LMAN2L (VIPL, "VIP36-like protein") is an ER-resident L-type (leguminous/ConA-like) lectin and a paralog of VIP36/LMAN2 and ERGIC-53/LMAN1. It is a single-pass type I membrane glycoprotein whose N-terminal luminal L-type lectin carbohydrate-recognition domain binds high-mannose glycans (D-mannose) and whose short cytoplasmic tail carries an RKR di-arginine ER-retention signal. Unlike the cycling lectins VIP36 and ERGIC-53, LMAN2L is predominantly a non-cycling resident of the endoplasmic reticulum, with a minor Golgi pool. It is not a glycosidase and has no catalytic activity; rather it is proposed to regulate ER export of a subset of glycoproteins and to act as a regulator of ERGIC-53, with overexpression redistributing ERGIC-53 to the ER and knockdown slowing glycoprotein secretion. LMAN2L is a neurodevelopmental disease gene: variants cause autosomal recessive (MRT52) and autosomal dominant (MRD69) intellectual developmental disorders.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0005793 endoplasmic reticulum-Golgi intermediate compartment | IBA GO_REF:0000033 | KEEP AS NON CORE | Summary: Phylogenetic (IBA) localization to the ERGIC, inherited from the cycling L-type lectins ERGIC-53/VIP36. VIPL acts in the early secretory pathway and its overexpression redistributes ERGIC-53, so an ERGIC association is plausible, though VIPL is itself predominantly ER-resident rather than a cycling ERGIC component. Reason: Defensible early-secretory-pathway localization consistent with the family, but VIPL is predominantly a non-cycling ER-resident protein; the ER membrane is the core compartment. Supporting Evidence: PMID:12609988 VIPL is a non-cycling resident protein of the ER |
| GO:0000139 Golgi membrane | IBA GO_REF:0000033 | KEEP AS NON CORE | Summary: Phylogenetic Golgi-membrane localization, consistent with the minor Golgi pool of VIPL observed experimentally. Reason: VIPL is only partly found in the Golgi; the ER is its predominant and core compartment. Supporting Evidence: PMID:12878160 VIPL localized primarily to the ER and partly to the Golgi complex |
| GO:0005789 endoplasmic reticulum membrane | IBA GO_REF:0000033 | ACCEPT | Summary: Phylogenetic ER-membrane localization, fully consistent with direct experimental evidence that VIPL is a non-cycling ER-resident type I membrane protein. Reason: ER membrane is the correct core compartment, supported by IDA and the UniProt subcellular location. Supporting Evidence: file:human/LMAN2L/LMAN2L-uniprot.txt SUBCELLULAR LOCATION: Endoplasmic reticulum membrane |
| GO:0005537 D-mannose binding | IBA GO_REF:0000033 | ACCEPT | Summary: Phylogenetic assignment of D-mannose binding based on the conserved L-type lectin carbohydrate-recognition domain shared with VIP36/ERGIC-53. Consistent with VIPL being a high-mannose-type lectin with the same domain organization as VIP36. Reason: D-mannose binding is the defensible family-level molecular function conferred by the conserved L-type lectin CRD; consistent with the TAS annotation. Supporting Evidence: PMID:12609988 high-mannose type I membrane glycoprotein with similar domain organization as |
| GO:0006888 endoplasmic reticulum to Golgi vesicle-mediated transport | IBA GO_REF:0000033 | ACCEPT | Summary: Phylogenetic assignment of ER-to-Golgi vesicle-mediated transport, consistent with VIPL's role in regulating ER export of glycoproteins. Reason: Consistent with the experimentally supported role in ER export of a subset of glycoproteins; core biological process. Supporting Evidence: PMID:12878160 knock-down of VIPL mRNA using siRNA significantly |
| GO:0030134 COPII-coated ER to Golgi transport vesicle | IBA GO_REF:0000033 | KEEP AS NON CORE | Summary: Phylogenetic localization to COPII transport vesicles, inherited from cycling family members. Plausible given VIPL's transport role, but VIPL is predominantly ER-resident and direct COPII-vesicle localization is not demonstrated. Reason: Plausible transport-vesicle association by homology, but not directly demonstrated for the predominantly ER-resident VIPL. Supporting Evidence: PMID:12878160 VIPL localized primarily to the ER and partly to the Golgi complex |
