PEX11G (peroxisomal membrane protein 11C, also known as PEX11-gamma) is the third and least characterized member of the human PEX11 family of peroxisomal membrane proteins (PMID:12559946). It is a multi-pass integral membrane protein of the peroxisome that promotes membrane protrusion and elongation on the peroxisomal surface, contributing to peroxisome proliferation and maintenance (PMID:20826455). PEX11G forms homodimers and heterodimers with PEX11A and PEX11B, and interacts with the fission adaptors FIS1 and MFF, linking membrane elongation to the fission machinery (PMID:20826455, PMID:22595523). The protein contains a functional amphipathic helix that promotes membrane bending/elongation (PMID:22595523). Unlike the inducible PEX11A, PEX11G is constitutively expressed and shows tissue-enhanced expression in liver and testis (PMID:12559946). Overexpression of PEX11G can partially rescue peroxisome morphology defects in PEX11B-deficient patient fibroblasts under stress conditions, suggesting functional compensation potential among isoforms (DOI:10.3390/cells11121922).
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0005778 peroxisomal membrane | IBA GO_REF:0000033 | ACCEPT | Summary: PEX11G is well-established as a peroxisomal membrane protein. IBA annotation via phylogenetic inference is consistent with experimental data from multiple studies showing localization to the peroxisomal membrane (PMID:12559946, PMID:20826455, PMID:12417726). UniProt records this as a multi-pass membrane protein of the peroxisome membrane with evidence from three independent publications. Koch and Brocard (PMID:22595523) further confirmed PEX11G as a true integral peroxisomal membrane protein not extractable by sodium carbonate. Reason: Peroxisomal membrane localization is a core property of PEX11G, confirmed by immunofluorescence colocalization with PTS1-tagged peroxisomal markers (PMID:12559946), carbonate extraction experiments (PMID:22595523), and additional studies (PMID:20826455, PMID:12417726). The IBA annotation is phylogenetically sound and experimentally validated. Supporting Evidence: PMID:12559946 Pex11pgamma was found to be a peroxisomal membrane protein, as assessed by colocalization with peroxisome targeting signal type 1 (PTS1)-proteins, in epitope-tagged Pex11pgamma-expressing Chinese hamster ovary cells. PMID:20826455 Dynamic changes of membrane structure are intrinsic to organelle morphogenesis and homeostasis. Ectopic expression of proteins of the PEX11 family from yeast, plant or human lead to the formation of juxtaposed elongated peroxisomes (JEPs) file:human/PEX11G/PEX11G-deep-research-falcon.md PEX11G is clearly a peroxisomal integral membrane protein with membrane-shaping motifs, and it can drive elongation when overexpressed |
| GO:0016559 peroxisome fission | IBA GO_REF:0000033 | ACCEPT | Summary: IBA annotation for peroxisome fission. PEX11 family members are established as membrane elongation factors that coordinate peroxisome proliferation (PMID:20826455). The Koch et al. 2010 paper demonstrates that PEX11 proteins induce formation of juxtaposed elongated peroxisomes (JEPs) as intermediates in the peroxisome fission process, and that FIS1 is the limiting factor for progression to fission. PEX11G is more precisely a membrane elongation factor that acts upstream of the actual fission event, but peroxisome fission is a reasonable annotation for the overall process it participates in. Reason: While PEX11G is more directly involved in the membrane elongation step rather than the fission step per se, the overall biological process of peroxisome fission encompasses the elongation-to-division pathway. The IBA annotation appropriately captures PEX11G involvement in this process. Supporting Evidence: PMID:20826455 Our results demonstrate that PEX11-induced JEPs represent intermediates in the process of peroxisome membrane proliferation and that hFis1 is the limiting factor for progression. |
| GO:0005778 peroxisomal membrane | IEA GO_REF:0000120 | ACCEPT | Summary: IEA annotation for peroxisomal membrane localization via combined automated methods. This is consistent with the experimentally validated IDA and IBA annotations for the same term. Redundant but not incorrect. Reason: Automated annotation is consistent with all experimental evidence. Peroxisomal membrane localization is the core cellular component for PEX11G. |
| GO:0016559 peroxisome fission | IEA GO_REF:0000002 | ACCEPT | Summary: IEA annotation for peroxisome fission via InterPro-to-GO mapping. The PEX11 InterPro domain (IPR008733) maps to this process. This is consistent with the IBA and IDA annotations for the same term and supported by the Koch et al. 2010 experimental data. Reason: The InterPro-based annotation is correct. PEX11G belongs to the PEX11 family (IPR008733, Pfam PF05648) which is functionally characterized as involved in peroxisome fission/proliferation. |
