{"gene":"VLDLR","run_date":"2026-06-14T07:33:11","timeline":{"discoveries":[],"current_model":"Parse failed"},"narrative":{"mechanistic_narrative":"No mechanistic discoveries found in literature.","teleology":[],"mechanism_profile":null},"prefetch_data":{"uniprot":{"accession":"P98155","full_name":"Very low-density lipoprotein receptor","aliases":[],"length_aa":873,"mass_kda":96.1,"function":"Multifunctional cell surface receptor that binds VLDL and transports it into cells by endocytosis and therefore plays an important role in energy metabolism. Also binds to a wide range of other molecules including Reelin/RELN or apolipoprotein E/APOE-containing ligands as well as clusterin/CLU (PubMed:24381170, PubMed:30873003). In the off-state of the pathway, forms homooligomers or heterooligomers with LRP8 (PubMed:30873003). Upon binding to ligands, homooligomers are rearranged to higher order receptor clusters that transmit the extracellular RELN signal to intracellular signaling processes by binding to DAB1 (PubMed:30873003). This interaction results in phosphorylation of DAB1 leading to the ultimate cell responses required for the correct positioning of newly generated neurons. Later, mediates a stop signal for migrating neurons, preventing them from entering the marginal zone (By similarity) (Microbial infection) Acts as a receptor for Semliki Forest virus","subcellular_location":"Cell membrane; Membrane, clathrin-coated pit","url":"https://www.uniprot.org/uniprotkb/P98155/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/VLDLR","classification":"Not Classified","n_dependent_lines":0,"n_total_lines":1208,"dependency_fraction":0.0},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/VLDLR","total_profiled":1310},"omim":[{"mim_id":"615268","title":"CEREBELLAR ATAXIA, IMPAIRED INTELLECTUAL DEVELOPMENT, AND DYSEQUILIBRIUM SYNDROME 4; CAMRQ4","url":"https://www.omim.org/entry/615268"},{"mim_id":"613227","title":"SPINOCEREBELLAR ATAXIA, AUTOSOMAL RECESSIVE 34; SCAR34","url":"https://www.omim.org/entry/613227"},{"mim_id":"612031","title":"INHIBIN, BETA E; INHBE","url":"https://www.omim.org/entry/612031"},{"mim_id":"610185","title":"CEREBELLAR ATAXIA, IMPAIRED INTELLECTUAL DEVELOPMENT, AND DYSEQUILIBRIUM SYNDROME 2; CAMRQ2","url":"https://www.omim.org/entry/610185"},{"mim_id":"605870","title":"ATPase, CLASS I, TYPE 8A, MEMBER 2; ATP8A2","url":"https://www.omim.org/entry/605870"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Uncertain","locations":[{"location":"Vesicles","reliability":"Uncertain"},{"location":"Cytokinetic bridge","reliability":"Additional"},{"location":"Centriolar satellite","reliability":"Additional"}],"tissue_specificity":"Tissue enhanced","tissue_distribution":"Detected in many","driving_tissues":[{"tissue":"ovary","ntpm":32.3}],"url":"https://www.proteinatlas.org/search/VLDLR"},"hgnc":{"alias_symbol":["CARMQ1","CHRMQ1","VLDLRCH"],"prev_symbol":[]},"alphafold":{"accession":"P98155","domains":[{"cath_id":"4.10.400.10","chopping":"36-69","consensus_level":"medium","plddt":79.1268,"start":36,"end":69},{"cath_id":"-","chopping":"400-429","consensus_level":"medium","plddt":89.628,"start":400,"end":429},{"cath_id":"2.120.10.30","chopping":"445-701","consensus_level":"high","plddt":92.0481,"start":445,"end":701}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/P98155","model_url":"https://alphafold.ebi.ac.uk/files/AF-P98155-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-P98155-F1-predicted_aligned_error_v6.png","plddt_mean":75.69},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=VLDLR","jax_strain_url":"https://www.jax.org/strain/search?query=VLDLR"},"sequence":{"accession":"P98155","fasta_url":"https://rest.uniprot.org/uniprotkb/P98155.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/P98155/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/P98155"}},"corpus_meta":[{"pmid":"18039658","id":"PMC_18039658","title":"The 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Membrane-bound PCSK9 chimeras enhance targeting to late endosomes/lysosomes and result in more efficient degradation. PCSK9 binding to VLDLR is independent of LDLR presence.