RLBP1 encodes cellular retinaldehyde-binding protein (CRALBP), a 317-residue soluble retinoid-binding protein of the CRAL-TRIO (Sec14-like) family with no catalytic activity. It carries the hydrophobic 11-cis retinoids 11-cis-retinol and 11-cis-retinaldehyde (and also all-trans-retinol) within its CRAL-TRIO ligand pocket. CRALBP is expressed abundantly in the retinal pigment epithelium (RPE) and in Mueller glial cells of the neuroretina, but not in photoreceptors, where it acts as a substrate carrier and chaperone in the visual (retinoid) cycle: it sequesters and protects the labile 11-cis retinoids generated during chromophore regeneration, presents 11-cis-retinol to 11-cis-retinol dehydrogenases for oxidation to 11-cis-retinal, and enhances flux through the cycle that regenerates the visual chromophore for rod and cone opsins. The protein is cytosolic. Loss-of-function mutations that abolish 11-cis-retinoid binding cause autosomal-recessive retinal dystrophies including retinitis punctata albescens, Bothnia retinal dystrophy, Newfoundland rod-cone dystrophy and retinitis pigmentosa, typically presenting with night blindness and delayed dark adaptation.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:1902936 phosphatidylinositol bisphosphate binding | IBA GO_REF:0000033 | MARK AS OVER ANNOTATED | Summary: Phylogenetically inferred (IBA) from the PANTHER CRAL-TRIO/Sec14-like family (PTN000019344), some members of which bind phosphoinositides. RLBP1's documented physiological ligands are retinoids (11-cis-retinal, 11-cis-retinol, all-trans-retinol), and its CRAL-TRIO pocket is a retinoid-binding pocket; no experimental evidence supports phosphatidylinositol bisphosphate binding by CRALBP. This is over-propagation of a family-level lipid-binding capacity to RLBP1. Not removed (family-based inference, not clearly-wrong IEA) but marked as an over-annotation and not a core function. Reason: Family-level (IBA) lipid-binding inference not supported for RLBP1. The PANTHER family (PTHR10174 / PTN000019344) groups CRAL-TRIO/Sec14-like proteins with heterogeneous lipid-ligand specificities; a phosphoinositide-binding capacity of some members was propagated to the retinoid-specific subfamily member RLBP1, whose characterized ligands are 11-cis and all-trans retinoids, not PIP2. Propagation Review Root cause: PROPAGATION BAD Failure modes: FUNCTIONAL DIVERGENCE Supporting Evidence: file:human/RLBP1/RLBP1-uniprot.txt Soluble retinoid carrier essential the proper function of |
| GO:0005737 cytoplasm | IEA GO_REF:0000044 | KEEP AS NON CORE | Summary: Electronic mapping from the UniProt Cytoplasm subcellular-location keyword. Consistent with CRALBP being a soluble cytosolic protein, but 'cytoplasm' is a less specific parent of the experimentally supported 'cytosol' (GO:0005829, IDA); kept as non-core. Reason: Correct but less specific than the IDA-supported cytosol location. Supporting Evidence: file:human/RLBP1/RLBP1-uniprot.txt SUBCELLULAR LOCATION: Cytoplasm. |
| GO:0005515 protein binding | IPI PMID:32296183 A reference map of the human binary protein interactome. | MARK AS OVER ANNOTATED | Summary: From the HuRI systematic binary interactome (yeast two-hybrid), reporting an interaction with KLHL8. Bare 'protein binding' is uninformative about CRALBP's molecular function, and this high-throughput interaction has no established functional or physiological context for RLBP1. Retained (an experimental IPI is never removed) but marked as an over-annotation; it does not describe a core function. Reason: Non-informative 'protein binding' from a high-throughput interactome screen; no functional context for RLBP1. |
| GO:0044297 cell body | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Automatic transfer from a rat ortholog via Ensembl Compara. CRALBP is expressed in Mueller glial cell bodies, so this is biologically plausible, but it rests on orthology transfer rather than direct evidence for the human protein and is peripheral to CRALBP's carrier function. Kept as non-core. Reason: Plausible localization by orthology transfer, but not directly evidenced for human CRALBP and not a core function. |
