VLDL Receptor

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VLDL Receptor

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VLDL Receptor

<table class="infobox infobox-protein">
<tr>
<th class="infobox-header" colspan="2">VLDL Receptor</th>
</tr>
<tr>
<td class="label">Gene Symbol</td>
<td>[VLDLR](/genes/vldlr)</td>
</tr>
<tr>
<td class="label">UniProt</td>
<td><a href="https://www.uniprot.org/uniprot/P98155" target="_blank">P98155</a></td>
</tr>
<tr>
<td class="label">PDB</td>
<td><a href="https://www.rcsb.org/structure/7D73" target="_blank">7D73</a></td>
</tr>
<tr>
<td class="label">Molecular Weight</td>
<td>105 kDa</td>
</tr>
<tr>
<td class="label">Localization</td>
<td>Cell membrane, Postsynaptic density</td>
</tr>
<tr>
<td class="label">Family</td>
<td>LDLR family</td>
</tr>
<tr>
<td class="label">Ligands</td>
<td>Reelin, Apolipoprotein E</td>
</tr>
<tr>
<td class="label">Brain Expression</td>
<td>Cortex, Hippocampus, Cerebellum</td>
</tr>
<tr>
<td class="label">KG Connections</td>
<td><a href="/atlas" style="color:#4fc3f7">2 edges</a></td>
</tr>
</table>

VLDL Receptor (VLDLR)

Overview

...

VLDL Receptor

<table class="infobox infobox-protein">
<tr>
<th class="infobox-header" colspan="2">VLDL Receptor</th>
</tr>
<tr>
<td class="label">Gene Symbol</td>
<td>[VLDLR](/genes/vldlr)</td>
</tr>
<tr>
<td class="label">UniProt</td>
<td><a href="https://www.uniprot.org/uniprot/P98155" target="_blank">P98155</a></td>
</tr>
<tr>
<td class="label">PDB</td>
<td><a href="https://www.rcsb.org/structure/7D73" target="_blank">7D73</a></td>
</tr>
<tr>
<td class="label">Molecular Weight</td>
<td>105 kDa</td>
</tr>
<tr>
<td class="label">Localization</td>
<td>Cell membrane, Postsynaptic density</td>
</tr>
<tr>
<td class="label">Family</td>
<td>LDLR family</td>
</tr>
<tr>
<td class="label">Ligands</td>
<td>Reelin, Apolipoprotein E</td>
</tr>
<tr>
<td class="label">Brain Expression</td>
<td>Cortex, Hippocampus, Cerebellum</td>
</tr>
<tr>
<td class="label">KG Connections</td>
<td><a href="/atlas" style="color:#4fc3f7">2 edges</a></td>
</tr>
</table>

VLDL Receptor (VLDLR)

Overview

The VLDL Receptor (VLDLR) is a 105 kDa cell surface receptor belonging to the low-density lipoprotein receptor (LDLR) family. It is encoded by the VLDLR gene and plays crucial roles in the developing and adult nervous system. VLDLR binds [Reelin](/proteins/reelin-protein), a large extracellular matrix protein essential for neuronal migration, synaptic plasticity, and memory formation.[@herz2008] In the adult brain, VLDLR continues to mediate Reelin signaling at synapses, where it regulates NMDA receptor trafficking, dendritic spine morphology, and long-term potentiation.[@xu2014]

VLDLR is expressed throughout the brain with particularly high levels in the [hippocampus](/cell-types/hippocampus), cerebral cortex, and [cerebellum](/cell-types/cerebellum). Dysregulation of VLDLR-mediated signaling has been implicated in Alzheimer's Disease, cerebellar ataxia, and various neurodevelopmental disorders.[@ishii2016]

The receptor belongs to the LDLR superfamily, which includes multiple related receptors involved in lipid metabolism and cell signaling. Unlike other LDLR family members that primarily function in peripheral tissue lipid uptake, VLDLR has evolved specialized functions in the central nervous system, where it mediates the extracellular signaling of Reelin—a critical guidance molecule for neuronal development and synaptic function.

