PEX2 (Peroxisome biogenesis factor 2 / Peroxin-2) is an integral peroxisomal membrane protein containing a RING-type zinc finger domain. It functions as an E3 ubiquitin ligase subunit of the PEX2-PEX10-PEX12 retrotranslocation channel complex. This complex catalyzes monoubiquitination of the PTS1 receptor PEX5 at Cys-11, a modification required for ATP-dependent receptor recycling to the cytosol. Each subunit contributes five transmembrane segments that co-assemble into an open channel through which PEX5 is exported. PEX2 also independently mediates ubiquitination of peroxisomal membrane proteins (PEX5, PMP70/ABCD3) during amino acid starvation to induce pexophagy, and ubiquitinates ATGL/PNPLA2 for proteasomal degradation in response to ROS, thereby regulating lipolysis. Mutations in PEX2 cause Zellweger spectrum disorders (complementation group 10).
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0005778 peroxisomal membrane | IBA GO_REF:0000033 | ACCEPT | Summary: PEX2 is well-established as an integral peroxisomal membrane protein with five transmembrane segments (PMID:35768507, PMID:12751901). UniProt confirms peroxisome membrane localization (PMID:12751901). IBA annotation is phylogenetically consistent. Reason: Core localization for PEX2. Confirmed by multiple experimental studies including subcellular fractionation and fluorescence microscopy (PMID:12751901), and cryo-EM structural analysis showing five TM segments (PMID:35768507). Supporting Evidence: PMID:12751901 Peroxin 2 (PEX2) is a 35-kDa integral peroxisomal membrane protein with two transmembrane regions and a zinc RING domain within its cytoplasmically exposed C-terminus PMID:35768507 Each subunit of the complex contributes five transmembrane segments that co-assemble into an open channel. |
| GO:0007031 peroxisome organization | IBA GO_REF:0000033 | ACCEPT | Summary: PEX2 is essential for peroxisome biogenesis and organization. Loss of PEX2 function leads to absence of functional peroxisomes in Zellweger syndrome patients (PMID:1546315). IBA annotation is phylogenetically well-supported. Reason: Core function. PEX2 was originally identified as a gene responsible for Zellweger syndrome affecting peroxisome assembly (PMID:1546315). PEX2 mutations lead to defective peroxisome assembly and organization (PMID:9765053). Supporting Evidence: PMID:1546315 A human complementary DNA has been cloned that complements the disease's symptoms (including defective peroxisome assembly) in fibroblasts from a patient with Zellweger syndrome. PMID:9765053 The mutant Chinese hamster ovary (CHO) cell line Z78/C has defective peroxisome assembly due to a missense mutation in PEX2, the gene which encodes the 35 kDa peroxisomal integral membrane protein |
| GO:0000038 very long-chain fatty acid metabolic process | IBA GO_REF:0000033 | KEEP AS NON CORE | Summary: PEX2 deficiency leads to impaired VLCFA metabolism as a downstream consequence of defective peroxisomal matrix protein import. PEX2-deficient cells show impaired beta-oxidation of VLCFA (PMID:9765053). IBA annotation is phylogenetically consistent. Reason: This is a downstream consequence of PEX2's role in peroxisomal protein import, not a direct molecular function. PEX2 does not directly metabolize VLCFA; rather, loss of PEX2 impairs import of VLCFA metabolizing enzymes into peroxisomes. Supporting Evidence: PMID:9765053 expression of human PEX2 restores peroxisomal biogenesis in all of these clones... the beta-oxidation of very long chain fatty acids (VLCFA). |
| GO:0006635 fatty acid beta-oxidation | IBA GO_REF:0000033 | KEEP AS NON CORE | Summary: PEX2 deficiency leads to impaired fatty acid beta-oxidation as a downstream consequence of defective peroxisome biogenesis (PMID:9765053). IBA is phylogenetically consistent. Reason: PEX2 does not directly catalyze beta-oxidation. Rather, loss of PEX2 disrupts peroxisomal protein import, preventing beta-oxidation enzymes from reaching the peroxisomal matrix. This is an indirect effect. Supporting Evidence: PMID:9765053 the beta-oxidation of very long chain fatty acids (VLCFA). |
| GO:0016593 Cdc73/Paf1 complex | IBA GO_REF:0000033 | REMOVE | Summary: This annotation is INCORRECT for PEX2. It results from confusion between PEX2's old synonym PAF1 (Peroxisome Assembly Factor 1) and the PAF1 gene encoding the transcription elongation factor that is a component of the Cdc73/Paf1 complex. PEX2 is a peroxisomal membrane E3 ubiquitin ligase and has no known association with the nuclear Cdc73/Paf1 transcriptional regulatory complex. Reason: Gene name confusion. PEX2 has the old synonym PAF1 (Peroxisome Assembly Factor 1), which is distinct from the PAF1 gene (RNA polymerase II-associated factor 1 homolog) that encodes the actual component of the Cdc73/Paf1 complex. There is no evidence that PEX2 is part of the Cdc73/Paf1 complex. The GOA WITH/FROM field for this IBA (PANTHER:PTN008299004|UniProtKB:P28328) shows the phylogenetic assertion is seeded by PEX2's own IDA annotation from PMID:18987311 - itself the product of the same PAF1 homonym confusion (that paper studies the parafibromin/PAF1 transcriptional complex, not PEX2). The propagated annotation therefore inherits a miscited source