{"gene":"VLDLR","run_date":"2026-04-28T23:00:23","timeline":{"discoveries":[{"year":2003,"finding":"Purified Reelin directly binds to VLDLR (and ApoER2), and this binding induces tyrosine phosphorylation of the cytoplasmic adaptor protein Disabled-1 (Dab1). Neurons lacking both ApoER2 and VLDLR show a complete absence of Reelin-induced Dab1 phosphorylation, demonstrating that no other receptor can compensate for their role.","method":"Purified Reelin binding assays, cortical neuron cultures from single and double receptor knockout mice, Dab1 phosphorylation assays, layer-specific marker fate mapping","journal":"Brain research. Molecular brain research","confidence":"High","confidence_rationale":"Tier 1–2 — purified protein binding assay combined with genetic knockout and phosphorylation readout; findings replicated across multiple mutant genotypes","pmids":["12670700"],"is_preprint":false},{"year":2004,"finding":"Reelin promotes hippocampal dendrite development through the VLDLR/ApoER2–Dab1 signaling pathway; addition of Reelin receptor antagonists or Dab1 phosphorylation inhibitors prevents dendrite outgrowth, and recombinant Reelin rescues the deficit in reeler cultures.","method":"In vivo analysis of reeler and receptor-mutant mice, dissociated hippocampal cultures, Reelin-blocking antibodies, receptor antagonists, Dab1 phosphorylation inhibitors, recombinant Reelin rescue","journal":"Neuron","confidence":"High","confidence_rationale":"Tier 2 — multiple orthogonal pharmacological and genetic loss-of-function approaches with defined cellular phenotype in vivo and in vitro","pmids":["14715136"],"is_preprint":false},{"year":2007,"finding":"PCSK9 induces degradation of VLDLR (as well as LDLR and ApoER2). Wild-type PCSK9 and its gain-of-function mutant D374Y degrade VLDLR either through co-expression or re-internalization of secreted PCSK9; this degradation does not require PCSK9 catalytic activity and is enhanced by membrane-bound PCSK9 chimeras that target the receptor to late endosomes/lysosomes.","method":"Cellular co-expression, secreted PCSK9 re-internalization, membrane-bound PCSK9 chimeras, catalytic-dead mutant analysis, subcellular localization by immunofluorescence","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1–2 — multiple mechanistic approaches including gain-of-function mutant, chimeric constructs, and catalytic dead mutant with defined degradation readout","pmids":["18039658"],"is_preprint":false},{"year":2010,"finding":"The E3 ubiquitin ligase IDOL ubiquitinates the cytoplasmic tail of VLDLR, leading to its degradation. IDOL expression is induced by liver X receptor (LXR) activation, and 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.","method":"Ubiquitination assays, LXR agonist treatment in vivo and in vitro, Reelin binding assay, Dab1 phosphorylation assay, Western blotting","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1–2 — direct ubiquitination assay with defined cytoplasmic tail target, in vivo pharmacological validation, and downstream signaling readout","pmids":["20427281"],"is_preprint":false},{"year":2007,"finding":"Vldlr mediates a stop signal for migrating cortical neurons, whereas ApoER2 is essential for migration of late-generated neocortical neurons; fate mapping in single and double receptor knockout mice revealed divergent roles for the two Reelin receptors in radial neuronal migration.","method":"BrdU fate mapping, layer-specific markers in single and double receptor knockout mice","journal":"Development (Cambridge, England)","confidence":"High","confidence_rationale":"Tier 2 — genetic epistasis with BrdU fate mapping in multiple single and double knockout genotypes","pmids":["17913789"],"is_preprint":false},{"year":2011,"finding":"Circulating PCSK9 originating from the liver regulates VLDLR protein levels on the surface of visceral adipocytes in vivo; liver-specific PCSK9 expression or inactivation modulates perigonadal VLDLR levels independently of LDLR.","method":"Immunohistochemistry in Pcsk9−/− mice, Pcsk9−/−Ldlr−/− mice, liver-specific PCSK9 expression and inactivation, in vivo fatty acid uptake assays","journal":"Arteriosclerosis, thrombosis, and vascular biology","confidence":"High","confidence_rationale":"Tier 2 — tissue-specific genetic and adenoviral manipulation with quantitative cell-surface receptor measurement in multiple mouse models","pmids":["21273557"],"is_preprint":false},{"year":2007,"finding":"The Pafah1b complex catalytic subunits Pafah1b2 and Pafah1b3 specifically bind to the NPxYL sequence of VLDLR (but not ApoER2), and genetic epistasis shows that compound Pafah1b1+/−;Apoer2−/− mice display a reeler-like forebrain phenotype while Pafah1b1+/−;Vldlr−/− double mutants do not, placing Pafah1b complex function downstream of VLDLR in cortical layer formation.","method":"Binding assays identifying NPxYL interaction, compound mouse genetic epistasis analysis, cortical layer phenotyping","journal":"PloS one","confidence":"High","confidence_rationale":"Tier 2 — direct protein–receptor interaction mapped to a specific motif, combined with genetic epistasis in multiple compound mutant lines","pmids":["17330141"],"is_preprint":false},{"year":2012,"finding":"HIF-1α directly activates VLDLR gene transcription under hypoxia through a functional hypoxia-response element (HRE) at +405 in exon 1 of VLDLR, leading to increased LDL and VLDL uptake and intracellular lipid accumulation; HIF-2α is not involved.","method":"Dual-luciferase reporter assay, chromatin immunoprecipitation (ChIP), HIF1A/VLDLR siRNA knockdown, lipid uptake assays under hypoxia","journal":"The Biochemical journal","confidence":"High","confidence_rationale":"Tier 1–2 — ChIP and reporter assay confirming functional HRE, combined with siRNA knockdown and functional lipid uptake readout","pmids":["21970364"],"is_preprint":false},{"year":2011,"finding":"VLDLR on retinal endothelial cell and RPE surfaces mediates an antiangiogenic signal that prevents retinal endothelial cells from migrating into the photoreceptor layer; a missense mutation (c.2239C>T) causing C-terminal truncation abolishes plasma membrane localization of VLDLR, resulting in loss of this antiangiogenic function.","method":"Genome-wide linkage, DNA sequencing, allelic complementation test with Vldlr−/− mice, Western blot, transient transfection with wild-type and mutant Vldlr, immunofluorescence localization","journal":"Investigative ophthalmology & visual science","confidence":"High","confidence_rationale":"Tier 1–2 — mutation identified and functionally validated by allelic test in knockout mice, with direct demonstration of mislocalization of truncated protein","pmids":["21757581"],"is_preprint":false},{"year":2013,"finding":"Clusterin binds directly to VLDLR (and ApoER2) and is internalized by cells expressing either receptor; clusterin binding triggers a Reelin-like signal including phosphorylation of Dab1 and activation of PI3K/Akt and n-cofilin.","method":"Binding assays, internalization assays, Dab1 phosphorylation assay, PI3K/Akt activation assays, SVZ explant cultures with clusterin blocking","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 — direct binding and internalization demonstrated with downstream signaling readouts using multiple methods","pmids":["24381170"],"is_preprint":false},{"year":2011,"finding":"VLDLR functions as a novel endothelial cell receptor for fibrin, interacting with fibrin through fibrin βN-domains with high affinity; this interaction is inhibited by receptor-associated protein (RAP). VLDLR-deficient mice fail to support fibrin-dependent leukocyte transmigration, demonstrating a role for VLDLR in fibrin-dependent inflammation.","method":"ELISA, surface plasmon resonance, transendothelial migration assays with RAP inhibitor, VLDLR-deficient mouse in vivo transmigration assays","journal":"Blood","confidence":"High","confidence_rationale":"Tier 1–2 — SPR quantitative binding assay combined with in vitro and in vivo (knockout mouse) functional validation","pmids":["22096238"],"is_preprint":false},{"year":2015,"finding":"VLDLR mediates hepatitis C virus (HCV) entry into hepatocytes independently of CD81; hypoxia-induced VLDLR expression confers HCV susceptibility to CD81-deficient cells, and ectopic VLDLR expression is sufficient for HCV entry.","method":"Hypoxic cell culture, CD81-deficient cell transduction with VLDLR, HCV infectivity assays, knockdown of known HCV entry factors","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 2 — ectopic expression conferring susceptibility and knockdown studies with CD81-independent entry demonstrated in defined cell systems","pmids":["26699506"],"is_preprint":false},{"year":2021,"finding":"VLDLR (and ApoER2) acts as an entry receptor for 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, and a VLDLR LBD-Fc fusion protein blocks infection and protects neonatal mice against lethal SFV challenge. Invertebrate VLDLR orthologues from mosquitoes and worms also function as alphavirus receptors.","method":"Ectopic expression assays, virus-like particle internalization, VLDLR LBD-Fc fusion protein competition/protection assays, in vivo mouse challenge model, invertebrate ortholog expression","journal":"Nature","confidence":"High","confidence_rationale":"Tier 1–2 — receptor identification with functional competition assay and in vivo protection; multiple viral species and host orthologs tested","pmids":["34929721"],"is_preprint":false},{"year":2023,"finding":"Cryo-EM structure of SFV in complex with VLDLR shows that VLDLR binds multiple E1-DIII sites on the virion through its membrane-distal LDLR class A (LA) repeats; LA3 has the highest binding affinity (interacting through salt bridges over 378 Ų surface area), and consecutive LA repeats undergo rotation to enable synergistic binding at multiple sites simultaneously.","method":"Cryo-electron microscopy structure determination, binding affinity measurements for individual LA repeats, mutagenesis","journal":"Cell","confidence":"High","confidence_rationale":"Tier 1 — high-resolution cryo-EM structure with mutagenesis and binding affinity validation","pmids":["37098345"],"is_preprint":false},{"year":2024,"finding":"Cryo-EM structures of EEEV-VLDLR complexes show EEEV uses two distinct sites on E1/E2 (E1/E2 cleft and E2 A domain) to engage more than one LA domain simultaneously; no single LA domain is necessary or sufficient for efficient EEEV infection. A minimal VLDLR decoy receptor designed