| GO:0005829 cytosol | IDA GO_REF:0000052 | ACCEPT | Summary: Direct-assay (immunofluorescence, HPA) localization to the cytosol. CRALBP is a soluble retinoid carrier acting in the cytosol of RPE and Mueller cells, so this is the best-supported and appropriate cellular location. Supporting Evidence: file:human/RLBP1/RLBP1-uniprot.txt SUBCELLULAR LOCATION: Cytoplasm. |
| GO:0005829 cytosol | TAS Reactome:R-HSA-2454081 | ACCEPT | Summary: Reactome reaction-derived cytosol location (RDH5 oxidises 11cROL to 11cRAL). Consistent with the IDA cytosol annotation; the location is correct but this is a redundant duplicate of the direct-assay cytosol annotation. Reason: Correct cytosol location; duplicates the IDA annotation. |
| GO:0005829 cytosol | TAS Reactome:R-HSA-2454264 | ACCEPT | Summary: Reactome reaction-derived cytosol location (11cROL binds to RLBP1). Correct cytosolic location; redundant with the IDA cytosol annotation. Reason: Correct cytosol location; duplicates the IDA annotation. |
| GO:0005829 cytosol | TAS Reactome:R-HSA-2465919 | ACCEPT | Summary: Reactome reaction-derived cytosol location. Correct cytosolic location; redundant with the IDA cytosol annotation. Reason: Correct cytosol location; duplicates the IDA annotation. |
| GO:0005829 cytosol | TAS Reactome:R-HSA-2465971 | ACCEPT | Summary: Reactome reaction-derived cytosol location (RLBP1 binds atROL). Correct cytosolic location; redundant with the IDA cytosol annotation. Reason: Correct cytosol location; duplicates the IDA annotation. |
| GO:0005829 cytosol | TAS Reactome:R-HSA-2466832 | ACCEPT | Summary: Reactome reaction-derived cytosol location. Correct cytosolic location; redundant with the IDA cytosol annotation. Reason: Correct cytosol location; duplicates the IDA annotation. |
| GO:0005829 cytosol | TAS Reactome:R-HSA-74872 | ACCEPT | Summary: Reactome reaction-derived cytosol location (RDH10,11 oxidise 11cROL to 11cRAL). Correct cytosolic location; redundant with the IDA cytosol annotation. Reason: Correct cytosol location; duplicates the IDA annotation. |
| GO:0005829 cytosol | TAS Reactome:R-HSA-8960973 | ACCEPT | Summary: Reactome reaction-derived cytosol location (RLBP1:11cRAL dissociates). Correct cytosolic location; redundant with the IDA cytosol annotation. Reason: Correct cytosol location; duplicates the IDA annotation. |
| GO:0006776 vitamin A metabolic process | TAS PMID:9326942 Mutation of the gene encoding cellular retinaldehyde-binding... | ACCEPT | Summary: CRALBP is central to retinal vitamin-A (retinoid) metabolism: it carries 11-cis-retinol and 11-cis-retinaldehyde in the RPE and Mueller cells, and loss of functional CRALBP disrupts retinal vitamin-A metabolism. This is a core biological process for the gene. Supporting Evidence: PMID:9326942 where it carries 11-cis-retinol and PMID:9326942 disruption of retinal vitamin-A metabolism. |
| GO:0007601 visual perception | TAS PMID:9326942 Mutation of the gene encoding cellular retinaldehyde-binding... | ACCEPT | Summary: As a retinoid carrier in the visual cycle, CRALBP is required for regeneration of the visual chromophore that supports rod and cone function; its loss causes retinal dystrophy with night blindness. Core biological process. Supporting Evidence: file:human/RLBP1/RLBP1-uniprot.txt Soluble retinoid carrier essential the proper function of |
| GO:0005502 11-cis retinal binding | IEA GO_REF:0000003 | NEW | Summary: Present in the UniProt GO cross-reference block (F:11-cis retinal binding, IEA:Ensembl) and directly supported by the crystal structure of CRALBP in complex with 11-cis-retinal and by the R150Q variant abolishing 11-cis-retinaldehyde binding. This is the core molecular function of CRALBP; added here as NEW to align existing annotations with the core function. Supporting Evidence: file:human/RLBP1/RLBP1-uniprot.txt ligand="11-cis-retinal" PMID:9326942 The mutant protein lacked the |
| GO:0019841 retinol binding | IEA GO_REF:0000003 | NEW | Summary: Present in the UniProt GO cross-reference block (F:retinol binding, IEA:UniProtKB-KW; Retinol-binding keyword). CRALBP binds 11-cis-retinol and all-trans-retinol as physiological ligands, so retinol binding is a genuine core molecular function; added here as NEW to align with the core function. Supporting Evidence: reactome:R-HSA-2454264 The natural ligands are 11-cis-retinol (11cROL) and 11-cis-retinal (11cRAL) PMID:9326942 where it carries 11-cis-retinol and |
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