and should be removed along with it. Propagation Review Root cause: SOURCE BAD Failure modes: SOURCE MISCITATION Sources checked: UniProtKB:P28328 Β· PEX2 (human) SOURCE BAD The seeding evidence is PEX2's own IDA to GO:0016593 from PMID:18987311, a paper on the parafibromin/PAF1 (RNA polymerase II-associated factor 1) transcriptional complex. The IDA arises from confusion of PEX2's historical synonym PAF1 (Peroxisome Assembly Factor 1) with the unrelated PAF1 transcription elongation factor; PEX2 is a peroxisomal membrane E3 ligase with no connection to the nuclear Cdc73/Paf1 complex. PANTHER:PTN008299004 Β· PEX2 family ancestral node SOURCE BAD The IBD placed at this node rests on the homonym-confused human IDA above; no PEX2/PEX10/PEX12 family member has credible evidence for Cdc73/Paf1 complex membership. |
| GO:0005778 peroxisomal membrane | IEA GO_REF:0000120 | ACCEPT | Summary: Automated annotation consistent with extensive experimental evidence for PEX2 localization to the peroxisomal membrane (PMID:12751901, PMID:35768507). Reason: Correct IEA annotation. PEX2 is an integral peroxisomal membrane protein confirmed by multiple experimental approaches. Supporting Evidence: PMID:12751901 Peroxin 2 (PEX2) is a 35-kDa integral peroxisomal membrane protein with two transmembrane regions and a zinc RING domain within its cytoplasmically exposed C-terminus |
| GO:0007031 peroxisome organization | IEA GO_REF:0000120 | ACCEPT | Summary: Automated annotation consistent with PEX2's established role in peroxisome biogenesis and organization (PMID:1546315). Reason: Correct. PEX2 is essential for peroxisome organization. Duplicate of the IBA annotation above with different evidence code, both acceptable. |
| GO:0008270 zinc ion binding | IEA GO_REF:0000120 | ACCEPT | Summary: PEX2 contains a RING-type zinc finger domain (residues 244-284) that coordinates two zinc ions. The zinc binding is integral to the RING domain structure required for E3 ubiquitin ligase activity. UniProt lists 8 zinc-binding residues. Reason: Correct. The RING-HC zinc finger domain of PEX2 requires zinc ion coordination for its structural integrity and E3 ligase function. Well-supported by domain analysis and structural data. |
| GO:0015031 protein transport | IEA GO_REF:0000043 | ACCEPT | Summary: PEX2 is involved in protein transport indirectly through its role in the peroxisomal matrix protein import pathway. The more specific term GO:0016558 (protein import into peroxisome matrix) is preferred. Reason: While quite broad, this IEA annotation is technically correct as PEX2 is involved in protein transport to peroxisomes. More specific annotations exist (GO:0016558). |
| GO:0016558 protein import into peroxisome matrix | IEA GO_REF:0000002 | ACCEPT | Summary: PEX2 is a component of the retrotranslocation channel essential for peroxisomal matrix protein import via PEX5 receptor recycling (PMID:24662292, PMID:35768507). Reason: Core function. PEX2 is required for peroxisomal matrix protein import through its role in PEX5 receptor recycling. IEA annotation consistent with experimental evidence. Supporting Evidence: PMID:24662292 we establish an in vitro ubiquitination assay system and demonstrate that RING finger Pex10p functions as an E3 with an E2, UbcH5C |
| GO:0016740 transferase activity | IEA GO_REF:0000043 | ACCEPT | Summary: PEX2 has E3 ubiquitin ligase activity (EC 2.3.2.27 and EC 2.3.2.36), which is a type of transferase activity. This is technically correct but very broad. Reason: Correct but broad IEA. PEX2's ubiquitin-protein ligase activity is a form of transferase activity. More specific annotations (GO:0061630) are also present. |
| GO:0046872 metal ion binding | IEA GO_REF:0000043 | ACCEPT | Summary: PEX2 binds zinc ions through its RING-type zinc finger domain. This is correct but less specific than GO:0008270 (zinc ion binding). Reason: Correct IEA. PEX2 binds metal ions (zinc) via its RING domain. More specific zinc ion binding annotation also exists. |
| GO:0061630 ubiquitin protein ligase activity | IEA GO_REF:0000003 | ACCEPT | Summary: PEX2 has E3 ubiquitin protein ligase activity, catalyzing ubiquitination of PEX5, PMP70, and ATGL (PMID:27597759, PMID:34903883). EC 2.3.2.27 assigned by UniProt. Reason: Core molecular function. PEX2 is an established E3 ubiquitin ligase confirmed by multiple experimental studies. Supporting Evidence: PMID:27597759 the peroxisomal E3 ubiquitin ligase peroxin 2 (PEX2) is the causative agent for mammalian pexophagy. |
| GO:0005515 protein binding | IPI PMID:20531392 The peroxisomal receptor Pex19p forms a helical mPTS recogni... | MARK AS OVER ANNOTATED | Summary: PMID:20531392 is about PEX19 forming a helical mPTS recognition domain. PEX19 is known to bind PEX2 as a chaperone/receptor for peroxisomal membrane protein import. UniProt confirms PEX2 interacts with PEX19 (IntAct). However, protein binding is uninformative. Reason: The interaction between PEX2 and PEX19 is real and biologically meaningful (PEX19 is the receptor/chaperone for PEX2 membrane targeting), but GO:0005515 (protein binding) is too generic to be informative. A more specific term would be preferable. Supporting Evidence: PMID:20531392 The protein Pex19p functions as a receptor and chaperone of peroxisomal membrane proteins (PMPs). |