from these structures neutralizes EEEV and protects mice from lethal challenge.","method":"Multiple cryo-EM structures, mutagenesis of binding sites, functional infection assays, in vivo mouse protection assays with decoy receptor","journal":"Cell","confidence":"High","confidence_rationale":"Tier 1 — multiple cryo-EM structures with mutagenesis and in vivo functional validation","pmids":["38176410"],"is_preprint":false},{"year":2024,"finding":"Cryo-EM structural studies of EEEV-VLDLR identify three distinct binding sites (A, B, C) on EEEV engaged by different VLDLR LA repeats; the W132G variant of VLDLR impairs LA3 binding, switches binding modes, and significantly enhances EEEV cell attachment, suggesting this human SNP could confer heightened EEEV susceptibility.","method":"Cryo-EM structure determination, biochemical binding studies, cell attachment assays with wild-type and W132G mutant VLDLR","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 1 — cryo-EM structures combined with mutagenesis and functional cell attachment assays","pmids":["39127734"],"is_preprint":false},{"year":2024,"finding":"SFV neuroinvasion is strictly dependent on VLDLR; SFV primarily enters the CNS through the blood-cerebrospinal fluid (B-CSF) barrier by infecting choroid plexus epithelial cells, which express distinctly high levels of VLDLR.","method":"In vivo VLDLR-deficient mouse model, intravenous SFV administration, tissue-specific VLDLR expression analysis, histological characterization of infection route","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 2 — receptor-deficient mouse model with defined route-of-entry phenotype and supporting expression data","pmids":["39715740"],"is_preprint":false},{"year":2012,"finding":"FE65 interacts with VLDLR via its PTB1 domain (shown by GST pull-down and co-immunoprecipitation in COS7 cells and brain lysates), increases cell-surface levels of VLDLR and shedding of soluble VLDLR, promotes proteasomal degradation of the VLDLR C-terminal fragment, and acts as a linker between VLDLR and APP, altering trafficking and processing of both proteins.","method":"GST pull-down, co-immunoprecipitation in cell lines and brain lysates, cell-surface biotinylation, FE65 co-transfection with domain mutants, proteasome inhibitor studies","journal":"Molecular neurodegeneration","confidence":"High","confidence_rationale":"Tier 2 — reciprocal co-IP in both cell lines and brain with domain mapping and functional trafficking readout","pmids":["22429478"],"is_preprint":false},{"year":2013,"finding":"Syntaxin 5 (Stx5) interacts with the C-terminal domain of VLDLR and prevents its advanced Golgi maturation while enabling transport of ER-glycosylated VLDLR to the plasma membrane via a Golgi-bypass pathway; Stx5 overexpression significantly interferes with VLDLR reaching the trans-Golgi network.","method":"Co-immunoprecipitation, pull-down assays, BFA treatment, low-temperature trafficking experiments, Western blot for glycosylation state, plasma membrane localization assays","journal":"Experimental cell research","confidence":"Medium","confidence_rationale":"Tier 2–3 — multiple in vitro interaction and trafficking assays from a single laboratory","pmids":["23701949"],"is_preprint":false},{"year":2017,"finding":"VLDLR expression in adipose tissue macrophages promotes obesity-induced adipose tissue inflammation and glucose intolerance; VLDL treatment upregulates intracellular C16:0 ceramide levels in a VLDLR-dependent manner, potentiating pro-inflammatory M1-like macrophage polarization. Adoptive transfer of VLDLR knockout bone marrow to wild-type mice relieves adipose tissue inflammation and improves insulin resistance.","method":"VLDLR knockout mice, bone marrow adoptive transfer, ceramide measurement, macrophage polarization assays, glucose tolerance tests","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 2 — bone marrow transfer establishes macrophage-specific mechanism; ceramide measurement provides molecular mediator with VLDLR-dependent readout","pmids":["29057873"],"is_preprint":false},{"year":2019,"finding":"IDOL (E3 ubiquitin ligase) controls energy balance and diet-induced obesity through degradation of neuronal VLDLR rather than LDLR; loss of IDOL in neurons protects against diet-induced obesity, and VLDLR is identified as the primary IDOL substrate mediating this metabolic effect.","method":"Tissue-specific IDOL knockout mice, single-cell RNA sequencing of hypothalamus, Western blot for receptor levels, metabolic phenotyping","journal":"Nature metabolism","confidence":"High","confidence_rationale":"Tier 2 — tissue-specific knockouts with scRNA-seq identifying neuronal context; VLDLR identified as primary substrate over LDLR","pmids":["32072135"],"is_preprint":false},{"year":2017,"finding":"RELN C-terminal region (CTR) confers receptor-binding specificity; CTR truncation significantly decreases RELN binding to VLDLR (but not ApoER2), as shown by direct RELN-binding assay, and cortical neurons in CTR-mutant mice overmigrate into the marginal zone (phenotype similar to Vldlr-null mice). Genetic epistasis confirms RelnCTRdel/Apoer2null mice resemble reeler while RelnCTRdel/Vldlrnull do not.","method":"In vitro RELN-binding assay with VLDLR and ApoER2, genetic epistasis with double-mutant mice, BrdU fate mapping, cortical phenotyping","journal":"The Journal of neuroscience","confidence":"High","confidence_rationale":"Tier 1–2 — direct binding assay combined with rigorous genetic epistasis in multiple compound mutant backgrounds","pmids":["28123028"],"is_preprint":false},{"year":2020,"finding":"VLDLR is not required for Reelin-induced neuronal aggregation but suppresses neuronal invasion into the marginal zone via a cell-autonomous mechanism; rescue experiments implicate Rap1, integrin, and Akt as downstream mediators of VLDLR's stop-migration signal.","method":"Vldlr-mutant mice, ectopic Reelin overexpression, in utero electroporation rescue experiments, Rap1/integrin/Akt pathway analysis","journal":"Development (Cambridge, England)","confidence":"High","confidence_rationale":"Tier 2 — cell-autonomous rescue experiments with pathway identification using multiple genetic tools","pmids":["32540847"],"is_preprint":false},{"year":2014,"finding":"Fenofibrate (a PPARα agonist) markedly upregulates hepatic VLDLR transcription through a PPAR response element in the VLDLR promoter, and this induction is essential for the triglyceride-lowering effect of fenofibrate; Vldlr−/− mice fail to show the TG reduction in response to fenofibrate or high-fat diet VLDLR overexpression rescues the phenotype.","method":"Fenofibrate treatment of hyperlipidemic and diabetic mice, Vldlr−/− mice and Pparα−/− mice, hepatic VLDLR overexpression via adenovirus, PPRE-luciferase reporter assay","journal":"Journal of lipid research","confidence":"High","confidence_rationale":"Tier 1–2 — reporter assay defining transcriptional mechanism, validated in multiple knockout mouse models and with receptor rescue","pmids":["24899625"],"is_preprint":false},{"year":2011,"finding":"miR-200c targets Vldlr (and its ligand Reelin) to reduce epithelial proliferation during submandibular gland branching morphogenesis; loss- and gain-of-function of miR-200c alter proliferation through a Vldlr-dependent FGFR signaling mechanism.","method":"miRNA loss- and gain-of-function in mouse submandibular gland organ culture, miR-200c target prediction and validation, FGFR signaling readout","journal":"Development (Cambridge, England)","confidence":"Medium","confidence_rationale":"Tier 2–3 — loss- and gain-of-function with target validation but pathway placement relies on indirect evidence","pmids":["22115756"],"is_preprint":false},{"year":2018,"finding":"Disease-causing missense VLDLR mutants associated with Dysequilibrium syndrome are retained in the ER where they associate with calnexin, become ubiquitinated, and are degraded predominantly by the proteasomal pathway via interaction with the ER degradation adaptor SEL1L; SEL1L knockout (CRISPR/Cas9) delays degradation of both wild-type and mutant VLDLR.","method":"Co-immunoprecipitation with calnexin, ubiquitination assay with proteasome inhibitors, CRISPR/Cas9 SEL1L knockout, ER stress markers, protein aggregation assays","journal":"Scientific reports","confidence":"High","confidence_rationale":"Tier 1–2 — CRISPR knockout validation of SEL1L involvement combined with ubiquitination and co-IP assays","pmids":["29371607"],"is_preprint":false},{"year":2022,"finding":"VLDLR-mediated VLDL uptake in brown adipocytes provides lipid fuels for mitochondrial oxidation via lysosomal processing and activates PPARβ/δ to drive thermogenic gene expression; VLDLR knockout mice show impaired cold-induced thermogenesis, and brown-adipocyte-specific PPARβ/δ knockout attenuates VLDL-induced thermogenic capacity.","method":"VLDLR knockout mice, cold exposure experiments, lysosomal inhibitors, PPARβ/δ adipocyte-specific knockout mice, thermogenic gene expression assays","journal":"Cell reports","confidence":"High","confidence_rationale":"Tier 2 — tissue-specific knockouts combined with mechanistic lipid processing and transcription factor activation studies","pmids":["36516764"],"is_preprint":false},{"year":2023,"finding":"VLDLR acts as a receptor in cardiomyocytes consolidating opposing signals: thrombospondin-1 (TSP-1) inhibits cardiomyocyte proliferation through VLDLR via Rac1 and subsequent Yap phosphorylation/nuclear translocation, while Reelin (from cardiac Schwann cells and lymphatic endothelial cells) promotes proliferation through the same receptor. Cardiac-specific Vldlr deletion promotes cardiomyocyte proliferation and is cardioprotective after myocardial infarction.","method":"Receptor profiling in postnatal cardiomyocytes, cardiac-specific Vldlr knockout mice, Reln mutant mice, Thbs1 cardiac deletion, cardiomyocyte cell cycle assays, Rac1/Yap signaling assays, apical resection model","journal":"Basic research in cardiology","confidence":"High","confidence_rationale":"Tier 2 — tissue-specific knockouts with multiple ligands, defined downstream signaling cascade (Rac1/Yap), and in vivo cardiac injury models","pmids":["38147128"],"is_preprint":false},{"year":2009,"finding":"The VLDLR-III splice variant (lacking the third complement-type repeat, exon 4) exhibits the highest capacity for binding apoE-containing beta-VLDL in vitro and is more effective than other variants in removing apoE-containing lipoproteins from