ERLIN2 (SPFH2, ER lipid raft-associated protein 2) is a single-pass type II endoplasmic reticulum (ER) membrane protein with a lumenal SPFH/prohibitin (band 7) domain, belonging to the band 7/mec-2 (stomatin-prohibitin-flotillin) family. It associates with lipid-raft-like domains of the ER membrane and functions as a scaffold rather than an enzyme. ERLIN2 forms a large ring-shaped heteromeric complex with its homolog ERLIN1 (SPFH1); the ERLIN1/ERLIN2 complex binds inositol 1,4,5-trisphosphate receptor (IP3R) tetramers and, together with the ER ubiquitin ligase RNF170, mediates the ER-associated degradation (ERAD) of activated IP3Rs, controlling calcium signaling. ERLIN2 also promotes sterol-accelerated ERAD of HMG-CoA reductase through an AMFR/gp78-containing ubiquitin ligase complex (with TMUB1 bridging ERLIN2 to gp78), and it binds cholesterol and restricts SREBP activation by associating with the SCAP-SREBP-Insig machinery, thereby negatively regulating cholesterol and fatty acid biosynthesis. Through these activities it recruits and binds multiple ER ubiquitin ligases (RNF170, AMFR/gp78, SYVN1, RNF139, RNF185/RNF5). Loss-of-function variants in ERLIN2 cause hereditary spastic paraplegia (SPG18A/SPG18B) and a recessive intellectual disability syndrome.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0005789 endoplasmic reticulum membrane | IBA GO_REF:0000033 | ACCEPT | Summary: Phylogenetic inference that ERLIN2 acts at the ER membrane, consistent with strong experimental evidence that it is an ER membrane SPFH protein. Reason: Core compartment and site of action; ERLIN2 is an integral ER membrane protein. Supporting Evidence: file:human/ERLIN2/ERLIN2-uniprot.txt SUBCELLULAR LOCATION: Endoplasmic reticulum membrane |
| GO:0015485 cholesterol binding | IBA GO_REF:0000033 | ACCEPT | Summary: Phylogenetic inference of cholesterol binding for ERLIN2, consistent with the experimental demonstration that erlins are cooperative cholesterol-binding proteins. Reason: Core molecular function of the erlin family; underlies sterol-sensing regulation of SREBP. Supporting Evidence: PMID:24217618 Erlins bound cholesterol with specificity and strong cooperativity |
| GO:0032933 SREBP signaling pathway | IBA GO_REF:0000033 | ACCEPT | Summary: Phylogenetic inference of involvement in SREBP signaling, consistent with experimental evidence that erlins restrict SREBP activation. Reason: Core biological process; redundant with experimental IMP evidence. Supporting Evidence: PMID:24217618 directly involved in regulating the SREBP machinery |
| GO:0005783 endoplasmic reticulum | IEA GO_REF:0000002 | ACCEPT | Summary: InterPro-based electronic ER localization; the more specific ER membrane term is preferred. Reason: Correct compartment; redundant with the ER membrane annotations. Supporting Evidence: file:human/ERLIN2/ERLIN2-uniprot.txt SUBCELLULAR LOCATION: Endoplasmic reticulum membrane |
| GO:0005789 endoplasmic reticulum membrane | IEA GO_REF:0000120 | ACCEPT | Summary: Electronic assignment of ER membrane localization from the UniProt subcellular location. Reason: Core compartment; redundant with experimental IDA evidence. Supporting Evidence: file:human/ERLIN2/ERLIN2-uniprot.txt SUBCELLULAR LOCATION: Endoplasmic reticulum membrane |