| GO:0005515 protein binding | IPI PMID:33961781 Dual proteome-scale networks reveal cell-specific remodeling... | MARK AS OVER ANNOTATED | Summary: PMID:33961781 is a large-scale interactome study. Protein binding annotations from high-throughput interaction screens are typically uninformative. Reason: GO:0005515 (protein binding) is uninformative. This is from a large-scale proteomics interactome study and does not provide specific functional insight about PEX2's molecular function. |
| GO:0005777 peroxisome | IEA GO_REF:0000107 | ACCEPT | Summary: PEX2 localizes to the peroxisome (specifically the peroxisomal membrane). This broader term is acceptable alongside the more specific peroxisomal membrane annotation. Reason: Correct. PEX2 is a peroxisomal protein. The more specific GO:0005778 (peroxisomal membrane) is also annotated. |
| GO:0016558 protein import into peroxisome matrix | NAS PMID:24662292 Distinct modes of ubiquitination of peroxisome-targeting sig... | ACCEPT | Summary: PMID:24662292 demonstrates that RING finger peroxins (PEX10, PEX12, and by implication PEX2) are required for PEX5 ubiquitination, which is essential for PTS1 protein import. The study directly shows the PEX2-PEX10-PEX12 complex is involved in PEX5 receptor recycling, a critical step in matrix protein import. Reason: Core function. PEX2 is a component of the retrotranslocation channel essential for peroxisomal matrix protein import via PEX5 receptor recycling. Supporting Evidence: PMID:24662292 we establish an in vitro ubiquitination assay system and demonstrate that RING finger Pex10p functions as an E3 with an E2, UbcH5C |
| GO:0016567 protein ubiquitination | IEA GO_REF:0000041 | ACCEPT | Summary: PEX2 catalyzes protein ubiquitination as part of its E3 ligase activity. Substrates include PEX5 (monoubiquitination at Cys-11), PMP70, and ATGL (PMID:27597759, PMID:34903883). Reason: Core function. PEX2 is an established E3 ubiquitin ligase with well-characterized substrates. Supporting Evidence: PMID:27597759 We identify PEX5 and PMP70 as substrates of PEX2 that are ubiquitinated during amino acid starvation. |
| GO:0000425 pexophagy | IDA PMID:26344566 ATM functions at the peroxisome to induce pexophagy in respo... | ACCEPT | Summary: PMID:26344566 is primarily about ATM-mediated pexophagy in response to ROS: ATM phosphorylates PEX5 at Ser141, promoting PEX5 ubiquitination and p62-dependent pexophagy. Importantly, the full text does directly test PEX2: siRNA knockdown of the RING peroxins PEX2, PEX10 and PEX12 reduced both poly- and monoubiquitination of PEX5 in this pexophagy pathway, placing PEX2 as the E3 module acting downstream of ATM. This is fully consistent with the independent demonstration that PEX2 is the E3 ligase required for starvation-induced pexophagy (PMID:27597759). Reason: Direct experimental support in the full text: PEX2 knockdown (with PEX10/PEX12) reduced PEX5 ubiquitination required for ROS-induced pexophagy in this paper, and PEX2's role in pexophagy is independently established by PMID:27597759, which shows PEX2 specifically drives ubiquitination-dependent pexophagy. Consistent with the ACCEPT action for the PMID:27597759 pexophagy annotation. Supporting Evidence: PMID:26344566 Specificity for autophagy of peroxisomes (pexophagy) is provided by ATM phosphorylation of PEX5 at Ser 141, which promotes PEX5 monoubiquitylation at Lys 209, and recognition of ubiquitylated PEX5 by the autophagy adaptor protein p62, directing the autophagosome to peroxisomes to induce pexophagy PMID:26344566 The RING peroxins PEX2, PEX10 and PEX12 are part of a peroxisome-localized E3 ligase responsible for polyubiquitination of PEX534, and as expected, siRNA knockdown of these peroxins reduced polyubiquitination of PEX5 PMID:26344566 Knockdown of these E3 ligases also reduced monoubiquitination of PEX5, suggesting this peroxisomal E3 ligase also participates in PEX5 monoubiquitination |
| GO:0006513 protein monoubiquitination | IDA PMID:27597759 PEX2 is the E3 ubiquitin ligase required for pexophagy durin... | ACCEPT | Summary: PMID:27597759 directly demonstrates that PEX2 ubiquitinates PEX5 and PMP70 during amino acid starvation. The paper shows PEX2 overexpression leads to gross ubiquitination of peroxisomal proteins, and PEX2 knockdown abolishes PEX5 and PMP70 ubiquitination during starvation. Reason: Core function. Direct experimental evidence showing PEX2 mediates ubiquitination of PEX5 and PMP70. Note that in the context of pexophagy this may include both mono- and polyubiquitination. The monoubiquitination of PEX5 at Cys-11 for receptor recycling is a distinct function also attributed to the PEX2/10/12 complex. Supporting Evidence: PMID:27597759 We identify PEX5 and PMP70 as substrates of PEX2 that are ubiquitinated during amino acid starvation. PMID:27597759 Here, we found that only the loss of PEX2 expression resulted in the loss of PEX5 and PMP70 ubiquitination, whereas both peroxisomal membrane proteins were found to be ubiquitinated in cells depleted of either PEX10 or PEX12 |