circulation in vivo; this exon 4-skipping is neuron-specific and absent in primary astrocytes.","method":"In vitro lipoprotein binding assays, in vivo lipoprotein clearance assays, RT-PCR of VLDLR splice variants in human cerebellum and mouse brain regions, primary neuron and astrocyte cultures","journal":"Brain research","confidence":"Medium","confidence_rationale":"Tier 2 — quantitative in vitro binding and in vivo clearance combined with cell-type-specific splicing analysis, single lab","pmids":["19393635"],"is_preprint":false},{"year":2013,"finding":"ApoER2 and VLDLr are required for Reelin-mediated migration and final positioning of mesencephalic dopaminergic (mDA) neurons in the substantia nigra, VTA, and retrorubral field; VLDLr−/− mice show a more pronounced reduction and mispositioning of mDA neurons than ApoER2−/− mice, and ApoER2/VLDLr double knockouts phenocopy Reelin and Dab1 mutants.","method":"Single and double receptor knockout mice, immunohistochemistry for dopaminergic neuron markers, neuronal counting and positioning analysis","journal":"PloS one","confidence":"High","confidence_rationale":"Tier 2 — genetic epistasis with single and double knockouts recapitulating full pathway loss-of-function phenotype","pmids":["23976984"],"is_preprint":false},{"year":2024,"finding":"SIRT1 attenuates hepatic lipid accumulation by suppressing VLDLR protein levels; SIRT1 loss increases VLDLR in a HIF-1α-dependent manner (not ER stress-dependent), and SIRT1 activation prevents ER stress-induced increases in hepatic VLDLR.","method":"Sirt1−/− mice, fructose-fed rat model, Huh-7 cells with SIRT1 siRNA/pharmacological inhibition, HIF-1α inhibitor, tunicamycin ER stress model with SIRT1 activator","journal":"Cell communication and signaling","confidence":"Medium","confidence_rationale":"Tier 2 — multiple genetic and pharmacological approaches converging on HIF-1α as mediator, but primary mechanism (direct vs indirect SIRT1 regulation of HIF-1α/VLDLR) not fully resolved","pmids":["38807218"],"is_preprint":false},{"year":2014,"finding":"A CRISPR-deleted intronic enhancer element spanning rs3780181 in VLDLR reduces VLDLR expression ~1.2-fold in HEK293T cells; the rs3780181-A risk allele (associated with increased TC/LDL-C) shows significantly less enhancer activity than the G allele, with differential binding to nuclear proteins including IRF2.","method":"CRISPR-Cas9 enhancer deletion, allele-specific luciferase reporter assay in HepG2/THP-1/SGBS cells, nuclear protein binding assay, eQTL analysis in liver","journal":"Human molecular genetics","confidence":"Medium","confidence_rationale":"Tier 1–2 — CRISPR deletion and allele-specific reporter assay with nuclear binding, but modest effect size and single lab","pmids":["30445632"],"is_preprint":false}],"current_model":"VLDLR is a multiligand lipoprotein receptor that functions as a co-receptor for Reelin (together with ApoER2), directly binding Reelin to trigger Dab1 tyrosine phosphorylation and downstream PI3K/Akt, Rac1/Yap, and cytoskeletal signaling cascades that govern neuronal migration, cortical layer formation, and dendrite development; its surface levels are post-translationally controlled by PCSK9-mediated lysosomal degradation and IDOL/LXR-induced ubiquitination of its cytoplasmic tail, while its transcription is activated by HIF-1α under hypoxia and PPARα/β/δ agonists; in the periphery VLDLR mediates VLDL lipid uptake driving thermogenesis, adipogenesis, and macrophage ceramide-dependent inflammation; it also serves as the entry receptor for multiple encephalitic alphaviruses (SFV, EEEV, WEEV) through interactions of viral E1/E2 glycoproteins with its LDLR class A ligand-binding repeats; and loss-of-function mutations in humans cause VLDLR-associated cerebellar hypoplasia (dysequilibrium syndrome) consistent with its Reelin-signaling role in brain development."},"narrative":{"teleology":[{"year":2003,"claim":"Establishing that Reelin directly binds VLDLR and ApoER2 to induce Dab1 phosphorylation resolved the identity of the obligate neuronal Reelin receptors and showed no other receptor can substitute.","evidence":"Purified Reelin binding assays and Dab1 phosphorylation in cortical neurons from single/double receptor knockout mice","pmids":["12670700"],"confidence":"High","gaps":["Structural basis of Reelin–VLDLR interaction not yet defined","Relative affinity contributions of each receptor unclear","Downstream signaling cascades beyond Dab1 not mapped"]},{"year":2004,"claim":"Demonstrating that Reelin promotes dendrite development through VLDLR/ApoER2–Dab1 extended the pathway's role beyond migration to post-migratory neuronal maturation.","evidence":"Pharmacological receptor blockade, Dab1 phosphorylation inhibitors, and recombinant Reelin rescue in hippocampal cultures and reeler mice","pmids":["14715136"],"confidence":"High","gaps":["Which downstream effectors of Dab1 mediate dendrite outgrowth specifically","Whether VLDLR and ApoER2 contribute equally to this phenotype"]},{"year":2007,"claim":"Genetic epistasis revealed that VLDLR specifically provides a stop signal for migrating neurons (preventing marginal zone invasion), while ApoER2 is needed for late-born neuron migration — establishing non-redundant receptor functions in cortical lamination.","evidence":"BrdU fate mapping and layer-specific markers in Vldlr−/−, ApoER2−/−, and double knockout mice; Pafah1b complex interaction mapped to VLDLR NPxYL motif with compound mutant epistasis","pmids":["17913789","17330141"],"confidence":"High","gaps":["Molecular basis distinguishing VLDLR stop signal from ApoER2 migration signal","Whether Pafah1b complex is sufficient for the VLDLR-specific stop signal"]},{"year":2007,"claim":"Discovery that PCSK9 degrades VLDLR through a catalytic-activity-independent mechanism identified the first post-translational pathway controlling VLDLR surface levels.","evidence":"Co-expression, secreted PCSK9 re-internalization, catalytic-dead mutant, and membrane-bound chimeras targeting VLDLR to lysosomes","pmids":["18039658"],"confidence":"High","gaps":["Which VLDLR extracellular domain contacts PCSK9","In vivo tissue-specific consequences beyond adipocytes not yet tested"]},{"year":2010,"claim":"Identification of IDOL as an LXR-induced E3 ligase that ubiquitinates the VLDLR cytoplasmic tail established a second, transcription-coupled degradation axis and showed it attenuates Reelin–Dab1 signaling.","evidence":"Ubiquitination assays, LXR agonist treatment in vivo, Reelin binding and Dab1 phosphorylation readouts","pmids":["20427281"],"confidence":"High","gaps":["Specific lysine residues ubiquitinated on VLDLR tail not mapped","Relative contribution of IDOL vs PCSK9 in different tissues"]},{"year":2011,"claim":"Multiple studies expanded VLDLR biology beyond Reelin: circulating PCSK9 regulates adipocyte VLDLR in vivo; VLDLR serves as a fibrin receptor for leukocyte transmigration; and a disease-causing VLDLR truncation mutation abolishes plasma membrane localization and retinal antiangiogenic function.","evidence":"Liver-specific PCSK9 manipulation in Pcsk9−/−/Ldlr−/− mice; SPR binding and transmigration assays in VLDLR-deficient mice; linkage/allelic complementation in Vldlr−/− mice with immunofluorescence of mutant protein","pmids":["21273557","22096238","21757581"],"confidence":"High","gaps":["Fibrin β-domain binding site on VLDLR not structurally resolved","Whether antiangiogenic signaling uses Dab1 or a distinct pathway"]},{"year":2012,"claim":"HIF-1α was shown to directly activate VLDLR transcription through a functional HRE, explaining hypoxia-induced lipid accumulation and later providing the basis for hypoxia-dependent viral receptor expression.","evidence":"ChIP, dual-luciferase HRE reporter, HIF1A/VLDLR siRNA, lipid uptake under hypoxia","pmids":["21970364"],"confidence":"High","gaps":["Whether HIF-1α–VLDLR axis operates in brain under physiological hypoxia","Interaction with other VLDLR transcriptional regulators (PPARs) under combined stimuli"]},{"year":2012,"claim":"FE65 was identified as a cytoplasmic adaptor linking VLDLR to APP via its PTB1 domain, modulating VLDLR surface levels and shedding, thus connecting Reelin receptor trafficking to amyloid precursor protein processing.","evidence":"Reciprocal co-IP in COS7 cells and brain lysates, cell-surface biotinylation, domain mapping, proteasome inhibitor studies","pmids":["22429478"],"confidence":"High","gaps":["Physiological relevance of FE65-mediated VLDLR–APP linkage in neurodegeneration not tested in vivo","Whether FE65 competes with Dab1 for NPxY binding"]},{"year":2014,"claim":"PPARα was shown to directly transactivate the VLDLR promoter, and hepatic VLDLR induction proved essential for the triglyceride-lowering effect of fenofibrate, establishing VLDLR as a pharmacologically relevant lipid-clearance receptor in the liver.","evidence":"PPRE-reporter assays, fenofibrate treatment of Vldlr−/− and Pparα−/− mice, adenoviral VLDLR rescue","pmids":["24899625"],"confidence":"High","gaps":["Whether hepatic VLDLR induction contributes to fenofibrate-associated hepatic steatosis","Relative roles of VLDLR vs LDLR in hepatic remnant clearance"]},{"year":2017,"claim":"The Reelin C-terminal region was shown to confer receptor-binding specificity for VLDLR over ApoER2, and VLDLR-dependent VLDL uptake in adipose macrophages was found to drive ceramide-mediated inflammatory polarization, linking VLDLR to metabolic inflammation.","evidence":"RELN-binding assays with CTR truncation, genetic epistasis in compound mutant mice; VLDLR KO bone marrow transplant, ceramide measurements, macrophage polarization","pmids":["28123028","29057873"],"confidence":"High","gaps":["Structural determinant of Reelin CTR–VLDLR specificity not resolved","Whether ceramide signaling feeds back to regulate VLDLR expression"]},{"year":2018,"claim":"Disease-causing VLDLR missense mutations were shown to cause ER retention, calnexin association, and SEL1L-dependent proteasomal degradation, defining the proteostatic fate of pathogenic VLDLR variants.","evidence":"Co-IP with calnexin, ubiquitination assays, CRISPR SEL1L knockout delaying mutant and WT VLDLR degradation","pmids":["29371607"],"confidence":"High","gaps":["Whether ER stress from accumulated mutant VLDLR contributes to cerebellar pathology","Proteostatic handling of VLDLR in neurons vs non-neuronal cells"]},{"year":2019,"claim":"Neuronal IDOL was found to control energy balance primarily through VLDLR (not LDLR) degradation, establishing VLDLR as a metabolically active receptor in hypothalamic neurons.","evidence":"Neuron-specific IDOL knockout mice, scRNA-seq of hypothalamus, metabolic phenotyping","pmids":["32072135"],"confidence":"High","gaps":["What ligand(s) VLDLR transduces in hypothalamic energy sensing","Whether neuronal VLDLR signals through Dab1 or alternative pathways in this context"]},{"year":2020,"claim":"Rescue experiments in Vldlr-mutant cortex showed that VLDLR's stop-migration signal is cell-autonomous and mediated by Rap1/integrin/Akt, distinguishing it from Reelin-induced neuronal aggregation which does not require VLDLR.","evidence":"In utero electroporation rescue in Vldlr mutants, ectopic Reelin overexpression, Rap1/integrin/Akt pathway dissection","pmids":["32540847"],"confidence":"High","gaps":["How Rap1 activation is mechanistically linked to Dab1 phosphorylation downstream of VLDLR","Whether the same pathway operates in non-cortical neurons"]},{"year":2021,"claim":"VLDLR was identified as the entry receptor for multiple encephalitic alphaviruses (SFV, EEEV, Sindbis), with viral E2–E1 engaging the VLDLR ligand-binding domain — a finding exploited to block infection in vivo with LBD-Fc decoys.","evidence":"Ectopic expression, VLP internalization, LBD-Fc competition and in vivo neonatal mouse protection, invertebrate orthologue functional assays","pmids":["34929721"],"confidence":"High","gaps":["Atomic details of virus–receptor interaction not yet resolved","Whether VLDLR mediates viral entry in all susceptible cell types"]},{"year":2022,"claim":"VLDLR-mediated VLDL uptake in brown adipocytes was shown to fuel mitochondrial oxidation via lysosomal lipid processing and to activate PPARβ/δ-driven thermogenic gene expression, establishing VLDLR as a metabolic sensor in thermogenesis.","evidence":"Vldlr KO mice with cold exposure, lysosomal inhibitors, brown-adipocyte-specific PPARβ/δ KO","pmids":["36516764"],"confidence":"High","gaps":["Identity of specific lipid species activating PPARβ/δ downstream of VLDLR-mediated uptake","Contribution of VLDLR vs other lipoprotein receptors in BAT under thermoneutral conditions"]},{"year":2023,"claim":"Cryo-EM structures of SFV–VLDLR revealed that multiple LA repeats (especially LA3) engage E1-DIII through salt bridges, with consecutive repeats rotating to enable multivalent binding — providing the first atomic-level view of VLDLR's virus-receptor interface and explaining its broad alphavirus tropism.","evidence":"Cryo-EM structure, individual LA repeat binding affinity measurements, mutagenesis","pmids":["37098345"],"confidence":"High","gaps":["How pH-dependent conformational changes in endosomes release virus from VLDLR","Whether LA repeat engagement differs for physiological ligands like Reelin"]},{"year":2023,"claim":"In cardiomyocytes, VLDLR integrates opposing proliferative signals — Reelin promotes and thrombospondin-1 inhibits proliferation — through a Rac1/Yap axis, and cardiac-specific Vldlr deletion is cardioprotective after infarction.","evidence":"Cardiac-specific Vldlr KO, Reln mutant and Thbs1 cardiac deletion mice, cardiomyocyte cell cycle and Rac1/Yap signaling assays, apical resection model","pmids":["38147128"],"confidence":"High","gaps":["How TSP-1 and Reelin compete or cooperate at the VLDLR ectodomain","Whether Dab1 is involved in cardiomyocyte VLDLR signaling"]},{"year":2024,"claim":"Cryo-EM structures of EEEV–VLDLR defined three distinct binding sites and showed that no single LA domain is necessary, enabling design of minimal decoy receptors that neutralize EEEV in vivo; the W132G human SNP was found to enhance EEEV attachment by switching binding modes.","evidence":"Multiple cryo-EM structures, mutagenesis, infection assays, in vivo decoy protection, W132G variant binding and attachment assays","pmids":["38176410","39127734"],"confidence":"High","gaps":["Population-level significance of W132G for EEEV susceptibility","Whether decoy receptors based on VLDLR can achieve therapeutic neutralization against diverse alphaviruses"]},{"year":2024,"claim":"SFV neuroinvasion was shown to be strictly VLDLR-dependent, occurring specifically through infection of choroid plexus epithelial cells at the blood-CSF barrier, which express high VLDLR levels.","evidence":"VLDLR-deficient mice with intravenous SFV challenge, tissue-specific expression analysis, histological route-of-entry characterization","pmids":["39715740"],"confidence":"High","gaps":["Whether other neurotropic viruses exploit VLDLR at the choroid plexus","Cell-type-specific VLDLR regulation in choroid plexus epithelium"]},{"year":null,"claim":"Key unresolved questions include: (1) the structural basis of Reelin–VLDLR binding and how it differs from viral glycoprotein engagement; (2) how VLDLR signaling is decoded differently across cell types (neurons, cardiomyocytes, macrophages, brown adipocytes); (3) the precise mechanism by which VLDLR integrates opposing ligand signals (Reelin vs TSP-1) through shared downstream effectors.","evidence":"","pmids":[],"confidence":"High","gaps":["No Reelin–VLDLR co-structure available","Cell-type-specific adaptor usage not systematically compared","In vivo relevance of multiple VLDLR splice variants incompletely characterized"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0038024","term_label":"cargo receptor activity","supporting_discovery_ids":[0,9,10,12,26]},{"term_id":"GO:0008289","term_label":"lipid binding","supporting_discovery_ids":[26,28]},{"term_id":"GO:0001618","term_label":"virus receptor activity","supporting_discovery_ids":[12,13,14,15,16]},{"term_id":"GO:0060089","term_label":"molecular transducer activity","supporting_discovery_ids":[0,1,22,27]}],"localization":[{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[0,5,8,10,12]},{"term_id":"GO:0005768","term_label":"endosome","supporting_discovery_ids":[2]},{"term_id":"GO:0005783","term_label":"endoplasmic reticulum","supporting_discovery_ids":[25]}],"pathway":[{"term_id":"R-HSA-1266738","term_label":"Developmental Biology","supporting_discovery_ids":[0,1,4,22,29]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[0,1,9,22,27]},{"term_id":"R-HSA-1430728","term_label":"Metabolism","supporting_discovery_ids":[23,26,28]},{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[10,19]},{"term_id":"R-HSA-1643685","term_label":"Disease","supporting_discovery_ids":[12,13,14,15,16]},{"term_id":"R-HSA-392499","term_label":"Metabolism of proteins","supporting_discovery_ids":[2,3,25]}],"complexes":[],"partners":["RELN","DAB1","APOER2","PCSK9","IDOL","FE65","CLU","SEL1L"],"other_free_text":[]},"mechanistic_narrative":"VLDLR is a multiligand lipoprotein receptor that serves as a core component of the Reelin signaling pathway, directly binding Reelin (with specificity conferred by the Reelin C-terminal region) and clusterin to trigger Dab1 tyrosine phosphorylation and downstream PI3K/Akt, Rap1/integrin, and Rac1/Yap cascades that govern neuronal migration, cortical lamination, dendrite development, and cardiomyocyte proliferation [PMID:12670700, PMID:14715136, PMID:24381170, PMID:28123028, PMID:38147128]. VLDLR provides a cell-autonomous stop signal for migrating cortical neurons distinct from the migration-promoting role of ApoER2, and is required for positioning of mesencephalic dopaminergic neurons and suppression of retinal angiogenesis [PMID:17913789, PMID:32540847, PMID:23976984, PMID:21757581]. Cell-surface VLDLR levels are tightly regulated by PCSK9-mediated lysosomal degradation, IDOL/LXR-induced ubiquitination of its cytoplasmic tail, SEL1L-dependent ER-associated degradation of misfolded mutants, and transcriptional control by HIF-1α under hypoxia and PPARα agonists [PMID:18039658, PMID:20427281, PMID:29371607, PMID:21970364, PMID:24899625]. In the periphery VLDLR mediates VLDL lipid uptake driving brown adipocyte thermogenesis and macrophage ceramide-dependent inflammation, serves as a fibrin receptor supporting leukocyte transmigration, and functions as the entry receptor for encephalitic alphaviruses (SFV, EEEV) and HCV through engagement of its LDLR class A repeats with viral glycoproteins, as defined by cryo-EM structures [PMID:36516764, PMID:29057873, PMID:34929721, PMID:37098345, PMID:38176410, PMID:26699506]."},"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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triglyceride accumulation in visceral adipose tissue.","date":"2011","source":"Arteriosclerosis, thrombosis, and vascular biology","url":"https://pubmed.ncbi.nlm.nih.gov/21273557","citation_count":211,"is_preprint":false},{"pmid":"16384981","id":"PMC_16384981","title":"Functional candidate genes in age-related macular degeneration: significant association with VEGF, VLDLR, and LRP6.","date":"2006","source":"Investigative ophthalmology & visual science","url":"https://pubmed.ncbi.nlm.nih.gov/16384981","citation_count":152,"is_preprint":false},{"pmid":"17913789","id":"PMC_17913789","title":"Divergent roles of ApoER2 and Vldlr in the migration of cortical neurons.","date":"2007","source":"Development (Cambridge, England)","url":"https://pubmed.ncbi.nlm.nih.gov/17913789","citation_count":134,"is_preprint":false},{"pmid":"20427281","id":"PMC_20427281","title":"The E3 ubiquitin ligase IDOL induces the degradation of the low density lipoprotein receptor family members VLDLR and ApoER2.","date":"2010","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/20427281","citation_count":116,"is_preprint":false},{"pmid":"21364932","id":"PMC_21364932","title":"Nanoceria inhibit the development and promote the regression of pathologic retinal neovascularization in the Vldlr knockout mouse.","date":"2011","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/21364932","citation_count":109,"is_preprint":false},{"pmid":"34929721","id":"PMC_34929721","title":"VLDLR and ApoER2 are receptors for multiple alphaviruses.","date":"2021","source":"Nature","url":"https://pubmed.ncbi.nlm.nih.gov/34929721","citation_count":105,"is_preprint":false},{"pmid":"18172119","id":"PMC_18172119","title":"Expression of VLDLR in the retina and evolution of subretinal neovascularization in the knockout mouse model's retinal angiomatous proliferation.","date":"2008","source":"Investigative ophthalmology & visual 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Neurons lacking both ApoER2 and VLDLR show a complete absence of Reelin-induced Dab1 phosphorylation, demonstrating that no other receptor can compensate for their role.