| GO:0005515 protein binding | IPI PMID:32296183 A reference map of the human binary protein interactome. | REMOVE | Summary: Protein binding annotation from the HuRI high-throughput yeast two-hybrid interactome study (Luck et al. 2020, PMID:32296183). The UniProt record lists interactions with AQP6, ERGIC3, KCNJ6, TMEM14B, and TMEM86B from IntAct with 3 experiments each. These are all membrane proteins but none have obvious biological connection to peroxisome biology. These interactions from a high-throughput screen likely represent non-physiological membrane protein interactions in the Y2H system. Reason: Generic protein binding is uninformative. The interactions reported from the HuRI high-throughput Y2H screen (PMID:32296183) are with proteins that have no known connection to peroxisome biology (AQP6 is an aquaporin, ERGIC3 is an ER-Golgi protein, KCNJ6 is a potassium channel). These are likely artifacts of the high-throughput assay. The biologically relevant interactions of PEX11G (with PEX11A, PEX11B, and FIS1) are documented in PMID:20826455 but are not captured by this annotation. Supporting Evidence: PMID:32296183 HI-III-20 (Human Interactome obtained from screening Space III, published in 2020), contains 52,569 verified PPIs involving 8,275 proteins |
| GO:0005778 peroxisomal membrane | IDA PMID:12559946 cDNA cloning and characterization of the third isoform of hu... | ACCEPT | Summary: Direct experimental evidence for peroxisomal membrane localization from the original PEX11G cloning and characterization paper (Tanaka et al. 2003). The authors showed colocalization of epitope-tagged PEX11G with PTS1-proteins in CHO cells and demonstrated a two-transmembrane-segment topology with both N- and C-termini facing the cytosol. Reason: This is the primary experimental evidence for PEX11G peroxisomal membrane localization. Direct immunofluorescence and topology studies provide strong evidence for this core annotation. Supporting Evidence: PMID:12559946 Pex11pgamma was found to be a peroxisomal membrane protein, as assessed by colocalization with peroxisome targeting signal type 1 (PTS1)-proteins, in epitope-tagged Pex11pgamma-expressing Chinese hamster ovary cells. Pex11pgamma exposes both of the N- and C-terminal parts to the cytosol. |
| GO:0005515 protein binding | IPI PMID:20826455 PEX11 family members are membrane elongation factors that co... | MODIFY | Summary: Protein binding annotation from Koch et al. 2010 which demonstrated homo- and heterodimerization of PEX11 family members and interaction with the fission factor FIS1. While the interactions are biologically meaningful, the generic term 'protein binding' fails to capture the specific nature of these interactions. PEX11G forms homodimers and heterodimers with PEX11A and PEX11B, and interacts with FIS1 to coordinate peroxisome elongation and fission. Reason: The term 'protein binding' (GO:0005515) is too generic and uninformative. The biologically relevant interactions are specific: homodimerization, heterodimerization with PEX11A/PEX11B, and interaction with FIS1. These should be captured with more specific molecular function terms. Proposed replacements: protein homodimerization activity protein heterodimerization activity Supporting Evidence: PMID:20826455 We established the homo- and heterodimerization properties of the human PEX11 proteins and their interaction with the fission factor hFis1 |
| GO:0005777 peroxisome | IDA PMID:20826455 PEX11 family members are membrane elongation factors that co... | ACCEPT | Summary: Annotation to the broader term 'peroxisome' (GO:0005777) based on Koch et al. 2010. PEX11G is more specifically localized to the peroxisomal membrane (GO:0005778), which is a child term of peroxisome. Since the more specific term is already annotated with both IDA and IBA evidence, this broader annotation is redundant but not incorrect. Reason: While redundant with the more specific GO:0005778 (peroxisomal membrane) annotations, this is not incorrect. The peroxisome annotation encompasses the membrane localization. Some annotation pipelines retain both levels. Supporting Evidence: PMID:20826455 Ectopic expression of proteins of the PEX11 family from yeast, plant or human lead to the formation of juxtaposed elongated peroxisomes (JEPs) |