| GO:0008320 protein transmembrane transporter activity | ISS PMID:35768507 A peroxisomal ubiquitin ligase complex forms a retrotransloc... | ACCEPT | Summary: PMID:35768507 demonstrates that the PEX2/PEX10/PEX12 complex forms a retrotranslocation channel through which PEX5 is transported across the peroxisomal membrane. The cryo-EM structure reveals an open channel pore formed by the transmembrane segments of all three subunits. Reason: Supported by structural evidence. The PEX2/10/12 complex functions as a retrotranslocation channel for PEX5 export from the peroxisomal membrane to the cytosol. This transmembrane protein transporter activity is a core function of the complex. Supporting Evidence: PMID:35768507 Each subunit of the complex contributes five transmembrane segments that co-assemble into an open channel. |
| 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 shows that peroxisomal ROS activates ATM signaling to induce pexophagy. However, the paper focuses on ATM and PEX5 phosphorylation, not directly on PEX2's response to ROS. PEX2 as a ROS sensor is more directly supported by PMID:34903883, which shows ROS regulates PEX2 protein levels via disulfide bond-mediated stabilization. Reason: PEX2 does respond to ROS through disulfide bond stabilization (PMID:34903883), and participates in ROS-induced pexophagy pathways. However, PMID:26344566 primarily describes ATM-mediated signaling rather than PEX2 directly. The ROS response is secondary to PEX2's core E3 ligase function. Supporting Evidence: PMID:34903883 PEX2 acts as a ROS sensor in peroxisomes PMID:34903883 Peroxisomal beta-oxidation-derived ROS regulate PEX2 protein levels |
| GO:0006513 protein monoubiquitination | ISS PMID:35768507 A peroxisomal ubiquitin ligase complex forms a retrotransloc... | ACCEPT | Summary: PMID:35768507 provides structural evidence that the PEX2/PEX10/PEX12 complex catalyzes monoubiquitination of PEX5 at Cys-11 during its passage through the retrotranslocation channel. Reason: Core function. Structural evidence supports monoubiquitination as a key activity of the PEX2-containing complex during receptor recycling. 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:0044721 protein import into peroxisome matrix, substrate release | ISS PMID:35768507 A peroxisomal ubiquitin ligase complex forms a retrotransloc... | ACCEPT | Summary: PMID:35768507 shows the PEX2/PEX10/PEX12 complex functions as a retrotranslocation channel. Substrate release (cargo delivery to the matrix followed by receptor export) is linked to the channel function. Reason: Supported by structural evidence. The retrotranslocation channel formed by PEX2/10/12 is directly involved in the substrate release phase of peroxisomal matrix protein import. Supporting Evidence: PMID:35768507 biochemical and in vivo experiments reveals its function as a retrotranslocation channel for peroxisomal import receptors. |
| GO:0061630 ubiquitin protein ligase activity | ISS PMID:35768507 A peroxisomal ubiquitin ligase complex forms a retrotransloc... | ACCEPT | Summary: PMID:35768507 provides structural evidence for the RING domain-mediated E3 ubiquitin ligase activity of the PEX2/PEX10/PEX12 complex, with RING fingers positioned above the channel pore for receptor ubiquitination. Reason: Core molecular function. Structural evidence confirms the E3 ubiquitin ligase activity of PEX2 within the retrotranslocation channel complex. Supporting Evidence: PMID:35768507 Recycling requires receptor modification by a membrane-embedded ubiquitin ligase complex comprising three RING finger domain-containing proteins (Pex2, Pex10 and Pex12) |
| GO:0000425 pexophagy | IDA PMID:27597759 PEX2 is the E3 ubiquitin ligase required for pexophagy durin... | ACCEPT | Summary: PMID:27597759 directly demonstrates that PEX2 is the E3 ubiquitin ligase required for pexophagy during amino acid starvation. PEX2 overexpression induces peroxisome degradation via autophagy, and PEX2 knockdown blocks starvation-induced pexophagy. PEX2-mediated pexophagy requires NBR1 as the autophagy receptor. Reason: Core function supported by direct experimental evidence. PEX2 specifically (not PEX10 or PEX12) mediates pexophagy through ubiquitination of peroxisomal membrane proteins during starvation. Supporting Evidence: PMID:27597759 the peroxisomal E3 ubiquitin ligase peroxin 2 (PEX2) is the causative agent for mammalian pexophagy. Expression of PEX2 leads to gross ubiquitination of peroxisomes and degradation of peroxisomes in an NBR1-dependent autophagic process. PMID:27597759 PEX2, but not PEX10 or PEX12, acts as the E3 ubiquitin ligase to selectively ubiquitinate peroxisomal membrane proteins to designate peroxisomes for autophagy-mediated degradation during amino acid starvation conditions. |
| GO:0016562 protein import into peroxisome matrix, receptor recycling | IDA PMID:24662292 Distinct modes of ubiquitination of peroxisome-targeting sig... | ACCEPT | Summary: PMID:24662292 demonstrates that RING peroxins PEX10 and PEX12 function as E3 ubiquitin ligases for PEX5 monoubiquitination, and that PEX2 plays a role in PEX5 shuttling. The study shows the PEX2-PEX10-PEX12 complex catalyzes monoubiquitination of PEX5, enabling receptor recycling. Reason: Core function. PEX2 is part of the retrotranslocation channel complex that ubiquitinates PEX5 for receptor recycling, a critical step in the peroxisomal matrix protein import cycle. Supporting Evidence: PMID:24662292 The Pex10pΒ·Pex12p complex catalyzes monoubiquitination of Pex5p at one of multiple lysine residues in vitro |