\",\n      \"method\": \"Purified Reelin binding assays, cortical neuron cultures from single and double receptor knockout mice, Dab1 phosphorylation assays, layer-specific marker fate mapping\",\n      \"journal\": \"Brain research. Molecular brain research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 — purified protein binding assay combined with genetic knockout and phosphorylation readout; findings replicated across multiple mutant genotypes\",\n      \"pmids\": [\"12670700\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"Reelin promotes hippocampal dendrite development through the VLDLR/ApoER2–Dab1 signaling pathway; addition of Reelin receptor antagonists or Dab1 phosphorylation inhibitors prevents dendrite outgrowth, and recombinant Reelin rescues the deficit in reeler cultures.\",\n      \"method\": \"In vivo analysis of reeler and receptor-mutant mice, dissociated hippocampal cultures, Reelin-blocking antibodies, receptor antagonists, Dab1 phosphorylation inhibitors, recombinant Reelin rescue\",\n      \"journal\": \"Neuron\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal pharmacological and genetic loss-of-function approaches with defined cellular phenotype in vivo and in vitro\",\n      \"pmids\": [\"14715136\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"PCSK9 induces degradation of VLDLR (as well as LDLR and ApoER2). Wild-type PCSK9 and its gain-of-function mutant D374Y degrade VLDLR either through co-expression or re-internalization of secreted PCSK9; this degradation does not require PCSK9 catalytic activity and is enhanced by membrane-bound PCSK9 chimeras that target the receptor to late endosomes/lysosomes.\",\n      \"method\": \"Cellular co-expression, secreted PCSK9 re-internalization, membrane-bound PCSK9 chimeras, catalytic-dead mutant analysis, subcellular localization by immunofluorescence\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 — multiple mechanistic approaches including gain-of-function mutant, chimeric constructs, and catalytic dead mutant with defined degradation readout\",\n      \"pmids\": [\"18039658\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"The E3 ubiquitin ligase IDOL ubiquitinates the cytoplasmic tail of VLDLR, leading to its degradation. IDOL expression is induced by liver X receptor (LXR) activation, and 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, LXR agonist treatment in vivo and in vitro, Reelin binding assay, Dab1 phosphorylation assay, Western blotting\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 — direct ubiquitination assay with defined cytoplasmic tail target, in vivo pharmacological validation, and downstream signaling readout\",\n      \"pmids\": [\"20427281\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"Vldlr mediates a stop signal for migrating cortical neurons, whereas ApoER2 is essential for migration of late-generated neocortical neurons; fate mapping in single and double receptor knockout mice revealed divergent roles for the two Reelin receptors in radial neuronal migration.\",\n      \"method\": \"BrdU fate mapping, layer-specific markers in single and double receptor knockout mice\",\n      \"journal\": \"Development (Cambridge, England)\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — genetic epistasis with BrdU fate mapping in multiple single and double knockout genotypes\",\n      \"pmids\": [\"17913789\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"Circulating PCSK9 originating from the liver regulates VLDLR protein levels on the surface of visceral adipocytes in vivo; liver-specific PCSK9 expression or inactivation modulates perigonadal VLDLR levels independently of LDLR.\",\n      \"method\": \"Immunohistochemistry in Pcsk9−/− mice, Pcsk9−/−Ldlr−/− mice, liver-specific PCSK9 expression and inactivation, in vivo fatty acid uptake assays\",\n      \"journal\": \"Arteriosclerosis, thrombosis, and vascular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — tissue-specific genetic and adenoviral manipulation with quantitative cell-surface receptor measurement in multiple mouse models\",\n      \"pmids\": [\"21273557\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"The Pafah1b complex catalytic subunits Pafah1b2 and Pafah1b3 specifically bind to the NPxYL sequence of VLDLR (but not ApoER2), and genetic epistasis shows that compound Pafah1b1+/−;Apoer2−/− mice display a reeler-like forebrain phenotype while Pafah1b1+/−;Vldlr−/− double mutants do not, placing Pafah1b complex function downstream of VLDLR in cortical layer formation.\",\n      \"method\": \"Binding assays identifying NPxYL interaction, compound mouse genetic epistasis analysis, cortical layer phenotyping\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — direct protein–receptor interaction mapped to a specific motif, combined with genetic epistasis in multiple compound mutant lines\",\n      \"pmids\": [\"17330141\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"HIF-1α directly activates VLDLR gene transcription under hypoxia through a functional hypoxia-response element (HRE) at +405 in exon 1 of VLDLR, leading to increased LDL and VLDL uptake and intracellular lipid accumulation; HIF-2α is not involved.\",\n      \"method\": \"Dual-luciferase reporter assay, chromatin immunoprecipitation (ChIP), HIF1A/VLDLR siRNA knockdown, lipid uptake assays under hypoxia\",\n      \"journal\": \"The Biochemical journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 — ChIP and reporter assay confirming functional HRE, combined with siRNA knockdown and functional lipid uptake readout\",\n      \"pmids\": [\"21970364\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"VLDLR on retinal endothelial cell and RPE surfaces mediates an antiangiogenic signal that prevents retinal endothelial cells from migrating into the photoreceptor layer; a missense mutation (c.2239C>T) causing C-terminal truncation abolishes plasma membrane localization of VLDLR, resulting in loss of this antiangiogenic function.\",\n      \"method\": \"Genome-wide linkage, DNA sequencing, allelic complementation test with Vldlr−/− mice, Western blot, transient transfection with wild-type and mutant Vldlr, immunofluorescence localization\",\n      \"journal\": \"Investigative ophthalmology & visual science\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 — mutation identified and functionally validated by allelic test in knockout mice, with direct demonstration of mislocalization of truncated protein\",\n      \"pmids\": [\"21757581\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"Clusterin binds directly to VLDLR (and ApoER2) and is internalized by cells expressing either receptor; clusterin binding triggers a Reelin-like signal including phosphorylation of Dab1 and activation of PI3K/Akt and n-cofilin.\",\n      \"method\": \"Binding assays, internalization assays, Dab1 phosphorylation assay, PI3K/Akt activation assays, SVZ explant cultures with clusterin blocking\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — direct binding and internalization demonstrated with downstream signaling readouts using multiple methods\",\n      \"pmids\": [\"24381170\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"VLDLR functions as a novel endothelial cell receptor for fibrin, interacting with fibrin through fibrin βN-domains with high affinity; this interaction is inhibited by receptor-associated protein (RAP). VLDLR-deficient mice fail to support fibrin-dependent leukocyte transmigration, demonstrating a role for VLDLR in fibrin-dependent inflammation.\",\n      \"method\": \"ELISA, surface plasmon resonance, transendothelial migration assays with RAP inhibitor, VLDLR-deficient mouse in vivo transmigration assays\",\n      \"journal\": \"Blood\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 — SPR quantitative binding assay combined with in vitro and in vivo (knockout mouse) functional validation\",\n      \"pmids\": [\"22096238\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"VLDLR mediates hepatitis C virus (HCV) entry into hepatocytes independently of CD81; hypoxia-induced VLDLR expression confers HCV susceptibility to CD81-deficient cells, and ectopic VLDLR expression is sufficient for HCV entry.\",\n      \"method\": \"Hypoxic cell culture, CD81-deficient cell transduction with VLDLR, HCV infectivity assays, knockdown of known HCV entry factors\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — ectopic expression conferring susceptibility and knockdown studies with CD81-independent entry demonstrated in defined cell systems\",\n      \"pmids\": [\"26699506\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"VLDLR (and ApoER2) acts as an entry receptor for 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, and a VLDLR LBD-Fc fusion protein blocks infection and protects neonatal mice against lethal SFV challenge. Invertebrate VLDLR orthologues from mosquitoes and worms also function as alphavirus receptors.\",\n      \"method\": \"Ectopic expression assays, virus-like particle internalization, VLDLR LBD-Fc fusion protein competition/protection assays, in vivo mouse challenge model, invertebrate ortholog expression\",\n      \"journal\": \"Nature\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 — receptor identification with functional competition assay and in vivo protection; multiple viral species and host orthologs tested\",\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 the virion through its membrane-distal LDLR class A (LA) repeats; LA3 has the highest binding affinity (interacting through salt bridges over 378 Ų surface area), and consecutive LA repeats undergo rotation to enable synergistic binding at multiple sites simultaneously.\",\n      \"method\": \"Cryo-electron microscopy structure determination, binding affinity measurements for individual LA repeats, mutagenesis\",\n      \"journal\": \"Cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — high-resolution cryo-EM structure with mutagenesis and binding affinity validation\",\n      \"pmids\": [\"37098345\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"Cryo-EM structures of EEEV-VLDLR complexes show EEEV uses two distinct sites on E1/E2 (E1/E2 cleft and E2 A domain) to engage more than one LA domain simultaneously; no single LA domain is necessary or sufficient for efficient EEEV infection. A minimal VLDLR decoy receptor designed from these structures neutralizes EEEV and protects mice from lethal challenge.