| GO:0031625 ubiquitin protein ligase binding | IEA GO_REF:0000002 | ACCEPT | Summary: InterPro-based assignment of ubiquitin protein ligase binding, consistent with ERLIN2 binding the ER ubiquitin ligases RNF170, AMFR/gp78, SYVN1, RNF139 and the RNF185/RNF5 module. Reason: Informative molecular function; ERLIN2 recruits E3 ubiquitin ligases to the ERAD complex. Supporting Evidence: file:human/ERLIN2/ERLIN2-uniprot.txt Interacts with SYVN1 and RNF139 |
| GO:0032933 SREBP signaling pathway | IEA GO_REF:0000117 | ACCEPT | Summary: ARBA machine-learning assignment of SREBP signaling involvement, consistent with experimental evidence. Reason: Correct biological process; redundant with IMP/IBA evidence. Supporting Evidence: PMID:24217618 directly involved in regulating the SREBP machinery |
| GO:0032991 protein-containing complex | IEA GO_REF:0000117 | KEEP AS NON CORE | Summary: Generic protein-containing complex assignment; ERLIN2 forms the specific ERLIN1/ERLIN2 complex. Reason: Correct but uninformative; the specific ERLIN1/ERLIN2 complex membership is captured elsewhere. Supporting Evidence: PMID:19240031 SPFH1 and its homolog SPFH2 form a heteromeric approximately 2 MDa complex |
| GO:0036503 ERAD pathway | IEA GO_REF:0000117 | ACCEPT | Summary: ARBA machine-learning assignment of ERAD involvement, consistent with the experimentally demonstrated role in ERAD of IP3 receptors and HMGCR. Reason: Core biological process; redundant with experimental IDA evidence. Supporting Evidence: PMID:19240031 mediates the ER-associated degradation of inositol 1,4,5-trisphosphate |
| GO:0045541 negative regulation of cholesterol biosynthetic process | IEA GO_REF:0000117 | ACCEPT | Summary: ARBA assignment of negative regulation of cholesterol biosynthesis, consistent with the erlins' restriction of SREBP activation. Reason: Correct biological process; redundant with experimental IMP evidence. Supporting Evidence: PMID:24217618 led to canonical activation of SREBPs and their target genes |
| GO:0045717 negative regulation of fatty acid biosynthetic process | IEA GO_REF:0000117 | ACCEPT | Summary: ARBA assignment of negative regulation of fatty acid biosynthesis, consistent with the erlins restricting SREBP. Reason: Correct biological process; redundant with experimental IMP evidence. Supporting Evidence: PMID:24217618 key transcription factors for cholesterol and fatty acid biosynthetic |
| GO:0005515 protein binding | IPI PMID:21343306 Membrane-associated ubiquitin ligase complex containing gp78... | KEEP AS NON CORE | Summary: IPI interactions with the gp78/AMFR ERAD module (AMFR, SYVN1, TMUB1, ERLIN1, HMGCR). Bare protein binding is uninformative; the E3-ligase binding is captured by the ubiquitin-protein-ligase-binding annotation. Reason: Real ERAD-module interactions but uninformative GO term. Supporting Evidence: file:human/ERLIN2/ERLIN2-uniprot.txt O94905; Q9UKV5: AMFR |
| GO:0005515 protein binding | IPI PMID:22119785 Defining human ERAD networks through an integrative mapping ... | KEEP AS NON CORE | Summary: ERAD-network interactome capture (ERLIN1, SYVN1, AMFR). Bare protein binding is uninformative. Reason: Real ERAD-network interactions but uninformative GO term. Supporting Evidence: file:human/ERLIN2/ERLIN2-uniprot.txt O94905; O75477: ERLIN1 |