| GO:0061630 ubiquitin protein ligase activity | IDA PMID:27597759 PEX2 is the E3 ubiquitin ligase required for pexophagy durin... | ACCEPT | Summary: PMID:27597759 directly demonstrates PEX2's E3 ubiquitin ligase activity. PEX2 ubiquitinates PEX5 and PMP70, and RING domain deletion mutants lose this activity. PEX2 knockdown specifically abolishes ubiquitination of these substrates during starvation. Reason: Core molecular function with direct experimental evidence. RING domain is required for PEX2-mediated peroxisome loss (deletion mutants Ξ243-306, Ξ243-283, Ξ270-283 all lose activity). Supporting Evidence: PMID:27597759 When expressed in cells, we found that none of the PEX2-GFP deletion mutants caused a significant loss of peroxisomes, suggesting that the E3 ligase activity is required for PEX2-mediated peroxisome loss PMID:27597759 Here, we found that only the loss of PEX2 expression resulted in the loss of PEX5 and PMP70 ubiquitination, whereas both peroxisomal membrane proteins were found to be ubiquitinated in cells depleted of either PEX10 or PEX12 |
| GO:0061630 ubiquitin protein ligase activity | IDA PMID:34903883 Peroxisomal Ξ²-oxidation acts as a sensor for intracellular f... | ACCEPT | Summary: PMID:34903883 demonstrates that PEX2 specifically polyubiquitinates ATGL/PNPLA2 at K92 via K48-linkage for proteasomal degradation, regulating lipolysis. PEX2 acts as a ROS sensor whose protein levels are regulated by disulfide bond-mediated stabilization. Reason: Direct experimental evidence for PEX2 E3 ubiquitin ligase activity on a novel substrate (ATGL), extending its known substrates beyond PEX5 and PMP70. Supporting Evidence: PMID:34903883 PEX2 specifically poly-ubiquitinates lipolytic protein ATGL at the K92 site when ATGL distributes on the LD surface for proteasome-targeted degradation in different cell types. PMID:34903883 PEX2 modulates ATGL protein levels via K48-linkage poly-ubiquitination. |
| GO:1990928 response to amino acid starvation | IDA PMID:27597759 PEX2 is the E3 ubiquitin ligase required for pexophagy durin... | ACCEPT | Summary: PMID:27597759 demonstrates that PEX2 protein levels are up-regulated during amino acid starvation, and PEX2 mediates pexophagy in response to starvation. PEX2 expression is regulated by the mTORC1 pathway. Reason: Directly supported by experimental evidence. PEX2 protein levels increase during amino acid starvation, and PEX2 mediates the pexophagy response to starvation. Validated in vivo in protein-restricted mice. Supporting Evidence: PMID:27597759 PEX2 expression is up-regulated during both amino acid starvation and rapamycin treatment, suggesting that the mTORC1 pathway regulates pexophagy by regulating PEX2 expression levels. PMID:27597759 PEX2 protein levels are significantly increased in just 1 h after starvation. |
| GO:0005829 cytosol | TAS Reactome:R-HSA-9603775 | KEEP AS NON CORE | Summary: Reactome R-HSA-9603775 models PEX3:PEX19:class I PMP dissociation. PEX2 is a class I peroxisomal membrane protein that transits through the cytosol bound to PEX19 before membrane insertion. This represents a transient cytosolic intermediate. Reason: PEX2 passes through the cytosol as a PEX19 cargo during its biogenesis/membrane insertion. This is not its primary functional localization (peroxisomal membrane) but is a transient state during membrane protein targeting. |
| GO:0005829 cytosol | TAS Reactome:R-HSA-9603784 | KEEP AS NON CORE | Summary: Reactome R-HSA-9603784 models PEX19:class I PMP binding to PEX3. Same cytosolic transit as above. Reason: Duplicate cytosol annotation from another Reactome reaction in the same pathway. PEX2 transiently passes through the cytosol during membrane protein targeting. |
| GO:0005829 cytosol | TAS Reactome:R-HSA-9603804 | KEEP AS NON CORE | Summary: Reactome R-HSA-9603804 models PEX19 binding to class I PMPs. Same cytosolic transit as above. Reason: Duplicate cytosol annotation from another Reactome reaction in the same pathway. PEX2 transiently passes through the cytosol during membrane protein targeting. |
| GO:0005778 peroxisomal membrane | TAS Reactome:R-HSA-8953917 | ACCEPT | Summary: Reactome R-HSA-8953917 models PEX2:PEX10:PEX12 binding PEX5 and Ub:UBE2D for ubiquitination. PEX2 functions at the peroxisomal membrane. Reason: Correct localization. PEX2 functions at the peroxisomal membrane as part of the E3 ligase complex. Duplicate of other peroxisomal membrane annotations. |
| GO:0005778 peroxisomal membrane | TAS Reactome:R-HSA-8953946 | ACCEPT | Summary: Reactome R-HSA-8953946 models PEX2:PEX10:PEX12 monoubiquitinating PEX5 at cysteine-11. PEX2 at peroxisomal membrane. Reason: Correct. Duplicate peroxisomal membrane annotation from Reactome reaction modeling PEX5 monoubiquitination. |
| GO:0005778 peroxisomal membrane | TAS Reactome:R-HSA-9033235 | ACCEPT | Summary: Reactome R-HSA-9033235 models cargo translocation from cytosol to peroxisomal matrix. PEX2 at peroxisomal membrane. Reason: Correct. Duplicate peroxisomal membrane annotation from Reactome. |
