id: GO:0005778
    label: peroxisomal membrane
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-9033527
  review:
    summary: >-
      Reactome annotation for E2 binding at peroxisomal membrane.
    action: ACCEPT
    reason: >-
      Consistent with PEX12's peroxisomal membrane 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 complex binding at peroxisomal membrane.
    action: ACCEPT
    reason: >-
      Consistent with PEX12's peroxisomal membrane 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 peroxisomal membrane.
    action: ACCEPT
    reason: >-
      Consistent with PEX12's peroxisomal membrane localization.
- term:
    id: GO:0005778
    label: peroxisomal membrane
  evidence_type: HDA
  original_reference_id: PMID:21525035
  review:
    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.
    action: ACCEPT
    reason: >-
      High-throughput data confirming PEX12's well-established peroxisomal membrane localization.
    supported_by:
      - reference_id: PMID:21525035
        supporting_text: >-
          Using mass spectrometric analysis, almost all known human peroxins involved in
          protein import were identified as constituents of the PEX14 complexes.
- term:
    id: GO:0005778
    label: peroxisomal membrane
  evidence_type: IDA
  original_reference_id: PMID:9090384
  review:
    summary: >-
      PMID:9090384 (Chang et al. 1997) identified human PEX12 and showed it localizes to the
      peroxisome membrane, sharing subcellular distribution with yeast Pex12p.
    action: ACCEPT
    reason: >-
      Original identification paper establishing PEX12's peroxisomal membrane localization.
    supported_by:
      - reference_id: PMID:9090384
        supporting_text: >-
          PEX12 shared the same subcellular distribution as yeast Pex12p and localized to the
          peroxisome membrane.
- term:
    id: GO:0005778
    label: peroxisomal membrane
  evidence_type: IDA
  original_reference_id: PMID:9354782
  review:
    summary: >-
      PMID:9354782 (Okumoto & Fujiki 1997) characterized PEX12 as an integral membrane protein
      of peroxisomes, establishing its topology with cytoplasmic N- and C-termini.
    action: ACCEPT
    reason: >-
      Key paper establishing PEX12 as an integral peroxisomal membrane protein.
    supported_by:
      - reference_id: PMID:9354782
        supporting_text: >-
          PEX12 encodes an integral membrane protein of peroxisomes.
- term:
    id: GO:0016558
    label: protein import into peroxisome matrix
  evidence_type: IMP
  original_reference_id: PMID:9090384
  review:
    summary: >-
      PMID:9090384 demonstrated that PEX12 expression restored peroxisomal protein import in
      CG3 patient fibroblasts, establishing PEX12's essential role in matrix protein import.
    action: ACCEPT
    reason: >-
      Mutant phenotype complementation directly demonstrates PEX12's requirement for
      peroxisomal matrix protein import.
    supported_by:
      - reference_id: PMID:9090384
        supporting_text: >-
          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.
- term:
    id: GO:0007031
    label: peroxisome organization
  evidence_type: IMP
  original_reference_id: PMID:17534573
  review:
    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.
    action: ACCEPT
    reason: >-
      Patient mutation study confirms PEX12 is required for normal peroxisome organization.
    supported_by:
      - reference_id: PMID:17534573
        supporting_text: >-
          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.
- term:
    id: GO:0016558
    label: protein import into peroxisome matrix
  evidence_type: IMP
  original_reference_id: PMID:10562279
  review:
    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.
    action: ACCEPT
    reason: >-
      Direct demonstration of PEX12's requirement for peroxisomal matrix protein import
      through analysis of patient mutations and protein interactions.
    supported_by:
      - reference_id: PMID:10562279
        supporting_text: >-
          PEX12 and PEX10 play direct roles in peroxisomal matrix protein import downstream
          of the receptor docking event.
- term:
    id: GO:0005777
    label: peroxisome
  evidence_type: IDA
  original_reference_id: PMID:9922452
  review:
    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.
    action: ACCEPT
    reason: >-
      Correct but less specific than peroxisomal membrane. Both annotations are acceptable.
    supported_by:
      - reference_id: PMID:9922452
        supporting_text: >-
          The CG3 cell line, PBD097, is a compound heterozygote for two inactivating frameshift
          mutations in PEX12 (Chang et al., 1997).
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:10837480
  review:
    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.
    action: MODIFY
    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_replacement_terms:
      - id: GO:1990757
        label: ubiquitin ligase activator activity
    supported_by:
      - reference_id: PMID:10837480
        supporting_text: >-
          The RING finger of Pex12p bound to Pex10p and the PTS1-receptor Pex5p.
- term:
    id: GO:0006625
    label: protein targeting to peroxisome
  evidence_type: NAS
  original_reference_id: PMID:12096124
  review:
    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.
    action: ACCEPT
    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.
- term:
    id: GO:0016558
    label: protein import into peroxisome matrix
  evidence_type: NAS
  original_reference_id: PMID:12456682
  review:
    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.
    action: ACCEPT
    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.
    supported_by:
      - reference_id: PMID:12456682
        supporting_text: >-
          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.