| GO:0005515 protein binding | IPI PMID:30021884 Histone Interaction Landscapes Visualized by Crosslinking Ma... | KEEP AS NON CORE | Summary: Crosslinking mass-spectrometry capture of an ERLIN2-ERLIN1 interaction. Bare protein binding is uninformative. Reason: Real ERLIN1 interaction but uninformative GO term. Supporting Evidence: file:human/ERLIN2/ERLIN2-uniprot.txt O94905; O75477: ERLIN1 |
| GO:0005515 protein binding | IPI PMID:33961781 Dual proteome-scale networks reveal cell-specific remodeling... | KEEP AS NON CORE | Summary: Dual proteome-scale network captures of ERLIN2 interactions (ERLIN1, TMUB1). Bare protein binding is uninformative. Reason: Real interactions but uninformative GO term. Supporting Evidence: file:human/ERLIN2/ERLIN2-uniprot.txt O94905; O75477: ERLIN1 |
| GO:0005783 endoplasmic reticulum | IDA GO_REF:0000052 | ACCEPT | Summary: Direct immunofluorescence (HPA) evidence for ER localization. Reason: Core compartment; directly demonstrated. Supporting Evidence: file:human/ERLIN2/ERLIN2-uniprot.txt SUBCELLULAR LOCATION: Endoplasmic reticulum membrane |
| GO:0005789 endoplasmic reticulum membrane | IDA PMID:19240031 An endoplasmic reticulum (ER) membrane complex composed of S... | ACCEPT | Summary: Direct evidence that ERLIN2/SPFH2 is an ER membrane protein, the site of the ERLIN1/ERLIN2 ERAD complex. Reason: Core compartment; directly demonstrated. Supporting Evidence: PMID:19240031 the ER membrane protein SPFH1 and its homolog SPFH2 form a heteromeric |
| GO:0036503 ERAD pathway | IDA PMID:19240031 An endoplasmic reticulum (ER) membrane complex composed of S... | ACCEPT | Summary: The ERLIN1/ERLIN2 complex binds IP3R tetramers and mediates their ER-associated degradation. Reason: Core biological process with direct (IDA) support; the defining function of the ERLIN complex. Supporting Evidence: PMID:19240031 mediates the ER-associated degradation of inositol 1,4,5-trisphosphate |
| GO:0045121 membrane raft | NAS PMID:34572057 Role of ERLINs in the Control of Cell Fate through Lipid Raf... | KEEP AS NON CORE | Summary: Erlins associate with lipid-raft-like domains of the ER membrane; the NAS membrane-raft localization reflects this SPFH-domain raft association. Reason: Supported by the lipid-raft characterization of erlins but secondary to the core ER-membrane ERAD/SREBP roles. Supporting Evidence: PMID:16835267 define lipid-raft-like domains of the ER |
| GO:0045540 regulation of cholesterol biosynthetic process | IDA PMID:24217618 Erlins restrict SREBP activation in the ER and regulate cell... | ACCEPT | Summary: ERLIN2 regulates cholesterol biosynthesis via the SREBP/SCAP/Insig machinery; the erlins restrict SREBP activation in response to ER cholesterol. Reason: Core biological process; directly supported. Supporting Evidence: PMID:24217618 regulate cellular cholesterol |
| GO:0005886 plasma membrane | TAS Reactome:R-HSA-1839094 | MARK AS OVER ANNOTATED | Summary: Reactome FGFR1-signaling pathway annotation placing ERLIN2 at the plasma membrane. ERLIN2 is an integral ER membrane protein; plasma-membrane localization is not supported by the experimental subcellular-location data. Reason: ERLIN2 is an ER membrane SPFH protein; the plasma-membrane localizations are over-annotations from FGFR1-pathway bulk-membrane curation, not its biological site. Supporting Evidence: file:human/ERLIN2/ERLIN2-uniprot.txt SUBCELLULAR LOCATION: Endoplasmic reticulum membrane |