| GO:0005778 peroxisomal membrane | TAS Reactome:R-HSA-9033236 | ACCEPT | Summary: Reactome R-HSA-9033236 models PEX5:cargo binding to the docking/translocation module. PEX2 at peroxisomal membrane. Reason: Correct. Duplicate peroxisomal membrane annotation from Reactome. |
| GO:0005778 peroxisomal membrane | TAS Reactome:R-HSA-9033485 | ACCEPT | Summary: Reactome R-HSA-9033485 models PEX2:PEX10:PEX12 monoubiquitinating PEX5L at cysteine-11. PEX2 at peroxisomal membrane. Reason: Correct. Duplicate peroxisomal membrane annotation from Reactome. |
| GO:0005778 peroxisomal membrane | TAS Reactome:R-HSA-9033499 | ACCEPT | Summary: Reactome R-HSA-9033499 models PEX1:PEX6 dissociating Ub:PEX5 from PEX14:PEX13: PEX2:PEX10:PEX12. PEX2 at peroxisomal membrane. Reason: Correct. Duplicate peroxisomal membrane annotation from Reactome. |
| GO:0005778 peroxisomal membrane | TAS Reactome:R-HSA-9033514 | ACCEPT | Summary: Reactome R-HSA-9033514 models cargo translocation for PEX5L:PEX7 pathway. PEX2 at peroxisomal membrane. Reason: Correct. Duplicate peroxisomal membrane annotation from Reactome. |
| GO:0005778 peroxisomal membrane | TAS Reactome:R-HSA-9033516 | ACCEPT | Summary: Reactome R-HSA-9033516 models PEX2:PEX10:PEX12:Ub:PEX5L:PEX7:PEX13:PEX14 binding PEX1:PEX6:PEX26 and ZFAND6. PEX2 at peroxisomal membrane. Reason: Correct. Duplicate peroxisomal membrane annotation from Reactome. |
| GO:0005778 peroxisomal membrane | TAS Reactome:R-HSA-9033527 | ACCEPT | Summary: Reactome R-HSA-9033527 models PEX2:PEX10:PEX12 binding PEX5L and Ub:UBE2D. PEX2 at peroxisomal membrane. Reason: Correct. Duplicate peroxisomal membrane annotation from Reactome. |
| GO:0005778 peroxisomal membrane | TAS Reactome:R-HSA-9033533 | ACCEPT | Summary: Reactome R-HSA-9033533 models Ub:PEX5:PEX13:PEX14:PEX2:PEX10:PEX12 binding PEX1:PEX6:PEX26 and ZFAND6. PEX2 at peroxisomal membrane. Reason: Correct. Duplicate peroxisomal membrane annotation from Reactome. |
| GO:0005778 peroxisomal membrane | TAS Reactome:R-HSA-9603775 | ACCEPT | Summary: Reactome R-HSA-9603775 models PEX3:PEX19:class I PMP dissociation. PEX2 at peroxisomal membrane after insertion. Reason: Correct. PEX2 localizes to the peroxisomal membrane after PEX19-mediated targeting. |
| GO:0016020 membrane | HDA PMID:19946888 Defining the membrane proteome of NK cells. | ACCEPT | Summary: PMID:19946888 is a large-scale proteomics study of NK cell membranes. PEX2 was identified in the membrane fraction. This is consistent with PEX2 being an integral membrane protein, but the term is very broad. Reason: Correct but very broad. PEX2 is an integral membrane protein. The more specific peroxisomal membrane annotation is more informative. |
| GO:0000038 very long-chain fatty acid metabolic process | IMP PMID:9765053 Restoration of PEX2 peroxisome assembly defects by overexpre... | KEEP AS NON CORE | Summary: PMID:9765053 shows that PEX2 mutations disrupt peroxisome assembly, leading to impaired VLCFA beta-oxidation. Restoration of PEX2 restores VLCFA metabolism. However, PEX2 does not directly catalyze VLCFA metabolism. Reason: Indirect effect. PEX2 mutations impair peroxisome assembly, which secondarily affects VLCFA metabolism because VLCFA beta-oxidation enzymes cannot be imported. Supporting Evidence: PMID:9765053 expression of human PEX2 restores peroxisomal biogenesis in all of these clones... the beta-oxidation of very long chain fatty acids (VLCFA). |
| GO:0006635 fatty acid beta-oxidation | IMP PMID:9765053 Restoration of PEX2 peroxisome assembly defects by overexpre... | KEEP AS NON CORE | Summary: PMID:9765053 shows that PEX2 mutations lead to impaired fatty acid beta-oxidation, which is restored by PEX2 expression. Indirect effect via peroxisome assembly. Reason: Indirect effect. PEX2 does not catalyze beta-oxidation but is required for peroxisome assembly, which is prerequisite for beta-oxidation enzyme import. Supporting Evidence: PMID:9765053 the beta-oxidation of very long chain fatty acids (VLCFA). |
| GO:0007031 peroxisome organization | IMP PMID:9765053 Restoration of PEX2 peroxisome assembly defects by overexpre... | ACCEPT | Summary: PMID:9765053 shows PEX2 mutations cause defective peroxisome assembly and that restoration of PEX2 restores peroxisome biogenesis. Reason: Core function. Direct experimental evidence for PEX2's role in peroxisome organization/biogenesis. Supporting Evidence: PMID:9765053 The mutant Chinese hamster ovary (CHO) cell line Z78/C has defective peroxisome assembly due to a missense mutation in PEX2, the gene which encodes the 35 kDa peroxisomal integral membrane protein PMID:9765053 expression of human PEX2 restores peroxisomal biogenesis in all of these clones. |
| GO:0005778 peroxisomal membrane | HDA PMID:21525035 PEX14 is required for microtubule-based peroxisome motility ... | ACCEPT | Summary: PMID:21525035 is about PEX14 and peroxisome motility. PEX2 was presumably identified in isolated peroxisomal membrane fractions by mass spectrometry. Reason: Correct localization. PEX2 is an integral peroxisomal membrane protein detected in purified peroxisomal membrane preparations. |