- term:
    id: GO:0005778
    label: peroxisomal membrane
  evidence_type: TAS
  original_reference_id: PMID:10562279
  review:
    summary: >-
      PMID:10562279 confirmed PEX12 as an integral peroxisomal membrane protein with a
      zinc ring domain at its carboxy terminus.
    action: ACCEPT
    reason: >-
      Well-established peroxisomal membrane localization.
    supported_by:
      - reference_id: PMID:10562279
        supporting_text: >-
          Peroxisomal matrix protein import requires PEX12, an integral peroxisomal membrane
          protein with a zinc ring domain at its carboxy terminus.
- term:
    id: GO:0008270
    label: zinc ion binding
  evidence_type: IMP
  original_reference_id: PMID:10562279
  review:
    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.
    action: ACCEPT
    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.
    supported_by:
      - reference_id: PMID:10562279
        supporting_text: >-
          Mutations in human PEX12 result in Zellweger syndrome, a lethal neurological disorder,
          and implicate the zinc ring domain in PEX12 function.
core_functions:
  - molecular_function:
      id: GO:1990757
      label: ubiquitin ligase activator activity
    directly_involved_in:
      - id: GO:0016562
        label: protein import into peroxisome matrix, receptor recycling
    locations:
      - id: GO:0005778
        label: peroxisomal membrane
    in_complex:
      id: GO:1990429
      label: peroxisomal importomer complex
    substrates:
      - id: UniProtKB:P50542
        label: PEX5
    description: >-
      PEX12 activates the E3 ubiquitin-protein ligase activity of PEX10 within the PEX2-PEX10-PEX12
      complex. PEX12's degenerate RING domain does not have intrinsic E3 activity but enhances
      PEX10-mediated monoubiquitination of PEX5, enabling PEX5 receptor recycling. PEX12 also
      contributes five transmembrane segments to the retrotranslocation channel (PMID:24662292,
      PMID:35768507).
    supported_by:
      - reference_id: PMID:24662292
        supporting_text: >-
          The E3 activity of Pex10p is essential for its peroxisome-restoring activity, being enhanced
          by another RING peroxin, Pex12p.
  - molecular_function:
      id: GO:0008320
      label: protein transmembrane transporter activity
    contributes_to_molecular_function:
      id: GO:0008320
      label: protein transmembrane transporter 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
    description: >-
      PEX12 contributes five transmembrane segments to the PEX2-PEX10-PEX12 retrotranslocation
      channel that facilitates PEX5 receptor export across the peroxisomal membrane (PMID:35768507).
    supported_by:
      - reference_id: PMID:35768507
        supporting_text: >-
          Each subunit of the complex contributes five transmembrane segments that co-assemble
          into an open channel.
references:
- id: GO_REF:0000002
  title: Gene Ontology annotation through association of InterPro records with GO
    terms
  findings: []
- id: GO_REF:0000033
  title: Annotation inferences using phylogenetic trees
  findings: []
- id: GO_REF:0000041
  title: Gene Ontology annotation based on UniPathway vocabulary mapping
  findings: []
- id: GO_REF:0000043
  title: Gene Ontology annotation based on UniProtKB/Swiss-Prot keyword mapping
  findings: []
- id: GO_REF:0000117
  title: Electronic Gene Ontology annotations created by ARBA machine learning models
  findings: []
- id: GO_REF:0000120
  title: Combined Automated Annotation using Multiple IEA Methods
  findings: []
- id: PMID:10562279
  title: PEX12 interacts with PEX5 and PEX10 and acts downstream of receptor docking
    in peroxisomal matrix protein import.
  findings:
    - statement: PEX12 zinc-binding domain binds PEX5 and PEX10
      supporting_text: >-
        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.
    - statement: S320F mutation reduces PEX12-PEX5 and PEX12-PEX10 interactions
      supporting_text: >-
        we identified a patient with a missense mutation in the PEX12 zinc-binding domain,
        S320F, and observed that this mutation reduces the binding of PEX12 to PEX5 and PEX10.
    - statement: PEX12 and PEX10 act downstream of receptor docking in import
      supporting_text: >-
        PEX12 and PEX10 play direct roles in peroxisomal matrix protein import downstream
        of the receptor docking event.
- id: PMID:10704444
  title: PEX19 binds multiple peroxisomal membrane proteins, is predominantly cytoplasmic,
    and is required for peroxisome membrane synthesis.
  findings:
    - statement: PEX19 binds PEX12 for membrane targeting
      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:10837480
  title: 'Molecular anatomy of the peroxin Pex12p: ring finger domain is essential
    for Pex12p function and interacts with the peroxisome-targeting signal type 1-receptor
    Pex5p and a ring peroxin, Pex10p.'
  findings:
    - statement: RING finger of PEX12 binds PEX5 and PEX10
      supporting_text: >-
        The RING finger of Pex12p bound to Pex10p and the PTS1-receptor Pex5p.
    - statement: RING finger is essential for PEX12 function but not peroxisomal targeting
      supporting_text: >-
        RING finger is essential for peroxisome-restoring activity of Pex12p but not
        necessary for targeting to peroxisomes.
    - statement: PEX12 co-immunoprecipitates with PEX10
      supporting_text: >-
        Pex12p was co-immunoprecipitated with Pex10p from CHO-K1 cells
- id: PMID:12096124
  title: Analysis of mammalian peroxin interactions using a non-transcription-based
    bacterial two-hybrid assay.
  findings:
    - statement: PEX12 RING domain interacts with PEX5
      supporting_text: >-
        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.
    - statement: PEX12 RING domain does not alter PEX5-PTS1 binding