| GO:0005886 plasma membrane | TAS Reactome:R-HSA-1839098 | MARK AS OVER ANNOTATED | Summary: Reactome FGFR1-signaling annotation placing ERLIN2 at the plasma membrane; inconsistent with its ER membrane localization. Reason: Over-annotation from FGFR1-pathway curation; ERLIN2 is an ER membrane protein. Supporting Evidence: file:human/ERLIN2/ERLIN2-uniprot.txt SUBCELLULAR LOCATION: Endoplasmic reticulum membrane |
| GO:0005886 plasma membrane | TAS Reactome:R-HSA-1839100 | MARK AS OVER ANNOTATED | Summary: Reactome FGFR1-signaling annotation placing ERLIN2 at the plasma membrane; inconsistent with its ER membrane localization. Reason: Over-annotation from FGFR1-pathway curation; ERLIN2 is an ER membrane protein. Supporting Evidence: file:human/ERLIN2/ERLIN2-uniprot.txt SUBCELLULAR LOCATION: Endoplasmic reticulum membrane |
| GO:0005886 plasma membrane | TAS Reactome:R-HSA-5655240 | MARK AS OVER ANNOTATED | Summary: Reactome FGFR1-signaling annotation placing ERLIN2 at the plasma membrane; inconsistent with its ER membrane localization. Reason: Over-annotation from FGFR1-pathway curation; ERLIN2 is an ER membrane protein. Supporting Evidence: file:human/ERLIN2/ERLIN2-uniprot.txt SUBCELLULAR LOCATION: Endoplasmic reticulum membrane |
| GO:0005886 plasma membrane | TAS Reactome:R-HSA-5655263 | MARK AS OVER ANNOTATED | Summary: Reactome FGFR1-signaling annotation placing ERLIN2 at the plasma membrane; inconsistent with its ER membrane localization. Reason: Over-annotation from FGFR1-pathway curation; ERLIN2 is an ER membrane protein. Supporting Evidence: file:human/ERLIN2/ERLIN2-uniprot.txt SUBCELLULAR LOCATION: Endoplasmic reticulum membrane |
| GO:0005886 plasma membrane | TAS Reactome:R-HSA-5655266 | MARK AS OVER ANNOTATED | Summary: Reactome FGFR1-signaling annotation placing ERLIN2 at the plasma membrane; inconsistent with its ER membrane localization. Reason: Over-annotation from FGFR1-pathway curation; ERLIN2 is an ER membrane protein. Supporting Evidence: file:human/ERLIN2/ERLIN2-uniprot.txt SUBCELLULAR LOCATION: Endoplasmic reticulum membrane |
| GO:0005886 plasma membrane | TAS Reactome:R-HSA-5655269 | MARK AS OVER ANNOTATED | Summary: Reactome FGFR1-signaling annotation placing ERLIN2 at the plasma membrane; inconsistent with its ER membrane localization. Reason: Over-annotation from FGFR1-pathway curation; ERLIN2 is an ER membrane protein. Supporting Evidence: file:human/ERLIN2/ERLIN2-uniprot.txt SUBCELLULAR LOCATION: Endoplasmic reticulum membrane |
| GO:0005886 plasma membrane | TAS Reactome:R-HSA-5655278 | MARK AS OVER ANNOTATED | Summary: Reactome FGFR1-signaling annotation placing ERLIN2 at the plasma membrane; inconsistent with its ER membrane localization. Reason: Over-annotation from FGFR1-pathway curation; ERLIN2 is an ER membrane protein. Supporting Evidence: file:human/ERLIN2/ERLIN2-uniprot.txt SUBCELLULAR LOCATION: Endoplasmic reticulum membrane |
| GO:0005886 plasma membrane | TAS Reactome:R-HSA-5655290 | MARK AS OVER ANNOTATED | Summary: Reactome FGFR1-signaling annotation placing ERLIN2 at the plasma membrane; inconsistent with its ER membrane localization. Reason: Over-annotation from FGFR1-pathway curation; ERLIN2 is an ER membrane protein. Supporting Evidence: file:human/ERLIN2/ERLIN2-uniprot.txt SUBCELLULAR LOCATION: Endoplasmic reticulum membrane |