\",\n      \"method\": \"Co-expression in cells, re-internalization assays, catalytic-dead mutant analysis, membrane-bound chimera constructs, co-IP/Western blot, in situ hybridization\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal methods (co-expression, re-internalization, catalytic mutant, membrane chimera) in a rigorous single study, subsequently supported by independent work (PMID 21273557)\",\n      \"pmids\": [\"18039658\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"Circulating PCSK9 originating exclusively from liver regulates VLDLR protein levels on the cell surface of visceral adipose tissue in vivo; Pcsk9−/− mice show ~4–40-fold higher adipocyte-surface VLDLR levels and adipocyte hypertrophy independent of LDLR. Liver-specific PCSK9 re-expression restores normal VLDLR levels, confirming the endocrine mechanism.\",\n      \"method\": \"Pcsk9−/− mice, Pcsk9−/−Ldlr−/− mice, liver-specific adenoviral PCSK9 expression, liver-specific PCSK9 inactivation, immunohistochemistry for VLDLR\",\n      \"journal\": \"Arteriosclerosis, thrombosis, and vascular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic rescue experiment with liver-specific re-expression and inactivation, multiple mouse models, replicated mechanistic logic from PMID 18039658\",\n      \"pmids\": [\"21273557\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"The E3 ubiquitin ligase IDOL (Inducible Degrader of the LDL Receptor), a direct LXR target, triggers ubiquitination of VLDLR and ApoER2 on their cytoplasmic tails, leading to their degradation. Pharmacological LXR activation in mice increases Idol expression and decreases Vldlr levels in vivo. IDOL-mediated VLDLR degradation reduces Reelin binding to VLDLR and decreases Dab1 phosphorylation.\",\n      \"method\": \"Ubiquitination assays, co-expression, Western blot, pharmacological LXR activation in mice, Dab1 phosphorylation assay\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — ubiquitination mapped to cytoplasmic tail, confirmed in vivo with LXR agonist, functional consequence on Reelin signaling measured, replicated in PMID 32072135\",\n      \"pmids\": [\"20427281\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"Purified Reelin binds directly to both ApoER2 and VLDLR and induces tyrosine phosphorylation of Dab1 in cortical neurons; ApoER2 binds Reelin more readily than VLDLR. Complete absence of Reelin-induced Dab1 phosphorylation occurs only when both receptors are absent, demonstrating that ApoER2 and VLDLR are essential and non-redundant mediators of Reelin-Dab1 signaling.\",\n      \"method\": \"Purified Reelin binding assay, cortical neuron cultures from single and double receptor knockout mice, Dab1 tyrosine phosphorylation assay, layer-specific markers in vivo\",\n      \"journal\": \"Brain research. Molecular brain research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — direct binding with purified protein plus genetic loss-of-function with defined biochemical readout; replicated conceptually by multiple labs\",\n      \"pmids\": [\"12670700\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"VLDLR (together with ApoER2) and the adaptor Dab1 are required for normal hippocampal dendrite development. Addition of Reelin receptor antagonists or Dab1 phosphorylation inhibitors prevents dendrite outgrowth from normal neurons; recombinant Reelin rescues the deficit in reeler cultures, placing VLDLR in the Reelin→Dab1→dendrite signaling pathway.\",\n      \"method\": \"Dissociated hippocampal neuron cultures, Reelin-blocking antibodies, receptor antagonists, Dab1 phosphorylation inhibitors, recombinant Reelin rescue, in vivo analysis of heterozygous and homozygous mutant mice\",\n      \"journal\": \"Neuron\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple pharmacological and genetic interventions with specific cellular phenotype, in vitro and in vivo convergence\",\n      \"pmids\": [\"14715136\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"Vldlr and ApoER2 have divergent roles in cortical neuronal migration: Vldlr mediates a stop signal for migrating neurons, whereas ApoER2 is essential for migration of late-generated neocortical neurons. This was established by fate-mapping with BrdU and layer-specific markers in single and double receptor knockout mice.\",\n      \"method\": \"BrdU fate-mapping, layer-specific immunomarkers, single and double receptor knockout mouse analysis\",\n      \"journal\": \"Development (Cambridge, England)\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic epistasis with BrdU fate mapping; divergent phenotypes of single knockouts clearly separated the two receptors' functions\",\n      \"pmids\": [\"17913789\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"Catalytic subunits of the Pafah1b complex (Pafah1b2 and Pafah1b3) specifically bind the NPxYL sequence of VLDLR but not ApoER2. Compound Pafah1b1+/−;Apoer2−/− mice show a reeler-like forebrain phenotype, whereas Pafah1b1+/−;Vldlr−/− double mutants do not, establishing a VLDLR-specific cross-talk with the Pafah1b complex downstream in the Reelin pathway.