      supporting_text: >-
        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.
- id: PMID:12456682
  title: PEX5 binds the PTS1 independently of Hsp70 and the peroxin PEX12.
  findings:
    - statement: PEX12 zinc RING domain has no effect on PEX5-PTS1 binding kinetics
      supporting_text: >-
        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.
- id: PMID:12751901
  title: The peroxisomal membrane targeting elements of human peroxin 2 (PEX2).
  findings:
    - statement: PEX12 used as peroxisomal membrane marker
- id: PMID:17534573
  title: A novel PEX12 mutation identified as the cause of a peroxisomal biogenesis
    disorder with mild clinical phenotype, mild biochemical abnormalities in fibroblasts
    and a mosaic catalase immunofluorescence pattern, even at 40 degrees C.
  findings:
    - statement: R34S mutation causes mild PBD
      supporting_text: >-
        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.
- id: PMID:21525035
  title: PEX14 is required for microtubule-based peroxisome motility in human cells.
  findings:
    - statement: PEX12 identified as constituent of PEX14 complexes at the peroxisomal membrane
      supporting_text: >-
        Using mass spectrometric analysis, almost all known human peroxins involved in
        protein import were identified as constituents of the PEX14 complexes.
- id: PMID:24662292
  title: Distinct modes of ubiquitination of peroxisome-targeting signal type 1 (PTS1)
    receptor Pex5p regulate PTS1 protein import.
  findings:
    - statement: PEX10 has intrinsic E3 activity enhanced by PEX12
      supporting_text: >-
        The E3 activity of Pex10p is essential for its peroxisome-restoring activity, being enhanced
        by another RING peroxin, Pex12p.
    - statement: PEX12 does not have intrinsic E3 ubiquitin ligase activity
      supporting_text: >-
        RING finger Pex10p functions as an E3 with an E2, UbcH5C.
    - statement: PEX10-PEX12 complex monoubiquitinates PEX5 at lysine residues
      supporting_text: >-
        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.
    - statement: RING peroxins required for both mono- and polyubiquitination of PEX5
      supporting_text: >-
        RING peroxins are required for both modes of Pex5p ubiquitination, thus playing
        a pivotal role in Pex5p shuttling.
    - statement: C304W mutation abolishes PEX12 ability to activate PEX10 E3 activity
      supporting_text: >-
        The E3 activity of Pex10p is essential for its peroxisome-restoring activity, being enhanced
        by another RING peroxin, Pex12p.
- id: PMID:26344566
  title: ATM functions at the peroxisome to induce pexophagy in response to ROS.
  findings:
    - statement: PEX2/10/12 E3 ligase participates in ROS-induced PEX5 ubiquitination for pexophagy
      supporting_text: >-
        The RING peroxins PEX2, PEX10 and PEX12 are part of a peroxisome-localized E3 ligase
        responsible for polyubiquitination of PEX5
- id: PMID:32296183
  title: A reference map of the human binary protein interactome.
  findings:
    - statement: High-throughput binary interactome data
- id: PMID:35768507
  title: A peroxisomal ubiquitin ligase complex forms a retrotranslocation channel.
  findings:
    - statement: Cryo-EM structure of fungal PEX2-PEX10-PEX12 complex
      supporting_text: >-
        Each subunit of the complex contributes five transmembrane segments that co-assemble
        into an open channel.
    - statement: Each subunit contributes 5 TM segments forming a retrotranslocation channel
      supporting_text: >-
        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.
    - statement: RF2 (PEX2) positioned above channel pore for monoubiquitination
      supporting_text: >-
        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.
    - statement: RF10 and RF12 cooperate for polyubiquitination in RADAR pathway
      supporting_text: >-
        If recycling is compromised, receptors are polyubiquitylated by the concerted action
        of RF10 and RF12 and degraded.
- id: PMID:9090384
  title: Isolation of the human PEX12 gene, mutated in group 3 of the peroxisome biogenesis
    disorders.
  findings:
    - statement: PEX12 identified as the gene mutated in CG3 PBD
      supporting_text: >-
        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.
    - statement: PEX12 localizes to peroxisome membrane
      supporting_text: >-
        PEX12 shared the same subcellular distribution as yeast Pex12p and localized to the
        peroxisome membrane.
    - statement: PEX12 is essential for matrix protein import
      supporting_text: >-
        PEX12 expression restored peroxisomal protein import in fibroblasts from PBD patients
        of complement group 3 (CG3)
- id: PMID:9354782
  title: PEX12 encodes an integral membrane protein of peroxisomes.
  findings:
    - statement: PEX12 is an integral peroxisomal membrane protein
      supporting_text: >-
        PEX12 encodes an integral membrane protein of peroxisomes.
    - statement: C-terminal region exposed to cytoplasm
- id: PMID:9922452
  title: Peroxisome synthesis in the absence of preexisting peroxisomes.
  findings:
    - statement: PEX12myc used as peroxisomal membrane protein marker
      supporting_text: >-
        The CG3 cell line, PBD097, is a compound heterozygote for two inactivating frameshift
        mutations in PEX12 (Chang et al., 1997).
- 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: []
- id: file:human/PEX12/PEX12-deep-research-falcon.md
  title: Deep research review of PEX12 function and biology
  findings:
    - statement: >-
        PEX12 is a core subunit of the PEX2-PEX10-PEX12 RING finger E3 ubiquitin ligase
        complex functioning as an activator of PEX10 E3 activity for PEX5 ubiquitination
        in the peroxisomal matrix protein import pathway