| GO:0005886 plasma membrane | TAS Reactome:R-HSA-5655326 | MARK AS OVER ANNOTATED | Summary: Reactome FGFR1-signaling annotation placing ERLIN2 at the plasma membrane; inconsistent with its ER membrane localization. Reason: Over-annotation from FGFR1-pathway curation; ERLIN2 is an ER membrane protein. Supporting Evidence: file:human/ERLIN2/ERLIN2-uniprot.txt SUBCELLULAR LOCATION: Endoplasmic reticulum membrane |
| GO:0005886 plasma membrane | TAS Reactome:R-HSA-8853322 | MARK AS OVER ANNOTATED | Summary: Reactome FGFR1-fusion annotation placing ERLIN2 at the plasma membrane; inconsistent with its ER membrane localization. Reason: Over-annotation from FGFR1-pathway curation; ERLIN2 is an ER membrane protein. Supporting Evidence: file:human/ERLIN2/ERLIN2-uniprot.txt SUBCELLULAR LOCATION: Endoplasmic reticulum membrane |
| GO:0005886 plasma membrane | TAS Reactome:R-HSA-8853325 | MARK AS OVER ANNOTATED | Summary: Reactome FGFR1-fusion annotation placing ERLIN2 at the plasma membrane; inconsistent with its ER membrane localization. Reason: Over-annotation from FGFR1-pathway curation; ERLIN2 is an ER membrane protein. Supporting Evidence: file:human/ERLIN2/ERLIN2-uniprot.txt SUBCELLULAR LOCATION: Endoplasmic reticulum membrane |
| GO:0005515 protein binding | IPI PMID:30352685 Stasimon/Tmem41b localizes to mitochondria-associated ER mem... | KEEP AS NON CORE | Summary: IPI capture of the ERLIN2-TMEM41B interaction (a MAM/ER protein). Bare protein binding is uninformative. Reason: Real interaction (TMEM41B) but uninformative GO term. Supporting Evidence: file:human/ERLIN2/ERLIN2-uniprot.txt Interacts with TMEM41B |
| GO:0032991 protein-containing complex | IDA PMID:18468998 Blood pressure is regulated by an alpha1D-adrenergic recepto... | KEEP AS NON CORE | Summary: IDA placing ERLIN2 in a protein-containing complex (alpha1D-adrenergic receptor/dystrophin signalosome study). The generic complex term is uninformative; ERLIN2's defining complex is the ERLIN1/ERLIN2 complex. Reason: Experimentally supported but uninformative generic complex term; not the core ERLIN1/ERLIN2 complex. Supporting Evidence: PMID:19240031 SPFH1 and its homolog SPFH2 form a heteromeric approximately 2 MDa complex |
| GO:0005789 endoplasmic reticulum membrane | TAS Reactome:R-HSA-8866542 | ACCEPT | Summary: Reactome curation placing ERLIN2 at the ER membrane within the CFTR ERAD machinery pathway. Reason: Correct compartment; redundant with experimental ER membrane annotations. Supporting Evidence: file:human/ERLIN2/ERLIN2-uniprot.txt SUBCELLULAR LOCATION: Endoplasmic reticulum membrane |
| GO:0005789 endoplasmic reticulum membrane | TAS Reactome:R-HSA-8866546 | ACCEPT | Summary: Reactome curation of ERLIN2 ER membrane localization (CFTR ERAD pathway). Reason: Correct compartment; redundant with experimental evidence. Supporting Evidence: file:human/ERLIN2/ERLIN2-uniprot.txt SUBCELLULAR LOCATION: Endoplasmic reticulum membrane |
| GO:0005789 endoplasmic reticulum membrane | TAS Reactome:R-HSA-8866551 | ACCEPT | Summary: Reactome curation of ERLIN2 ER membrane localization (CFTR ERAD pathway). Reason: Correct compartment; redundant with experimental evidence. Supporting Evidence: file:human/ERLIN2/ERLIN2-uniprot.txt SUBCELLULAR LOCATION: Endoplasmic reticulum membrane |