| GO:0000139 Golgi membrane | IEA GO_REF:0000044 | KEEP AS NON CORE | Summary: Electronic transfer of Golgi-membrane localization from the UniProt subcellular location, consistent with the minor Golgi pool of VIPL. Reason: Correct minor compartment; VIPL is only partly found in the Golgi and the ER is core. Supporting Evidence: file:human/LMAN2L/LMAN2L-uniprot.txt Golgi apparatus membrane |
| GO:0005789 endoplasmic reticulum membrane | IEA GO_REF:0000044 | ACCEPT | Summary: Electronic transfer of ER-membrane localization from the UniProt subcellular location, consistent with stronger experimental (IDA) evidence. Reason: Correct core compartment; redundant with IDA ER membrane. Supporting Evidence: file:human/LMAN2L/LMAN2L-uniprot.txt SUBCELLULAR LOCATION: Endoplasmic reticulum membrane |
| GO:0016020 membrane | IEA GO_REF:0000002 | MARK AS OVER ANNOTATED | Summary: Generic InterPro-based membrane localization. VIPL is a single-pass type I membrane protein, but the specific ER (and partly Golgi) membrane terms are far more informative. Reason: Uninformative high-level compartment; the specific ER membrane (GO:0005789) term is the appropriate localization. Proposed replacements: endoplasmic reticulum membrane Supporting Evidence: file:human/LMAN2L/LMAN2L-uniprot.txt SUBCELLULAR LOCATION: Endoplasmic reticulum membrane |
| GO:0005515 protein binding | IPI PMID:32296183 A reference map of the human binary protein interactome. | KEEP AS NON CORE | Summary: High-throughput binary interactome (HuRI) capture; the GOA WITH field records MAL (P21145) as the interactor. Bare protein binding is uninformative and the partner does not reflect VIPL's lectin/ER-export function. Reason: Records a real IntAct interaction (MAL) but bare protein binding is uninformative per curation guidelines; not elevated to core. Supporting Evidence: file:human/LMAN2L/LMAN2L-uniprot.txt Q9H0V9; P21145: MAL |
| GO:0005515 protein binding | IPI PMID:32814053 Interactome Mapping Provides a Network of Neurodegenerative ... | KEEP AS NON CORE | Summary: Neurodegenerative-disease interactome (Y2H) capture; the GOA WITH field records huntingtin HTT (P42858) as the interactor. Bare protein binding is uninformative and the partner does not reflect VIPL's core function. Reason: Records a real IntAct interaction (HTT) from a disease-focused screen, but bare protein binding is uninformative; not elevated to core. Supporting Evidence: file:human/LMAN2L/LMAN2L-uniprot.txt Q9H0V9; P42858: HTT |
| GO:0005537 D-mannose binding | TAS PMID:12609988 Profile-based data base scanning for animal L-type lectins a... | ACCEPT | Summary: TAS assignment of D-mannose binding based on VIPL being a high-mannose-type lectin with the same domain organization as VIP36 and the conserved L-type lectin CRD. The cited abstract establishes the lectin domain and high-mannose glycoprotein status but does not itself report a direct carbohydrate-binding assay for VIPL; the assignment is therefore homology/domain-based. Reason: D-mannose binding is the family-level molecular function conferred by the conserved L-type lectin CRD and is consistent across TAS/IBA assignments. The cached abstract supports lectin/high-mannose-glycoprotein status but is homology/domain-based rather than a direct binding assay for VIPL; no catalytic activity is assigned. Supporting Evidence: PMID:12609988 high-mannose type I membrane glycoprotein with similar domain organization as |
| GO:0005789 endoplasmic reticulum membrane | IDA PMID:12609988 Profile-based data base scanning for animal L-type lectins a... | ACCEPT | Summary: Direct experimental evidence that VIPL is a non-cycling resident protein of the ER, retained by an RKR di-arginine signal. This is the core localization of VIPL. Reason: Core compartment; VIPL is predominantly an ER-resident type I membrane protein, supported directly and by the UniProt subcellular location. Supporting Evidence: PMID:12609988 VIPL is a non-cycling resident protein of the ER |
| GO:0005794 Golgi apparatus | IDA PMID:12878160 VIPL, a VIP36-like membrane protein with a putative function... | ACCEPT | Summary: Direct evidence that VIPL localizes partly to the Golgi complex in addition to its predominant ER pool. Reason: Correct minor compartment; VIPL is partly found in the Golgi, consistent with the UniProt subcellular location. Supporting Evidence: PMID:12878160 VIPL localized primarily to the ER and partly to the Golgi complex |