\",\n      \"method\": \"Multiple cryo-EM structures, mutagenesis of binding sites, functional infection assays, in vivo mouse protection assays with decoy receptor\",\n      \"journal\": \"Cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — multiple cryo-EM structures with mutagenesis and in vivo functional validation\",\n      \"pmids\": [\"38176410\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"Cryo-EM structural studies of EEEV-VLDLR identify three distinct binding sites (A, B, C) on EEEV engaged by different VLDLR LA repeats; the W132G variant of VLDLR impairs LA3 binding, switches binding modes, and significantly enhances EEEV cell attachment, suggesting this human SNP could confer heightened EEEV susceptibility.\",\n      \"method\": \"Cryo-EM structure determination, biochemical binding studies, cell attachment assays with wild-type and W132G mutant VLDLR\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — cryo-EM structures combined with mutagenesis and functional cell attachment assays\",\n      \"pmids\": [\"39127734\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"SFV neuroinvasion is strictly dependent on VLDLR; SFV primarily enters the CNS through the blood-cerebrospinal fluid (B-CSF) barrier by infecting choroid plexus epithelial cells, which express distinctly high levels of VLDLR.\",\n      \"method\": \"In vivo VLDLR-deficient mouse model, intravenous SFV administration, tissue-specific VLDLR expression analysis, histological characterization of infection route\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — receptor-deficient mouse model with defined route-of-entry phenotype and supporting expression data\",\n      \"pmids\": [\"39715740\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"FE65 interacts with VLDLR via its PTB1 domain (shown by GST pull-down and co-immunoprecipitation in COS7 cells and brain lysates), increases cell-surface levels of VLDLR and shedding of soluble VLDLR, promotes proteasomal degradation of the VLDLR C-terminal fragment, and acts as a linker between VLDLR and APP, altering trafficking and processing of both proteins.\",\n      \"method\": \"GST pull-down, co-immunoprecipitation in cell lines and brain lysates, cell-surface biotinylation, FE65 co-transfection with domain mutants, proteasome inhibitor studies\",\n      \"journal\": \"Molecular neurodegeneration\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — reciprocal co-IP in both cell lines and brain with domain mapping and functional trafficking readout\",\n      \"pmids\": [\"22429478\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"Syntaxin 5 (Stx5) interacts with the C-terminal domain of VLDLR and prevents its advanced Golgi maturation while enabling transport of ER-glycosylated VLDLR to the plasma membrane via a Golgi-bypass pathway; Stx5 overexpression significantly interferes with VLDLR reaching the trans-Golgi network.\",\n      \"method\": \"Co-immunoprecipitation, pull-down assays, BFA treatment, low-temperature trafficking experiments, Western blot for glycosylation state, plasma membrane localization assays\",\n      \"journal\": \"Experimental cell research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 — multiple in vitro interaction and trafficking assays from a single laboratory\",\n      \"pmids\": [\"23701949\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"VLDLR expression in adipose tissue macrophages promotes obesity-induced adipose tissue inflammation and glucose intolerance; VLDL treatment upregulates intracellular C16:0 ceramide levels in a VLDLR-dependent manner, potentiating pro-inflammatory M1-like macrophage polarization. Adoptive transfer of VLDLR knockout bone marrow to wild-type mice relieves adipose tissue inflammation and improves insulin resistance.\",\n      \"method\": \"VLDLR knockout mice, bone marrow adoptive transfer, ceramide measurement, macrophage polarization assays, glucose tolerance tests\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — bone marrow transfer establishes macrophage-specific mechanism; ceramide measurement provides molecular mediator with VLDLR-dependent readout\",\n      \"pmids\": [\"29057873\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"IDOL (E3 ubiquitin ligase) controls energy balance and diet-induced obesity through degradation of neuronal VLDLR rather than LDLR; loss of IDOL in neurons protects against diet-induced obesity, and VLDLR is identified as the primary IDOL substrate mediating this metabolic effect.\",\n      \"method\": \"Tissue-specific IDOL knockout mice, single-cell RNA sequencing of hypothalamus, Western blot for receptor levels, metabolic phenotyping\",\n      \"journal\": \"Nature metabolism\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — tissue-specific knockouts with scRNA-seq identifying neuronal context; VLDLR identified as primary substrate over LDLR\",\n      \"pmids\": [\"32072135\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"RELN C-terminal region (CTR) confers receptor-binding specificity; CTR truncation significantly decreases RELN binding to VLDLR (but not ApoER2), as shown by direct RELN-binding assay, and cortical neurons in CTR-mutant mice overmigrate into the marginal zone (phenotype similar to Vldlr-null mice). Genetic epistasis confirms RelnCTRdel/Apoer2null mice resemble reeler while RelnCTRdel/Vldlrnull do not.\",\n      \"method\": \"In vitro RELN-binding assay with VLDLR and ApoER2, genetic epistasis with double-mutant mice, BrdU fate mapping, cortical phenotyping\",\n      \"journal\": \"The Journal of neuroscience\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 — direct binding assay combined with rigorous genetic epistasis in multiple compound mutant backgrounds\",\n      \"pmids\": [\"28123028\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"VLDLR is not required for Reelin-induced neuronal aggregation but suppresses neuronal invasion into the marginal zone via a cell-autonomous mechanism; rescue experiments implicate Rap1, integrin, and Akt as downstream mediators of VLDLR's stop-migration signal.\",\n      \"method\": \"Vldlr-mutant mice, ectopic Reelin overexpression, in utero electroporation rescue experiments, Rap1/integrin/Akt pathway analysis\",\n      \"journal\": \"Development (Cambridge, England)\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — cell-autonomous rescue experiments with pathway identification using multiple genetic tools\",\n      \"pmids\": [\"32540847\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"Fenofibrate (a PPARα agonist) markedly upregulates hepatic VLDLR transcription through a PPAR response element in the VLDLR promoter, and this induction is essential for the triglyceride-lowering effect of fenofibrate; Vldlr−/− mice fail to show the TG reduction in response to fenofibrate or high-fat diet VLDLR overexpression rescues the phenotype.\",\n      \"method\": \"Fenofibrate treatment of hyperlipidemic and diabetic mice, Vldlr−/− mice and Pparα−/− mice, hepatic VLDLR overexpression via adenovirus, PPRE-luciferase reporter assay\",\n      \"journal\": \"Journal of lipid research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 — reporter assay defining transcriptional mechanism, validated in multiple knockout mouse models and with receptor rescue\",\n      \"pmids\": [\"24899625\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"miR-200c targets Vldlr (and its ligand Reelin) to reduce epithelial proliferation during submandibular gland branching morphogenesis; loss- and gain-of-function of miR-200c alter proliferation through a Vldlr-dependent FGFR signaling mechanism.\",\n      \"method\": \"miRNA loss- and gain-of-function in mouse submandibular gland organ culture, miR-200c target prediction and validation, FGFR signaling readout\",\n      \"journal\": \"Development (Cambridge, England)\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 — loss- and gain-of-function with target validation but pathway placement relies on indirect evidence\",\n      \"pmids\": [\"22115756\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"Disease-causing missense VLDLR mutants associated with Dysequilibrium syndrome are retained in the ER where they associate with calnexin, become ubiquitinated, and are degraded predominantly by the proteasomal pathway via interaction with the ER degradation adaptor SEL1L; SEL1L knockout (CRISPR/Cas9) delays degradation of both wild-type and mutant VLDLR.\",\n      \"method\": \"Co-immunoprecipitation with calnexin, ubiquitination assay with proteasome inhibitors, CRISPR/Cas9 SEL1L knockout, ER stress markers, protein aggregation assays\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 — CRISPR knockout validation of SEL1L involvement combined with ubiquitination and co-IP assays\",\n      \"pmids\": [\"29371607\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"VLDLR-mediated VLDL uptake in brown adipocytes provides lipid fuels for mitochondrial oxidation via lysosomal processing and activates PPARβ/δ to drive thermogenic gene expression; VLDLR knockout mice show impaired cold-induced thermogenesis, and brown-adipocyte-specific PPARβ/δ knockout attenuates VLDL-induced thermogenic capacity.\",\n      \"method\": \"VLDLR knockout mice, cold exposure experiments, lysosomal inhibitors, PPARβ/δ adipocyte-specific knockout mice, thermogenic gene expression assays\",\n      \"journal\": \"Cell reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — tissue-specific knockouts combined with mechanistic lipid processing and transcription factor activation studies\",\n      \"pmids\": [\"36516764\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"VLDLR acts as a receptor in cardiomyocytes consolidating opposing signals: thrombospondin-1 (TSP-1) inhibits cardiomyocyte proliferation through VLDLR via Rac1 and subsequent Yap phosphorylation/nuclear translocation, while Reelin (from cardiac Schwann cells and lymphatic endothelial cells) promotes proliferation through the same receptor. Cardiac-specific Vldlr deletion promotes cardiomyocyte proliferation and is cardioprotective after myocardial infarction.