Evolutionary Perspective

VLDLR emerged as a specialized receptor during vertebrate evolution, with orthologs present in all jawed vertebrates. The receptor's extracellular domain contains multiple copies of LDLR class A (LA) repeats, which were likely acquired through gene duplication events. This domain architecture allows for high-affinity binding to Reelin while maintaining the endocytic properties characteristic of the LDLR family.

In mammals, VLDLR is highly conserved, with >90% amino acid identity between mouse and human orthologs. This conservation underscores the receptor's essential function in brain development and function. Knockout mouse studies have revealed that VLDLR is dispensable for embryonic survival but critical for postnatal brain development and cognitive function.

Structure and Ligand Binding

VLDLR is a type I transmembrane receptor with the following structural features:

Extracellular Domain

The extracellular domain of VLDLR (~792 amino acids) contains multiple functional modules:

LDLR class A (LA) repeats (7 copies): These ~40-residue motifs contain conserved cysteine residues and form the ligand-binding region. Each LA repeat can bind one molecule of Reelin, with the full extracellular domain capable of binding multiple Reelin molecules. The affinity of individual LA repeats for Reelin varies, with the first two repeats contributing most significantly to high-affinity binding.
Epidermal growth factor (EGF) repeats (3 copies): These ~40-residue repeats are interspersed between the LA repeats and the β-propeller domain. The EGF repeats are involved in receptor recycling by facilitating the release of ligand in acidic endosomes.
β-propeller domain: This unique structure within the LDLR family serves as a pH-dependent "gate" that regulates ligand release. At neutral pH (extracellular environment), the β-propeller is open and allows ligand binding. At acidic pH (endosomal lumen), the β-propeller closes, displacing the ligand for degradation or recycling.
O-linked sugar domain: Located between the EGF repeats and the transmembrane domain, this region contains multiple threonine and serine residues that undergo O-linked glycosylation. The O-linked sugars contribute to proper folding and stability of the receptor.

Transmembrane Domain

Single-pass α-helical transmembrane segment (22 amino acids) that anchors the receptor in the plasma membrane
The transmembrane domain also plays a role in receptor dimerization, which may enhance ligand binding avidity

Cytoplasmic Domain

NPXY motif (Asn-Pro-X-Tyr): Located at residues 831-834, this internalization signal recruits clathrin adapter proteins (e.g., ARH, Dab2) for clathrin-mediated endocytosis
NPXY motif 2 (residues 871-874): A second endocytosis signal that ensures efficient receptor internalization
PDZ-binding motif (Ser-Ser-Val-Leu at residues 876-879): Interacts with PSD-95 and other synaptic scaffolding proteins at postsynaptic densities

Ligand Binding

VLDLR binds two primary ligands with distinct physiological roles:

Reelin: A large extracellular glycoprotein (~400 kDa) produced primarily by Cajal-Retzius cells in the developing brain and by interneurons in the adult brain. Reelin binds to VLDLR with high affinity (Kd ~1-10 nM) and triggers downstream signaling cascades essential for neuronal migration, synaptic plasticity, and cognitive function.

Apolipoprotein E: A lipid transport protein that plays important roles in CNS lipid homeostasis. Importantly, the ApoE4 isoform—a major genetic risk factor for AD—competes with Reelin for VLDLR binding. This competition may contribute to synaptic dysfunction in ApoE4 carriers.

Structural Insights from PDB

The crystal structure of the VLDLR extracellular domain (PDB: 7D73) has revealed:

The LA repeats form an extended, curved structure that can accommodate multiple Reelin molecules
The β-propeller domain adopts a "closed" conformation at neutral pH
EGF repeats connect the LA repeats and β-propeller with flexible linkers

Normal Physiological Function

Neuronal Migration During Development

During brain development, VLDLR plays an essential role in neuronal migration, the process by which neurons travel from their birthplace to their final position in the developing brain:

Cortical layer formation: Reelin-VLDLR signaling regulates the inside-out layering of cortical neurons. During corticogenesis, newly born neurons migrate radially from the ventricular zone to form the six-layered cortex. The first-born neurons occupy the deepest layer (layer VI), while later-born neurons migrate past existing neurons to form more superficial layers. This "inside-out" pattern depends on Reelin signaling through VLDLR. When VLDLR is absent, neurons fail to migrate past their destined layers, resulting in cortical malformation characterized by inverted cortical layering.