PEX12

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

Research Report: Human PEX12 (UniProt O00623) — Functional Annotation, Mechanisms, and Clinical Relevance

Executive summary

1) Key concepts and definitions (current understanding)

1.1 Peroxins, peroxisomal matrix protein import, and the receptor cycle

1.2 The RING peroxins and PEX12’s molecular identity

1.3 What PEX12 does not do

2) Primary function and mechanism of action of PEX12

2.1 PEX12 in the ubiquitination machinery controlling PEX5 recycling

2.2 PEX12 as part of a membrane channel for receptor retrotranslocation (conceptual shift)

2.3 Experimental signatures used to study this step

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

3.1 2024 expert synthesis: “towards solving the mystery” of import

3.2 2024 updates in peroxisome quality control (pexophagy) context

3.3 Visual/structural evidence (high-impact primary literature)

4) Current applications and real-world implementations

4.1 Clinical genetics and newborn screening workflows relevant to PEX12/ZSD

4.2 Quantitative biomarkers used in diagnostic confirmation

4.3 Translational/therapeutic example (supportive management)

5) Expert opinions and analysis (authoritative perspectives)

5.1 “Channel + ligase” model as a unifying framework

5.2 E3 division of labor remains nuanced

6) Data and statistics from recent studies

6.1 Newborn screening quantitative values (ZSD detection via X-ALD screening)

6.2 Diagnostic assay performance (C27 bile acids)

7) Subcellular localization and pathway placement

7.1 Localization

7.2 Pathway placement: importomer/export module coupling

8) Disease relevance: PEX12 and Zellweger spectrum disorders (ZSD)

Limitations of the current evidence base for PEX12 specifically

Key cited sources (with dates and URLs)

Citations

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