| GO:0016559 peroxisome fission | IDA PMID:20826455 PEX11 family members are membrane elongation factors that co... | ACCEPT | Summary: Direct experimental evidence for involvement in peroxisome fission from Koch et al. 2010. The study demonstrated that ectopic expression of PEX11 family members (including PEX11G) leads to formation of juxtaposed elongated peroxisomes (JEPs), which are intermediates in the peroxisome fission process. Excess FIS1 fragments these JEPs into normal round peroxisomes, demonstrating that PEX11-induced elongation is an intermediate step in fission. This is a core function of PEX11G. Reason: Koch et al. 2010 provides direct experimental evidence that PEX11G promotes the membrane elongation step of peroxisome fission. While PEX11G acts specifically at the elongation stage rather than the scission step, the overall process annotation to peroxisome fission is appropriate as the elongation is an integral part of the fission pathway. Supporting Evidence: PMID:20826455 Our results demonstrate that PEX11-induced JEPs represent intermediates in the process of peroxisome membrane proliferation and that hFis1 is the limiting factor for progression. Hence, we propose a model for a conserved role of PEX11 proteins in peroxisome maintenance through peroxisome polarization, membrane elongation and segregation. |
| GO:0032991 protein-containing complex | IDA PMID:20826455 PEX11 family members are membrane elongation factors that co... | MARK AS OVER ANNOTATED | Summary: Annotation to the generic 'protein-containing complex' term based on Koch et al. 2010, which demonstrated that PEX11G forms homodimers and heterodimers with PEX11A and PEX11B. While the formation of these complexes is experimentally supported, the term is extremely generic and uninformative. A more specific complex term would be preferable but none exists in GO for PEX11 complexes. Reason: The term 'protein-containing complex' (GO:0032991) is too broad to be informative. While PEX11G does form homo- and heterodimeric complexes, annotating to this very generic CC term adds little value. The specific interaction partners are better captured through molecular function annotations (e.g., homodimerization activity). Supporting Evidence: PMID:20826455 We established the homo- and heterodimerization properties of the human PEX11 proteins and their interaction with the fission factor hFis1 |
| GO:0044375 regulation of peroxisome size | IDA PMID:20826455 PEX11 family members are membrane elongation factors that co... | ACCEPT | Summary: Annotation for regulation of peroxisome size based on Koch et al. 2010. PEX11G promotes membrane elongation, which changes peroxisome morphology from round to elongated tubular structures (JEPs). This does affect peroxisome size/shape as an intermediate in the proliferation process. The term definition is "any process that modulates the volume of a peroxisome," which is consistent with the membrane elongation activity of PEX11G. Reason: PEX11G-induced membrane elongation directly modulates peroxisome size and shape, converting round peroxisomes into elongated tubular structures. This is a core function of PEX11G and the term accurately captures this activity. Supporting Evidence: PMID:20826455 Ectopic expression of proteins of the PEX11 family from yeast, plant or human lead to the formation of juxtaposed elongated peroxisomes (JEPs),which is evocative of an evolutionary conserved function of these proteins in membrane tubulation. |
| GO:0042803 protein homodimerization activity | IDA PMID:20826455 PEX11 family members are membrane elongation factors that co... | NEW | Summary: New annotation proposed to replace the generic 'protein binding' annotation from PMID:20826455. Koch et al. 2010 established that PEX11G forms homodimers, which is part of its functional mechanism in membrane elongation. Reason: Koch et al. 2010 demonstrated homodimerization of PEX11G as part of its functional characterization. This is a more informative molecular function term than generic protein binding. Supporting Evidence: PMID:20826455 We established the homo- and heterodimerization properties of the human PEX11 proteins and their interaction with the fission factor hFis1 |
| GO:0180020 membrane bending activity | IDA PMID:22595523 PEX11 proteins attract Mff and human Fis1 to coordinate pero... | NEW | Summary: New annotation proposed for the primary PEX11G molecular function. PEX11G uses membrane-anchored domains and an amphipathic region to dock into the peroxisomal membrane and regulate membrane elongation/protrusion, which is better captured as membrane bending activity than by dimerization alone. Reason: The core molecular activity supported by the topology and mutagenesis work is membrane remodeling/bending during peroxisome elongation. Homo- and heterodimerization are mechanistic supporting interactions, but membrane bending is the most specific GO molecular function for the primary activity. Supporting Evidence: PMID:22595523 we establish that the PEX11gamma sequence includes two membrane-anchored domains, which dock an amphipathic region onto the peroxisomal membrane thereby regulating its elongation |
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