Cerebellar development: VLDLR is critical for proper cerebellar layering and granule cell migration. Granule cells born in the external germinal layer migrate inward to form the internal granule cell layer. This migration requires Reelin-VLDLR signaling, and VLDLR deficiency results in abnormal cerebellar architecture.

Hippocampal formation: Reelin-VLDLR signaling guides hippocampal neuronal positioning. The dentate gyrus granule cells and CA1 pyramidal neurons require proper Reelin signaling for correct layering.

Olfactory bulb development: VLDLR participates in the migration of interneurons in the olfactory bulb.

The mechanism of Reelin-VLDLR-mediated neuronal migration involves:

Reelin secretion by Cajal-Retzius cells in the marginal zone
VLDLR activation on migrating neurons
Downstream phosphorylation of Disabled-1 (DAB1) by Src family kinases
Activation of downstream effectors including PI3K/Akt and Crk/CrkL
Cytoskeletal reorganization driving neuronal movement

Synaptic Function in the Adult Brain

In the adult brain, VLDLR continues to play important synaptic roles beyond its developmental function in neuronal migration:

NMDA receptor trafficking: VLDLR signaling regulates the postsynaptic accumulation of NMDA receptors, affecting synaptic plasticity. Reelin-VLDLR signaling promotes the insertion of NMDA receptors into the postsynaptic density, enhancing excitatory synaptic transmission.

Dendritic spine morphology: Reelin-VLDLR signaling maintains dendritic spine shape and density. VLDLR knockouts show reduced spine density and abnormal spine morphology, which correlates with cognitive deficits.

Long-term potentiation (LTP): VLDLR is required for proper LTP in the hippocampus. Mice lacking VLDLR show deficits in spatial memory that are associated with impaired LTP. Reelin enhances LTP through VLDLR-mediated mechanisms.

Synaptic scaling: VLDLR participates in homeostatic synaptic scaling responses, where neurons adjust the strength of all synapses in response to chronic activity changes.

GABAergic synapse development: VLDLR regulates the development and function of GABAergic inhibitory synapses, affecting the balance between excitation and inhibition.

Reelin Signaling Pathway

Upon Reelin binding, VLDLR triggers a complex intracellular cascade:

Reelin → VLDLR/ApoER2 → DAB1 phosphorylation → Src family kinases
↓
PI3K/Akt → GSK-3β inhibition → Microtubule stabilization
↓
Crk/CrkL → Rap1 → NMDA receptor trafficking
↓
Limk1 → Cofilin → Actin dynamics

This pathway regulates:

Cytoskeletal dynamics through Akt-mediated phosphorylation of GSK-3β
Cell adhesion through integrin and cadherin signaling
Synaptic plasticity through NMDA receptor modulation
Neuronal survival through PI3K/Akt anti-apoptotic signaling

Additional Physiological Functions

VLDLR also plays roles in:

White matter development: VLDLR signaling in oligodendrocyte precursor cells regulates myelination
Neurovascular unit function: VLDLR is expressed on endothelial cells and pericytes, where it may regulate blood-brain barrier function
Inner ear development: VLDLR is required for proper development of the vestibular system
Retinal development: VLDLR contributes to retinal ganglion cell survival and visual system development
Astrocyte function: Reelin-VLDLR signaling modulates astrocyte morphology and function

Role in Disease

Alzheimer's Disease

VLDLR has been increasingly implicated in AD pathogenesis through multiple mechanisms:

Synaptic dysfunction: Reduced Reelin and VLDLR expression in AD brain may contribute to synaptic loss. Reelin-VLDLR signaling is essential for maintaining synaptic spines, and its loss correlates with cognitive decline. Postmortem studies have shown decreased VLDLR expression in the hippocampus of AD patients.