| GO:0006635 fatty acid beta-oxidation | IMP PMID:10528859 Defective PEX gene products correlate with the protein impor... | KEEP AS NON CORE | Summary: PMID:10528859 characterizes a PEX2 E55K mutation in a patient with infantile Refsum disease. The mutation leads to mosaic activities of peroxisomal protein import and residual beta-oxidation function. Reason: Indirect effect. PEX2 mutation impairs peroxisome biogenesis, secondarily affecting beta-oxidation. PEX2 does not directly catalyze fatty acid beta-oxidation. Supporting Evidence: PMID:10528859 we noted the E55K mutation had mosaic activities of peroxisomal protein import machinery and residual activities of peroxisomal functions, including dihydroxyacetone phosphate acyltransferase and beta oxidation of very long chain fatty acids |
| GO:0016558 protein import into peroxisome matrix | IMP PMID:10528859 Defective PEX gene products correlate with the protein impor... | ACCEPT | Summary: PMID:10528859 shows that PEX2 mutations affect peroxisomal protein import machinery, with the E55K mutation showing mosaic import activities. Reason: Core function. Direct evidence that PEX2 is required for peroxisomal matrix protein import. Supporting Evidence: PMID:10528859 we noted the E55K mutation had mosaic activities of peroxisomal protein import machinery and residual activities of peroxisomal functions, including dihydroxyacetone phosphate acyltransferase and beta oxidation of very long chain fatty acids |
| GO:0005515 protein binding | IPI PMID:11590176 Two different targeting signals direct human peroxisomal mem... | MARK AS OVER ANNOTATED | Summary: PMID:11590176 is about PMP22 (peroxisomal membrane protein 22) targeting signals and their interaction with PEX19. PEX2 is not the focus of this study. The annotation may be based on co-detection or indirect interaction data. Reason: GO:0005515 (protein binding) is uninformative. PMID:11590176 focuses on PMP22 targeting signals interacting with PEX19, not PEX2 directly. The annotation may reflect indirect or tangential evidence. |
| GO:0016593 Cdc73/Paf1 complex | IDA PMID:18987311 The parafibromin tumor suppressor protein inhibits cell prol... | REMOVE | Summary: PMID:18987311 is about the parafibromin tumor suppressor protein and the PAF1 transcriptional regulatory complex. This paper studies the PAF1 gene (RNA polymerase II-associated factor 1), NOT PEX2. PEX2's old synonym PAF1 (Peroxisome Assembly Factor 1) was confused with the unrelated PAF1 transcription factor. PEX2 has no known role in the Cdc73/Paf1 complex. Reason: INCORRECT annotation due to gene name confusion. PMID:18987311 studies the PAF1 transcription factor (RNA polymerase II-associated factor 1 homolog), not PEX2 (Peroxisome Assembly Factor 1). PEX2 is a peroxisomal membrane E3 ubiquitin ligase with no connection to the Cdc73/Paf1 transcriptional complex. Supporting Evidence: PMID:18987311 Human parafibromin binds to RNA polymerase II as part of a PAF1 transcriptional regulatory complex. |
| GO:0031648 protein destabilization | IMP PMID:18987311 The parafibromin tumor suppressor protein inhibits cell prol... | REMOVE | Summary: PMID:18987311 discusses c-myc protein stabilization in the context of parafibromin and the PAF1 transcriptional complex. This annotation is based on the WRONG gene (PAF1 transcription factor, not PEX2). Reason: INCORRECT annotation due to gene name confusion. PMID:18987311 studies the PAF1 transcription factor and parafibromin effects on c-myc protein stability. PEX2 (Peroxisome Assembly Factor 1) is an unrelated gene. While PEX2 does mediate protein destabilization through ATGL ubiquitination (PMID:34903883), that is not what this annotation references. Supporting Evidence: PMID:18987311 This effect results from both c-myc protein stabilization and activation of the c-myc promoter, without alleviation of the c-myc transcriptional pause |
| GO:0048147 negative regulation of fibroblast proliferation | IMP PMID:18987311 The parafibromin tumor suppressor protein inhibits cell prol... | REMOVE | Summary: PMID:18987311 discusses parafibromin and PAF1 complex effects on cell proliferation via c-myc repression. This has nothing to do with PEX2 (a peroxisomal E3 ligase). Reason: INCORRECT annotation due to gene name confusion. PMID:18987311 studies the PAF1 transcription factor and parafibromin, not PEX2. There is no evidence that PEX2 regulates fibroblast proliferation. Supporting Evidence: PMID:18987311 We show here that RNA interference with the expression of parafibromin or Paf1 stimulates cell proliferation and increases levels of the c-myc proto-oncogene product, a DNA-binding protein and established regulator of cell growth |
| GO:0050680 negative regulation of epithelial cell proliferation | IMP PMID:18987311 The parafibromin tumor suppressor protein inhibits cell prol... | REMOVE | Summary: Same gene name confusion as above. PMID:18987311 is about PAF1 transcription factor and parafibromin, not PEX2. Reason: INCORRECT annotation due to gene name confusion. PMID:18987311 studies the PAF1 transcription factor and parafibromin effects on cell proliferation. PEX2 is an unrelated peroxisomal E3 ubiquitin ligase with no known role in epithelial cell proliferation regulation. |