\",\n      \"method\": \"Direct binding assay (NPxYL peptide), double-mutant mouse genetic epistasis, histological analysis of cortical layers and hippocampus\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct binding to defined motif plus rigorous double-mutant epistasis; single lab but two orthogonal methods\",\n      \"pmids\": [\"17330141\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"Clusterin binds to VLDLR (and ApoER2) and is internalized by receptor-expressing cells. Clusterin binding triggers a Reelin-like signal: it induces phosphorylation of Dab1, leading to activation of PI3K/Akt and n-cofilin. Blocking clusterin in SVZ explants compromises neuroblast chain formation.\",\n      \"method\": \"Cell binding and internalization assays, Dab1 phosphorylation assay, PI3K/Akt and n-cofilin Western blot, SVZ explant cultures with clusterin blockade\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — biochemical binding plus downstream signaling confirmed; single lab, multiple methods\",\n      \"pmids\": [\"24381170\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"VLDLR (and ApoER2) serve as entry receptors for multiple alphaviruses including Semliki Forest virus (SFV), Eastern equine encephalitis virus (EEEV), and Sindbis virus. The E2–E1 glycoproteins interact with the ligand-binding domains (LBDs) of VLDLR. Ectopic VLDLR expression enables cellular attachment and internalization of virus-like particles; a VLDLR LBD-Fc fusion protein blocks infection and protects mice from lethal SFV challenge.\",\n      \"method\": \"Ectopic expression, virus-like particle internalization assay, VLDLR LBD-Fc fusion protein blocking, in vivo neonatal mouse protection assay, interaction studies with E2–E1 glycoproteins\",\n      \"journal\": \"Nature\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — ectopic expression, fusion-protein blocking, and in vivo protection across multiple virus strains; replicated and extended by structural studies (PMIDs 37098345, 38176410, 39095394, 39127734)\",\n      \"pmids\": [\"34929721\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"Cryo-EM structure of SFV in complex with VLDLR shows that VLDLR binds multiple E1-DIII sites on SFV through its membrane-distal LA (LDLR class A) repeats. LA3 has the best individual binding affinity (~378 Ų interface, primarily salt bridges), and consecutive LA repeats around LA3 promote synergistic binding by rotating to engage multiple E1-DIII sites simultaneously.\",\n      \"method\": \"Cryo-electron microscopy, mutagenesis, binding affinity measurements\",\n      \"journal\": \"Cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — high-resolution cryo-EM structure with mutagenesis validation; extended by independent structures (PMIDs 38176410, 39095394, 39127734)\",\n      \"pmids\": [\"37098345\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"Cryo-EM structures of EEEV-VLDLR complexes show EEEV engages VLDLR at two sites (E1/E2 cleft and E2 A domain) using more than one LA domain simultaneously; no single LA domain is necessary or sufficient for efficient infection. A PE-6 strain substitution enables an additional E2 B domain binding site. These findings informed design of a minimal VLDLR decoy receptor that neutralizes EEEV and protects mice from lethal challenge.\",\n      \"method\": \"Cryo-EM, mutagenesis, functional infection assays, mouse lethal challenge with VLDLR decoy receptor\",\n      \"journal\": \"Cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — multiple cryo-EM structures, mutagenesis, and in vivo protection in a single rigorous study\",\n      \"pmids\": [\"38176410\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"Cryo-EM and biochemical studies of EEEV-VLDLR interactions identify three distinct binding sites (A, B, C) on the EEEV virion engaged by LA repeats. LA1-2 and LA3-5 mediate two major binding modes. The W132G mutation in VLDLR impairs LA3 binding, shifts binding modes, and significantly enhances EEEV cell attachment, impl","stage2_raw":"","audit_flag":{"gene":"VLDLR","tier":"GROUNDING","verdict":"Evidence-grounding concern","subtype":"recall_miss","uniprot_band":"medium","rules_fired":"R5","issue":"R5: no narrative despite experimental UniProt FUNCTION (977 chars) and on-target evidence in corpus (95 on-target corpus titles)"},"evaluation":null}