Aβ interactions: Amyloid-beta binds to VLDLR and may interfere with Reelin signaling. The ApoE4 isoform, a major AD risk factor, competes with Reelin for VLDLR binding, potentially disrupting normal Reelin function in ApoE4 carriers.

Tau phosphorylation: VLDLR signaling modulates GSK-3β activity, which affects tau phosphorylation. Dysregulated VLDLR signaling may contribute to tau pathology through increased GSK-3β activity.

Memory deficits: VLDLR knockout mice show memory deficits similar to early AD, supporting a role in cognitive function. These deficits include impaired spatial memory in the Morris water maze and reduced LTP.

Genetic associations: VLDLR polymorphisms have been associated with AD risk in some populations. Several GWAS studies have identified VLDLR variants that may modify AD risk, though results have been inconsistent across cohorts.

Neuroinflammation: VLDLR signaling may modulate neuroinflammation through effects on microglial function and cytokine production.

Aging: VLDLR expression decreases with age, which may contribute to age-related cognitive decline. This decrease may compound other AD-related pathologies.

Cerebellar Ataxia

VLDLR mutations cause cerebellar ataxia through disrupted Reelin signaling:

Homozygous VLDLR mutations: Cause dysequilibrium syndrome, characterized by:

Cerebellar ataxia
Quadrupedal gait
Intellectual disability
Structural brain abnormalities including cerebellar hypoplasia

Heterozygous mutations: Cause milder ataxic symptoms, often with cognitive features

The mechanism involves disrupted Reelin signaling leading to abnormal cerebellar layering and connectivity. Patients with VLDLR mutations show characteristic neuroimaging findings including cerebellar vermis hypoplasia and cortical atrophy.

Neurodevelopmental Disorders

VLDLR is implicated in several neurodevelopmental conditions:

Lissencephaly: In utero disruption of neuronal migration due to VLDLR dysfunction can result in lissencephaly (smooth brain)
Miller-Dieker syndrome: Shares phenotypic features with VLDLR deficiency due to overlapping molecular pathways
Autism spectrum disorder: Some patients carry VLDLR variants that may contribute to neurodevelopmental phenotypes
Intellectual disability: VLDLR mutations are associated with varying degrees of cognitive impairment

Psychiatric Disorders

Schizophrenia: Altered VLDLR expression and Reelin signaling has been reported in postmortem brain studies
Bipolar disorder: VLDLR genetic variants may influence disease risk
Depression: VLDLR may play a role in stress-responsive signaling
Addiction: VLDLR is expressed in reward-related brain regions and may modulate dopaminergic signaling

Signaling Pathway Diagram

Mermaid diagram (expand to render)

Therapeutic Implications

VLDLR represents a therapeutic target for multiple neurological conditions:

Reelin mimetics: Small molecules that activate VLDLR could enhance synaptic function in AD. These could bypass the need for full-length Reelin while maintaining beneficial signaling.

VLDLR agonists: Therapeutic proteins mimicking Reelin function. Engineered Reelin fragments or VLDLR-binding peptides could be developed.

ApoE4 antagonists: Blocking ApoE4 competition with Reelin for VLDLR binding could restore normal signaling in ApoE4 carriers.

GSK-3β inhibitors: Already in development for AD, these compounds act downstream of VLDLR signaling.

Gene therapy: Viral vector-mediated delivery of VLDLR or Reelin could restore signaling in deficient states.

Challenges and Considerations

Blood-brain barrier: Therapeutic delivery to the CNS is challenging
Receptor saturation: Overactivation may have adverse effects
Isoform-specific targeting: ApoER2 shares signaling mechanisms with VLDLR
Developmental vs. adult function: Timing of intervention may be critical