\",\n      \"method\": \"Receptor profiling in postnatal cardiomyocytes, cardiac-specific Vldlr knockout mice, Reln mutant mice, Thbs1 cardiac deletion, cardiomyocyte cell cycle assays, Rac1/Yap signaling assays, apical resection model\",\n      \"journal\": \"Basic research in cardiology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — tissue-specific knockouts with multiple ligands, defined downstream signaling cascade (Rac1/Yap), and in vivo cardiac injury models\",\n      \"pmids\": [\"38147128\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"The VLDLR-III splice variant (lacking the third complement-type repeat, exon 4) exhibits the highest capacity for binding apoE-containing beta-VLDL in vitro and is more effective than other variants in removing apoE-containing lipoproteins from circulation in vivo; this exon 4-skipping is neuron-specific and absent in primary astrocytes.\",\n      \"method\": \"In vitro lipoprotein binding assays, in vivo lipoprotein clearance assays, RT-PCR of VLDLR splice variants in human cerebellum and mouse brain regions, primary neuron and astrocyte cultures\",\n      \"journal\": \"Brain research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — quantitative in vitro binding and in vivo clearance combined with cell-type-specific splicing analysis, single lab\",\n      \"pmids\": [\"19393635\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"ApoER2 and VLDLr are required for Reelin-mediated migration and final positioning of mesencephalic dopaminergic (mDA) neurons in the substantia nigra, VTA, and retrorubral field; VLDLr−/− mice show a more pronounced reduction and mispositioning of mDA neurons than ApoER2−/− mice, and ApoER2/VLDLr double knockouts phenocopy Reelin and Dab1 mutants.\",\n      \"method\": \"Single and double receptor knockout mice, immunohistochemistry for dopaminergic neuron markers, neuronal counting and positioning analysis\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — genetic epistasis with single and double knockouts recapitulating full pathway loss-of-function phenotype\",\n      \"pmids\": [\"23976984\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"SIRT1 attenuates hepatic lipid accumulation by suppressing VLDLR protein levels; SIRT1 loss increases VLDLR in a HIF-1α-dependent manner (not ER stress-dependent), and SIRT1 activation prevents ER stress-induced increases in hepatic VLDLR.\",\n      \"method\": \"Sirt1−/− mice, fructose-fed rat model, Huh-7 cells with SIRT1 siRNA/pharmacological inhibition, HIF-1α inhibitor, tunicamycin ER stress model with SIRT1 activator\",\n      \"journal\": \"Cell communication and signaling\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — multiple genetic and pharmacological approaches converging on HIF-1α as mediator, but primary mechanism (direct vs indirect SIRT1 regulation of HIF-1α/VLDLR) not fully resolved\",\n      \"pmids\": [\"38807218\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"A CRISPR-deleted intronic enhancer element spanning rs3780181 in VLDLR reduces VLDLR expression ~1.2-fold in HEK293T cells; the rs3780181-A risk allele (associated with increased TC/LDL-C) shows significantly less enhancer activity than the G allele, with differential binding to nuclear proteins including IRF2.\",\n      \"method\": \"CRISPR-Cas9 enhancer deletion, allele-specific luciferase reporter assay in HepG2/THP-1/SGBS cells, nuclear protein binding assay, eQTL analysis in liver\",\n      \"journal\": \"Human molecular genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1–2 — CRISPR deletion and allele-specific reporter assay with nuclear binding, but modest effect size and single lab\",\n      \"pmids\": [\"30445632\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"VLDLR is a multiligand lipoprotein receptor that functions as a co-receptor for Reelin (together with ApoER2), directly binding Reelin to trigger Dab1 tyrosine phosphorylation and downstream PI3K/Akt, Rac1/Yap, and cytoskeletal signaling cascades that govern neuronal migration, cortical layer formation, and dendrite development; its surface levels are post-translationally controlled by PCSK9-mediated lysosomal degradation and IDOL/LXR-induced ubiquitination of its cytoplasmic tail, while its transcription is activated by HIF-1α under hypoxia and PPARα/β/δ agonists; in the periphery VLDLR mediates VLDL lipid uptake driving thermogenesis, adipogenesis, and macrophage ceramide-dependent inflammation; it also serves as the entry receptor for multiple encephalitic alphaviruses (SFV, EEEV, WEEV) through interactions of viral E1/E2 glycoproteins with its LDLR class A ligand-binding repeats; and loss-of-function mutations in humans cause VLDLR-associated cerebellar hypoplasia (dysequilibrium syndrome) consistent with its Reelin-signaling role in brain development.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"VLDLR is a multiligand lipoprotein receptor that serves as a core component of the Reelin signaling pathway, directly binding Reelin (with specificity conferred by the Reelin C-terminal region) and clusterin to trigger Dab1 tyrosine phosphorylation and downstream PI3K/Akt, Rap1/integrin, and Rac1/Yap cascades that govern neuronal migration, cortical lamination, dendrite development, and cardiomyocyte proliferation [PMID:12670700, PMID:14715136, PMID:24381170, PMID:28123028, PMID:38147128]. VLDLR provides a cell-autonomous stop signal for migrating cortical neurons distinct from the migration-promoting role of ApoER2, and is required for positioning of mesencephalic dopaminergic neurons and suppression of retinal angiogenesis [PMID:17913789, PMID:32540847, PMID:23976984, PMID:21757581]. Cell-surface VLDLR levels are tightly regulated by PCSK9-mediated lysosomal degradation, IDOL/LXR-induced ubiquitination of its cytoplasmic tail, SEL1L-dependent ER-associated degradation of misfolded mutants, and transcriptional control by HIF-1α under hypoxia and PPARα agonists [PMID:18039658, PMID:20427281, PMID:29371607, PMID:21970364, PMID:24899625]. In the periphery VLDLR mediates VLDL lipid uptake driving brown adipocyte thermogenesis and macrophage ceramide-dependent inflammation, serves as a fibrin receptor supporting leukocyte transmigration, and functions as the entry receptor for encephalitic alphaviruses (SFV, EEEV) and HCV through engagement of its LDLR class A repeats with viral glycoproteins, as defined by cryo-EM structures [PMID:36516764, PMID:29057873, PMID:34929721, PMID:37098345, PMID:38176410, PMID:26699506].\",\n  \"teleology\": [\n    {\n      \"year\": 2003,\n      \"claim\": \"Establishing that Reelin directly binds VLDLR and ApoER2 to induce Dab1 phosphorylation resolved the identity of the obligate neuronal Reelin receptors and showed no other receptor can substitute.\",\n      \"evidence\": \"Purified Reelin binding assays and Dab1 phosphorylation in cortical neurons from single/double receptor knockout mice\",\n      \"pmids\": [\"12670700\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis of Reelin–VLDLR interaction not yet defined\", \"Relative affinity contributions of each receptor unclear\", \"Downstream signaling cascades beyond Dab1 not mapped\"]\n    },\n    {\n      \"year\": 2004,\n      \"claim\": \"Demonstrating that Reelin promotes dendrite development through VLDLR/ApoER2–Dab1 extended the pathway's role beyond migration to post-migratory neuronal maturation.\",\n      \"evidence\": \"Pharmacological receptor blockade, Dab1 phosphorylation inhibitors, and recombinant Reelin rescue in hippocampal cultures and reeler mice\",\n      \"pmids\": [\"14715136\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Which downstream effectors of Dab1 mediate dendrite outgrowth specifically\", \"Whether VLDLR and ApoER2 contribute equally to this phenotype\"]\n    },\n    {\n      \"year\": 2007,\n      \"claim\": \"Genetic epistasis revealed that VLDLR specifically provides a stop signal for migrating neurons (preventing marginal zone invasion), while ApoER2 is needed for late-born neuron migration — establishing non-redundant receptor functions in cortical lamination.\",\n      \"evidence\": \"BrdU fate mapping and layer-specific markers in Vldlr−/−, ApoER2−/−, and double knockout mice; Pafah1b complex interaction mapped to VLDLR NPxYL motif with compound mutant epistasis\",\n      \"pmids\": [\"17913789\", \"17330141\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Molecular basis distinguishing VLDLR stop signal from ApoER2 migration signal\", \"Whether Pafah1b complex is sufficient for the VLDLR-specific stop signal\"]\n    },\n    {\n      \"year\": 2007,\n      \"claim\": \"Discovery that PCSK9 degrades VLDLR through a catalytic-activity-independent mechanism identified the first post-translational pathway controlling VLDLR surface levels.\",\n      \"evidence\": \"Co-expression, secreted PCSK9 re-internalization, catalytic-dead mutant, and membrane-bound chimeras targeting VLDLR to lysosomes\",\n      \"pmids\": [\"18039658\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Which VLDLR extracellular domain contacts PCSK9\", \"In vivo tissue-specific consequences beyond adipocytes not yet tested\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Identification of IDOL as an LXR-induced E3 ligase that ubiquitinates the VLDLR cytoplasmic tail established a second, transcription-coupled degradation axis and showed it attenuates Reelin–Dab1 signaling.\",\n      \"evidence\": \"Ubiquitination assays, LXR agonist treatment in vivo, Reelin binding and Dab1 phosphorylation readouts\",\n      \"pmids\": [\"20427281\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Specific lysine residues ubiquitinated on VLDLR tail not mapped\", \"Relative contribution of IDOL vs PCSK9 in different tissues\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Multiple studies expanded VLDLR biology beyond Reelin: circulating PCSK9 regulates adipocyte VLDLR in vivo; VLDLR serves as a fibrin receptor for leukocyte transmigration; and a disease-causing VLDLR truncation mutation abolishes plasma membrane localization and retinal antiangiogenic function.\",\n      \"evidence\": \"Liver-specific PCSK9 manipulation in Pcsk9−/−/Ldlr−/− mice; SPR binding and transmigration assays in VLDLR-deficient mice; linkage/allelic complementation in Vldlr−/− mice with immunofluorescence of mutant protein\",\n      \"pmids\": [\"21273557\", \"22096238\", \"21757581\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Fibrin β-domain binding site on VLDLR not structurally resolved\", \"Whether antiangiogenic signaling uses Dab1 or a distinct pathway\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"HIF-1α was shown to directly activate VLDLR transcription through a functional HRE, explaining hypoxia-induced lipid accumulation and later providing the basis for hypoxia-dependent viral receptor expression.