| GO:0005789 endoplasmic reticulum membrane | TAS Reactome:R-HSA-8866854 | ACCEPT | Summary: Reactome curation of ERLIN2 ER membrane localization (CFTR F508del ERAD pathway). Reason: Correct compartment; redundant with experimental evidence. Supporting Evidence: file:human/ERLIN2/ERLIN2-uniprot.txt SUBCELLULAR LOCATION: Endoplasmic reticulum membrane |
| GO:0005789 endoplasmic reticulum membrane | TAS Reactome:R-HSA-8866856 | ACCEPT | Summary: Reactome curation of ERLIN2 ER membrane localization (CFTR F508del ERAD pathway). Reason: Correct compartment; redundant with experimental evidence. Supporting Evidence: file:human/ERLIN2/ERLIN2-uniprot.txt SUBCELLULAR LOCATION: Endoplasmic reticulum membrane |
| GO:0005789 endoplasmic reticulum membrane | TAS Reactome:R-HSA-8866857 | ACCEPT | Summary: Reactome curation of ERLIN2 ER membrane localization (CFTR F508del ERAD pathway). Reason: Correct compartment; redundant with experimental evidence. Supporting Evidence: file:human/ERLIN2/ERLIN2-uniprot.txt SUBCELLULAR LOCATION: Endoplasmic reticulum membrane |
| GO:0005789 endoplasmic reticulum membrane | TAS Reactome:R-HSA-9931264 | ACCEPT | Summary: Reactome curation of ERLIN2 ER membrane localization (CD274/PD-L1 ERAD pathway). Reason: Correct compartment; redundant with experimental evidence. Supporting Evidence: file:human/ERLIN2/ERLIN2-uniprot.txt SUBCELLULAR LOCATION: Endoplasmic reticulum membrane |
| GO:0005789 endoplasmic reticulum membrane | TAS Reactome:R-HSA-9931298 | ACCEPT | Summary: Reactome curation of ERLIN2 ER membrane localization (CD274/PD-L1 ERAD pathway). Reason: Correct compartment; redundant with experimental evidence. Supporting Evidence: file:human/ERLIN2/ERLIN2-uniprot.txt SUBCELLULAR LOCATION: Endoplasmic reticulum membrane |
| GO:0005789 endoplasmic reticulum membrane | TAS Reactome:R-HSA-9931313 | ACCEPT | Summary: Reactome curation of ERLIN2 ER membrane localization (CD274/PD-L1 ERAD pathway). Reason: Correct compartment; redundant with experimental evidence. Supporting Evidence: file:human/ERLIN2/ERLIN2-uniprot.txt SUBCELLULAR LOCATION: Endoplasmic reticulum membrane |
| GO:0031625 ubiquitin protein ligase binding | IPI PMID:24019521 RNF185 is a novel E3 ligase of endoplasmic reticulum-associa... | ACCEPT | Summary: ERLIN2 interacts with the ER ubiquitin ligases RNF185 and RNF5, an informative molecular function reflecting its recruitment of E3 ligases to ERAD. Reason: Directly supported (IPI); ERLIN2 binds ER ubiquitin ligases, consistent with its ERAD scaffold role. Supporting Evidence: PMID:24019521 RNF185 and RNF5 as a novel E3 ligase module |
| GO:0032933 SREBP signaling pathway | IMP PMID:24217618 Erlins restrict SREBP activation in the ER and regulate cell... | ACCEPT | Summary: Depletion of erlins led to canonical activation of SREBPs and their target genes, demonstrating that ERLIN2 restricts SREBP signaling. Reason: Core biological process with direct depletion (IMP) support. Supporting Evidence: PMID:24217618 led to canonical activation of SREBPs and their target genes |
| GO:0045541 negative regulation of cholesterol biosynthetic process | IMP PMID:24217618 Erlins restrict SREBP activation in the ER and regulate cell... | ACCEPT | Summary: By restricting SREBP activation, ERLIN2 negatively regulates cholesterol biosynthesis. Reason: Core biological process with direct (IMP) support. Supporting Evidence: PMID:24217618 led to canonical activation of SREBPs and their target genes |