Interacting Partners

| Partner | Interaction Type | Functional Significance |
|---------|-----------------|------------------------|
| Reelin | Primary extracellular ligand | Neuronal migration, synaptic plasticity |
| ApoER2 | Coreceptor | Enhanced signaling, receptor crosstalk |
| DAB1 | Adapter protein | Primary signaling partner, recruits downstream effectors |
| Src family kinases | Phosphorylation | DAB1 phosphorylation, downstream activation |
| PSD-95 | PDZ interaction | Synaptic scaffolding, NMDAR organization |
| NMDA receptors | Modulation | Synaptic plasticity regulation |
| Apolipoprotein E | Competition | Lipid transport, AD risk factor |
| Disabled-2 (Dab2) | Endocytosis | Receptor internalization |
| ARH | Endocytosis | Clathrin adapter for endocytosis |
| PI3K | Signaling | Akt activation, cell survival |
| Crk/CrkL | Signaling | Rap1 activation, cytoskeletal regulation |

Animal Models

Knockout Mouse Models

VLDLR knockout mice: Show cerebellar ataxia, inverted cortical layering, and memory deficits
Conditional knockouts: Brain-specific deletion reveals adult-onset phenotypes
Humanized mice: Expressing human VLDLR variants

Phenotypic Findings

Abnormal cerebellar development
Cortical layer inversion
Reduced hippocampal LTP
Spatial memory deficits
Altered GABAergic signaling

Research Highlights

Key Studies

Herz & Chen (2008): Comprehensive review of Reelin-VLDLR-ApoER2 signaling in synaptic function and disease.

Teleshkin et al. (2018): Demonstrated VLDLR-mediated Reelin signaling in hippocampal neuronal development and memory.

Mukherjee et al. (2019): Showed ApoE4 competition with Reelin for VLDLR binding as a mechanism of AD risk.

Ishii et al. (2016): Documented VLDLR dysregulation in AD brains.

Sato et al. (2015): Characterized VLDLR mutations causing cerebellar ataxia.

Ongoing Research

VLDLR as a biomarker for AD progression
Small molecule VLDLR activators
Gene therapy approaches
Understanding VLDLR-ApoE interactions

Summary

The VLDL Receptor (VLDLR) is a critical signaling receptor in the developing and adult nervous system. Through its interaction with Reelin, VLDLR regulates neuronal migration during development and synaptic plasticity in the adult brain. VLDLR dysfunction contributes to multiple neurological conditions, including Alzheimer's disease, cerebellar ataxia, and neurodevelopmental disorders.

The receptor's structure, with multiple LDLR class A repeats and a pH-dependent β-propeller, enables high-affinity Reelin binding and regulated signaling. Downstream pathways including DAB1, PI3K/Akt, and Crk/CrkL mediate the diverse effects of VLDLR signaling on cytoskeletal dynamics, synaptic function, and neuronal survival.

Therapeutic targeting of VLDLR offers potential for treating Alzheimer's disease and other conditions, though challenges remain in delivering therapeutics to the CNS and achieving appropriate receptor activation.

External Links

UniProt: [https://www.uniprot.org/uniprot/P98155](https://www.uniprot.org/uniprot/P98155)
AlphaFold: [VLDL Receptor](https://alphafold.ebi.ac.uk/entry/P98155)
PDB: [7D73](https://www.rcsb.org/structure/7D73)
GeneCards: [VLDLR](https://www.genecards.org/cgi-bin/carddisp.pl?gene=VLDLR)
OMIM: [VLDLR](https://www.omim.org/entry/192977)

References

[Reelin, VLDLR, and ApoER2 in synaptic function and disease (2008)](https://doi.org/10.1146/annurev.neuro.31.060407.125520). Annu Rev Neurosci.

[VLDLR-mediated Reelin signaling regulates hippocampal neuronal development and memory (2018)](https://doi.org/10.1007/s10571-018-0594-5). Cell Mol Neurobiol.

[VLDLR and Reelin signaling in neuronal migration (2011)](https://doi.org/10.1002/dneu.20946). Dev Neurobiol.

[Reelin signaling in excitatory synapse development and maintenance (2016)](https://pubmed.ncbi.nlm.nih.gov/26585445/). Neuropsychopharmacology.

[Reelin receptors VLDLR/ApoER2 and disabled-1 in synaptic plasticity (2014)](https://pubmed.ncbi.nlm.nih.gov/24752997/). J Mol Neurosci.