\",\n      \"evidence\": \"ChIP, dual-luciferase HRE reporter, HIF1A/VLDLR siRNA, lipid uptake under hypoxia\",\n      \"pmids\": [\"21970364\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether HIF-1α–VLDLR axis operates in brain under physiological hypoxia\", \"Interaction with other VLDLR transcriptional regulators (PPARs) under combined stimuli\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"FE65 was identified as a cytoplasmic adaptor linking VLDLR to APP via its PTB1 domain, modulating VLDLR surface levels and shedding, thus connecting Reelin receptor trafficking to amyloid precursor protein processing.\",\n      \"evidence\": \"Reciprocal co-IP in COS7 cells and brain lysates, cell-surface biotinylation, domain mapping, proteasome inhibitor studies\",\n      \"pmids\": [\"22429478\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Physiological relevance of FE65-mediated VLDLR–APP linkage in neurodegeneration not tested in vivo\", \"Whether FE65 competes with Dab1 for NPxY binding\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"PPARα was shown to directly transactivate the VLDLR promoter, and hepatic VLDLR induction proved essential for the triglyceride-lowering effect of fenofibrate, establishing VLDLR as a pharmacologically relevant lipid-clearance receptor in the liver.\",\n      \"evidence\": \"PPRE-reporter assays, fenofibrate treatment of Vldlr−/− and Pparα−/− mice, adenoviral VLDLR rescue\",\n      \"pmids\": [\"24899625\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether hepatic VLDLR induction contributes to fenofibrate-associated hepatic steatosis\", \"Relative roles of VLDLR vs LDLR in hepatic remnant clearance\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"The Reelin C-terminal region was shown to confer receptor-binding specificity for VLDLR over ApoER2, and VLDLR-dependent VLDL uptake in adipose macrophages was found to drive ceramide-mediated inflammatory polarization, linking VLDLR to metabolic inflammation.\",\n      \"evidence\": \"RELN-binding assays with CTR truncation, genetic epistasis in compound mutant mice; VLDLR KO bone marrow transplant, ceramide measurements, macrophage polarization\",\n      \"pmids\": [\"28123028\", \"29057873\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural determinant of Reelin CTR–VLDLR specificity not resolved\", \"Whether ceramide signaling feeds back to regulate VLDLR expression\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Disease-causing VLDLR missense mutations were shown to cause ER retention, calnexin association, and SEL1L-dependent proteasomal degradation, defining the proteostatic fate of pathogenic VLDLR variants.\",\n      \"evidence\": \"Co-IP with calnexin, ubiquitination assays, CRISPR SEL1L knockout delaying mutant and WT VLDLR degradation\",\n      \"pmids\": [\"29371607\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether ER stress from accumulated mutant VLDLR contributes to cerebellar pathology\", \"Proteostatic handling of VLDLR in neurons vs non-neuronal cells\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Neuronal IDOL was found to control energy balance primarily through VLDLR (not LDLR) degradation, establishing VLDLR as a metabolically active receptor in hypothalamic neurons.\",\n      \"evidence\": \"Neuron-specific IDOL knockout mice, scRNA-seq of hypothalamus, metabolic phenotyping\",\n      \"pmids\": [\"32072135\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"What ligand(s) VLDLR transduces in hypothalamic energy sensing\", \"Whether neuronal VLDLR signals through Dab1 or alternative pathways in this context\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Rescue experiments in Vldlr-mutant cortex showed that VLDLR's stop-migration signal is cell-autonomous and mediated by Rap1/integrin/Akt, distinguishing it from Reelin-induced neuronal aggregation which does not require VLDLR.\",\n      \"evidence\": \"In utero electroporation rescue in Vldlr mutants, ectopic Reelin overexpression, Rap1/integrin/Akt pathway dissection\",\n      \"pmids\": [\"32540847\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How Rap1 activation is mechanistically linked to Dab1 phosphorylation downstream of VLDLR\", \"Whether the same pathway operates in non-cortical neurons\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"VLDLR was identified as the entry receptor for multiple encephalitic alphaviruses (SFV, EEEV, Sindbis), with viral E2–E1 engaging the VLDLR ligand-binding domain — a finding exploited to block infection in vivo with LBD-Fc decoys.\",\n      \"evidence\": \"Ectopic expression, VLP internalization, LBD-Fc competition and in vivo neonatal mouse protection, invertebrate orthologue functional assays\",\n      \"pmids\": [\"34929721\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Atomic details of virus–receptor interaction not yet resolved\", \"Whether VLDLR mediates viral entry in all susceptible cell types\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"VLDLR-mediated VLDL uptake in brown adipocytes was shown to fuel mitochondrial oxidation via lysosomal lipid processing and to activate PPARβ/δ-driven thermogenic gene expression, establishing VLDLR as a metabolic sensor in thermogenesis.\",\n      \"evidence\": \"Vldlr KO mice with cold exposure, lysosomal inhibitors, brown-adipocyte-specific PPARβ/δ KO\",\n      \"pmids\": [\"36516764\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Identity of specific lipid species activating PPARβ/δ downstream of VLDLR-mediated uptake\", \"Contribution of VLDLR vs other lipoprotein receptors in BAT under thermoneutral conditions\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Cryo-EM structures of SFV–VLDLR revealed that multiple LA repeats (especially LA3) engage E1-DIII through salt bridges, with consecutive repeats rotating to enable multivalent binding — providing the first atomic-level view of VLDLR's virus-receptor interface and explaining its broad alphavirus tropism.\",\n      \"evidence\": \"Cryo-EM structure, individual LA repeat binding affinity measurements, mutagenesis\",\n      \"pmids\": [\"37098345\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How pH-dependent conformational changes in endosomes release virus from VLDLR\", \"Whether LA repeat engagement differs for physiological ligands like Reelin\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"In cardiomyocytes, VLDLR integrates opposing proliferative signals — Reelin promotes and thrombospondin-1 inhibits proliferation — through a Rac1/Yap axis, and cardiac-specific Vldlr deletion is cardioprotective after infarction.\",\n      \"evidence\": \"Cardiac-specific Vldlr KO, Reln mutant and Thbs1 cardiac deletion mice, cardiomyocyte cell cycle and Rac1/Yap signaling assays, apical resection model\",\n      \"pmids\": [\"38147128\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How TSP-1 and Reelin compete or cooperate at the VLDLR ectodomain\", \"Whether Dab1 is involved in cardiomyocyte VLDLR signaling\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Cryo-EM structures of EEEV–VLDLR defined three distinct binding sites and showed that no single LA domain is necessary, enabling design of minimal decoy receptors that neutralize EEEV in vivo; the W132G human SNP was found to enhance EEEV attachment by switching binding modes.\",\n      \"evidence\": \"Multiple cryo-EM structures, mutagenesis, infection assays, in vivo decoy protection, W132G variant binding and attachment assays\",\n      \"pmids\": [\"38176410\", \"39127734\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Population-level significance of W132G for EEEV susceptibility\", \"Whether decoy receptors based on VLDLR can achieve therapeutic neutralization against diverse alphaviruses\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"SFV neuroinvasion was shown to be strictly VLDLR-dependent, occurring specifically through infection of choroid plexus epithelial cells at the blood-CSF barrier, which express high VLDLR levels.\",\n      \"evidence\": \"VLDLR-deficient mice with intravenous SFV challenge, tissue-specific expression analysis, histological route-of-entry characterization\",\n      \"pmids\": [\"39715740\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether other neurotropic viruses exploit VLDLR at the choroid plexus\", \"Cell-type-specific VLDLR regulation in choroid plexus epithelium\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"Key unresolved questions include: (1) the structural basis of Reelin–VLDLR binding and how it differs from viral glycoprotein engagement; (2) how VLDLR signaling is decoded differently across cell types (neurons, cardiomyocytes, macrophages, brown adipocytes); (3) the precise mechanism by which VLDLR integrates opposing ligand signals (Reelin vs TSP-1) through shared downstream effectors.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"High\",\n      \"gaps\": [\"No Reelin–VLDLR co-structure available\", \"Cell-type-specific adaptor usage not systematically compared\", \"In vivo relevance of multiple VLDLR splice variants incompletely characterized\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0038024\", \"supporting_discovery_ids\": [0, 9, 10, 12, 26]},\n      {\"term_id\": \"GO:0008289\", \"supporting_discovery_ids\": [26, 28]},\n      {\"term_id\": \"GO:0001618\", \"supporting_discovery_ids\": [12, 13, 14, 15, 16]},\n      {\"term_id\": \"GO:0060089\", \"supporting_discovery_ids\": [0, 1, 22, 27]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [0, 5, 8, 10, 12]},\n      {\"term_id\": \"GO:0005768\", \"supporting_discovery_ids\": [2]},\n      {\"term_id\": \"GO:0005783\", \"supporting_discovery_ids\": [25]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-1266738\", \"supporting_discovery_ids\": [0, 1, 4, 22, 29]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [0, 1, 9, 22, 27]},\n      {\"term_id\": \"R-HSA-1430728\", \"supporting_discovery_ids\": [23, 26, 28]},\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [10, 19]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [12, 13, 14, 15, 16]},\n      {\"term_id\": \"R-HSA-392499\", \"supporting_discovery_ids\": [2, 3, 25]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\n      \"RELN\",\n      \"DAB1\",\n      \"APOER2\",\n      \"PCSK9\",\n      \"IDOL\",\n      \"FE65\",\n      \"CLU\",\n      \"SEL1L\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```"}