| GO:0006457 protein folding | NAS PMID:12609988 Profile-based data base scanning for animal L-type lectins a... | MARK AS OVER ANNOTATED | Summary: NAS assertion of a protein-folding role. VIPL is a lectin/transport regulator, not a folding catalyst or chaperone; any connection is to glycoprotein quality control and ER export rather than to catalysis of folding. This is a generic, over-broad assignment. Reason: VIPL has no folding/chaperone activity; its function is lectin-mediated regulation of ER export, better captured by transport terms. Supporting Evidence: PMID:12609988 VIPL is a non-cycling resident protein of the ER |
| GO:0006888 endoplasmic reticulum to Golgi vesicle-mediated transport | TAS PMID:12878160 VIPL, a VIP36-like membrane protein with a putative function... | ACCEPT | Summary: VIPL is proposed to function as an ER export receptor for a subset of glycoproteins; its knockdown slows their secretion. This ER-to-Golgi transport role is the core biological process of VIPL. Reason: Core biological process; experimentally supported regulation of ER export of glycoproteins. Supporting Evidence: PMID:12878160 Subsets of glycoproteins are thought to require lectin-like membrane receptors |
| GO:0015031 protein transport | IMP PMID:12878160 VIPL, a VIP36-like membrane protein with a putative function... | ACCEPT | Summary: siRNA knockdown of VIPL significantly slowed secretion of two glycoproteins, providing perturbation evidence that VIPL functions in the export (transport) of glycoproteins from the ER. Core biological process. Reason: Core biological process directly supported by knockdown evidence; VIPL regulates ER export of a subset of glycoproteins. Supporting Evidence: PMID:12878160 knock-down of VIPL mRNA using siRNA significantly |
| GO:0016020 membrane | TAS PMID:12609988 Profile-based data base scanning for animal L-type lectins a... | MARK AS OVER ANNOTATED | Summary: Generic membrane localization. VIPL is a single-pass type I membrane protein, but the specific ER membrane term is the appropriate, informative localization. Reason: Uninformative high-level compartment; superseded by the specific ER membrane term. Proposed replacements: endoplasmic reticulum membrane Supporting Evidence: file:human/LMAN2L/LMAN2L-uniprot.txt SUBCELLULAR LOCATION: Endoplasmic reticulum membrane |
| GO:0030134 COPII-coated ER to Golgi transport vesicle | NAS PMID:12878160 VIPL, a VIP36-like membrane protein with a putative function... | KEEP AS NON CORE | Summary: NAS assertion that VIPL associates with COPII ER-to-Golgi transport vesicles, in line with its proposed ER export receptor role. Plausible but not directly demonstrated; VIPL is predominantly ER-resident. Reason: Plausible transport-vesicle association consistent with the ER export role, but not a directly demonstrated localization; kept as supporting. Supporting Evidence: PMID:12878160 conserved carbohydrate recognition domain (CRD) as a search string |
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Download this section (compressed HTML)Q: Does VIPL bind D-mannose / high-mannose N-glycans directly in vitro, and what is its glycan specificity relative to VIP36 and ERGIC-53?
Q: Is VIPL a positive or negative regulator of ERGIC-53-mediated ER export, and does it act by sequestering ERGIC-53 in the ER or by handing off glycoprotein cargo?
Q: How do the MRT52 (R53Q) and MRD69 disease variants alter VIPL lectin binding, ER retention, or ERGIC-53 regulation to cause intellectual disability?
Experiment: Quantitative glycan-array or ITC/SPR binding assays with purified VIPL luminal CRD against high-mannose and processed N-glycans to directly establish D-mannose binding and specificity.
Experiment: Define the endogenous glycoprotein cargo whose ER export depends on VIPL using secretomics/pulse-chase in VIPL knockout versus wild-type cells.
Experiment: Test whether VIPL disease variants (R53Q; dominant MRD69 allele) perturb ERGIC-53 localization and glycoprotein secretion in patient-derived or engineered cells.
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