| GO:0045717 negative regulation of fatty acid biosynthetic process | IMP PMID:24217618 Erlins restrict SREBP activation in the ER and regulate cell... | ACCEPT | Summary: ERLIN2 negatively regulates fatty acid biosynthesis through restriction of SREBP, which activates fatty-acid biosynthetic genes. Reason: Directly supported (IMP); a consequence of the erlins' SREBP restriction. Supporting Evidence: PMID:24217618 key transcription factors for cholesterol and fatty acid biosynthetic |
| GO:0045121 membrane raft | IDA PMID:25204797 Flotillin-1 facilitates toll-like receptor 3 signaling in hu... | KEEP AS NON CORE | Summary: IDA membrane-raft localization of ERLIN2, consistent with the erlins associating with lipid-raft-like domains of the ER membrane. Reason: Experimentally supported raft association but secondary to the core ER-membrane ERAD/SREBP roles. Supporting Evidence: PMID:16835267 define lipid-raft-like domains of the ER |
| GO:0005783 endoplasmic reticulum | IDA GO_REF:0000054 | ACCEPT | Summary: Fusion-protein localization (LIFEdb) evidence for ER localization of ERLIN2. Reason: Correct compartment; redundant with experimental ER membrane evidence. Supporting Evidence: file:human/ERLIN2/ERLIN2-uniprot.txt SUBCELLULAR LOCATION: Endoplasmic reticulum membrane |
| GO:0005515 protein binding | IPI PMID:19240031 An endoplasmic reticulum (ER) membrane complex composed of S... | KEEP AS NON CORE | Summary: IPI capture of the ERLIN2-ERLIN1 (SPFH2-SPFH1) interaction. Bare protein binding is uninformative; the ERLIN1/ERLIN2 complex is captured by the ERAD/complex annotations. Reason: Real ERLIN1 interaction but uninformative GO term. Supporting Evidence: PMID:19240031 SPFH1 and its homolog SPFH2 form a heteromeric approximately 2 MDa complex |
| GO:0005789 endoplasmic reticulum membrane | IDA PMID:16835267 Erlin-1 and erlin-2 are novel members of the prohibitin fami... | ACCEPT | Summary: Direct evidence that erlin-2 localizes to lipid-raft-like domains of the ER membrane. Reason: Core compartment; directly demonstrated. Supporting Evidence: PMID:16835267 define lipid-raft-like domains of the ER |
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Download this section (compressed HTML)Q: What is the architecture and substrate-selection mechanism of the ERLIN1/ERLIN2 ring complex (recently resolved by cryo-EM), and how does ERLIN2 recognize activated/ubiquitinated IP3R tetramers versus HMGCR?
Q: How do ERLIN2 SPG18A/SPG18B disease variants impair complex assembly, IP3R ERAD, or cholesterol/SREBP regulation to cause corticospinal motor neuron degeneration?
Q: How is cholesterol binding by the ERLIN2 SPFH domain coupled to retention of the SCAP-SREBP-Insig complex and to sterol-accelerated HMGCR degradation?
Experiment: Reconstitute the ERLIN1/ERLIN2 complex with RNF170 and a model IP3R substrate to determine ERLIN2's contribution to substrate binding versus E3-ligase recruitment in IP3R ERAD.
Experiment: Introduce SPG18 variants (e.g. S129T, R180C, D300V) into neurons and assay ERLIN complex assembly, IP3R degradation, calcium signaling, and ER cholesterol/SREBP signaling to link molecular defects to disease.
Experiment: Use cholesterol photoaffinity probes and SPFH-domain mutants of ERLIN2 to map the cholesterol-binding site and test its requirement for SREBP restriction and sterol-accelerated HMGCR ERAD.
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