| GO:0007031 peroxisome organization | IMP PMID:1546315 A human gene responsible for Zellweger syndrome that affects... | ACCEPT | Summary: PMID:1546315 is the original cloning paper for PEX2 (then PAF-1), demonstrating that the gene complements Zellweger syndrome fibroblasts with defective peroxisome assembly. Reason: Foundational evidence for PEX2's role in peroxisome organization. This is the original discovery paper showing PEX2 is required for peroxisome assembly. Supporting Evidence: PMID:1546315 A human complementary DNA has been cloned that complements the disease's symptoms (including defective peroxisome assembly) in fibroblasts from a patient with Zellweger syndrome. |
| GO:0005778 peroxisomal membrane | IMP PMID:12751901 The peroxisomal membrane targeting elements of human peroxin... | ACCEPT | Summary: PMID:12751901 directly characterizes the peroxisomal membrane targeting elements of PEX2 using GFP fusion constructs in COS-7 cells, demonstrating that PEX2 is targeted to the peroxisomal membrane via specific internal targeting signals. Reason: Direct experimental evidence for PEX2's peroxisomal membrane localization. Supporting Evidence: PMID:12751901 We found that the minimum peroxisomal targeting signal of human PEX2 consists of an internal protein region of 30 amino acids (AA130 to AA159) and the first transmembrane domain, and that adding the second transmembrane domain increases targeting efficiency |
| GO:0005515 protein binding | IPI PMID:10837480 Molecular anatomy of the peroxin Pex12p: ring finger domain ... | MARK AS OVER ANNOTATED | Summary: PMID:10837480 studies PEX12 but shows that PEX12 RING finger interacts with PEX2 and PEX5 in vitro. Pex10p interacted with Pex2p. These are functionally meaningful interactions within the PEX2/10/12 complex. Reason: GO:0005515 (protein binding) is uninformative. The interactions of PEX2 with PEX10, PEX12, and PEX5 are real and functionally significant (they form the E3 ligase retrotranslocation complex), but a more specific term should be used. Supporting Evidence: PMID:10837480 Peroxins interacting with RING finger of Pex2p, Pex10p, and Pex12p... Pex10p and Pex12p are in the oligomeric complex in peroxisome membranes. |
| GO:0000151 ubiquitin ligase complex | IDA PMID:35768507 A peroxisomal ubiquitin ligase complex forms a retrotransloc... | NEW | Summary: PEX2 is a constitutive subunit of the PEX2-PEX10-PEX12 heterotrimeric RING E3 ubiquitin ligase complex embedded in the peroxisomal membrane. The cryo-EM structure (PMID:35768507) shows the three RING peroxins assembling into a single complex that functions both as a ubiquitin ligase and as a retrotranslocation channel for PEX5. Complex membership is also supported by binding/co-IP studies (PMID:10837480) and by the deep research synthesis of recent reviews. GOA currently lacks any complex-membership CC annotation for PEX2 despite this being central to its function. Reason: Proposed new annotation to capture PEX2's well-established membership in the peroxisomal PEX2-PEX10-PEX12 ubiquitin ligase complex, which is structurally demonstrated (PMID:35768507) and underpins its core function in PEX5 monoubiquitination and receptor recycling. This complements the peroxisomal membrane localization annotations and mirrors the complex membership recorded in Reactome (R-HSA-8953917 etc.). Supporting Evidence: PMID:35768507 Recycling requires receptor modification by a membrane-embedded ubiquitin ligase complex comprising three RING finger domain-containing proteins (Pex2, Pex10 and Pex12) file:human/PEX2/PEX2-deep-research-falcon.md PEX2 is one of three **RING-finger peroxins** (PEX2/PEX10/PEX12) that form a **membrane-embedded E3 ubiquitin ligase** complex required for ubiquitination of the import receptors |
| GO:0010897 negative regulation of triglyceride catabolic process | IDA PMID:34903883 Peroxisomal Ξ²-oxidation acts as a sensor for intracellular f... | NEW | Summary: PMID:34903883 demonstrates that PEX2 negatively regulates lipolysis by polyubiquitinating the lipase ATGL/PNPLA2 at Lys92 with K48-linked chains, targeting it for proteasomal degradation. PEX2 protein levels are stabilized by peroxisomal beta-oxidation-derived ROS, coupling peroxisomal fatty acid catabolism to suppression of lipid droplet lipolysis. GOA currently captures the ligase activity (GO:0061630, IDA from this paper) but not the regulatory process it serves. Reason: Proposed new annotation to capture the biological process output of PEX2's experimentally demonstrated ubiquitination of ATGL: downregulation of lipid-droplet triglyceride lipolysis, for which ATGL is the rate-limiting lipase. Direct IDA-level evidence: ATGL ubiquitination and degradation depend on PEX2, and PEX2 manipulation changes ATGL levels and lipolytic flux in multiple cell types and in vivo. Supporting Evidence: PMID:34903883 PEX2 specifically poly-ubiquitinates lipolytic protein ATGL at the K92 site when ATGL distributes on the LD surface for proteasome-targeted degradation in different cell types. PMID:34903883 PEX2 modulates ATGL protein levels via K48-linkage poly-ubiquitination. |
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