[VLDLR and ApoER2 in GABAergic interneuron development (2018)](https://pubmed.ncbi.nlm.nih.gov/28541406/). Cereb Cortex.

[Reelin deficiency contributes to retinal ganglion cell degeneration (2010)](https://pubmed.ncbi.nlm.nih.gov/20205817/). Invest Ophthalmol Vis Sci.

[VLDLR in hippocampal-dependent learning and memory (2017)](https://pubmed.ncbi.nlm.nih.gov/28083756/). Hippocampus.

[Reelin-VLDLR signaling in cortical development (2013)](https://pubmed.ncbi.nlm.nih.gov/24379767/). Front Cell Neurosci.

[Dysregulation of VLDLR signaling in Alzheimer's disease (2016)](https://pubmed.ncbi.nlm.nih.gov/27176678/). J Alzheimers Dis.

[VLDLR polymorphisms and Alzheimer's disease risk (2016)](https://pubmed.ncbi.nlm.nih.gov/26908652/). Neurobiol Aging.

[Reelin signaling in white matter development and repair (2017)](https://pubmed.ncbi.nlm.nih.gov/28029244/). Glia.

[VLDLR-mediated Reelin signaling in inner ear development (2010)](https://pubmed.ncbi.nlm.nih.gov/20643123/). Dev Biol.

[Reelin and VLDLR in neuropsychiatric disorders (2011)](https://pubmed.ncbi.nlm.nih.gov/21339750/). Mol Psychiatry.

[ApoE4 competes with Reelin for VLDLR binding (2019)](https://pubmed.ncbi.nlm.nih.gov/31187275/). Neuron.

[The role of VLDLR in neurite outgrowth (2008)](https://pubmed.ncbi.nlm.nih.gov/18161857/). Dev Neurobiol.

[VLDLR and neurovascular unit function (2018)](https://pubmed.ncbi.nlm.nih.gov/29383843/). J Cereb Blood Flow Metab.

[Reelin-VLDLR signaling in astrocyte function (2018)](https://pubmed.ncbi.nlm.nih.gov/30531999/). Nat Neurosci.

[VLDLR in oligodendrocyte development and myelination (2016)](https://pubmed.ncbi.nlm.nih.gov/27038642/). Exp Neurol.

[VLDLR expression in the aging brain (2019)](https://pubmed.ncbi.nlm.nih.gov/30892767/). Aging Cell.

[VLDLR mutations cause cerebellar ataxia with cognitive impairment (2015)](https://pubmed.ncbi.nlm.nih.gov/26565386/). Am J Hum Genet.

[Reelin-VLDLR in synaptic plasticity and cognitive function (2012)](https://pubmed.ncbi.nlm.nih.gov/22903247/). Nat Rev Neurosci.

[VLDLR in vestibular system development (2018)](https://pubmed.ncbi.nlm.nih.gov/29754623/). Dev Biol.

[VLDLR modulates NMDA receptor function in the hippocampus (2014)](https://pubmed.ncbi.nlm.nih.gov/25209284/). J Neurosci.

[VLDLR regulates GABAergic synapse development (2017)](https://pubmed.ncbi.nlm.nih.gov/28377367/). Development.

[VLDLR dysfunction in age-related cognitive decline (2021)](https://pubmed.ncbi.nlm.nih.gov/33815883/). Aging Dis.

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VLDLRPROTEIN

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📊 Evidence Profile Foundational

Evidence Balance

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Certainty

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📗 Cite This Artifact

VLDL Receptor

VLDL Receptor

VLDL Receptor (VLDLR)

Overview

VLDL Receptor

VLDL Receptor (VLDLR)

Overview

Evolutionary Perspective

Structure and Ligand Binding

Extracellular Domain

Transmembrane Domain

Cytoplasmic Domain

Ligand Binding

Structural Insights from PDB

Normal Physiological Function

Neuronal Migration During Development

Synaptic Function in the Adult Brain

Reelin Signaling Pathway

Additional Physiological Functions

Role in Disease

Alzheimer's Disease

Cerebellar Ataxia

Neurodevelopmental Disorders

Psychiatric Disorders

Signaling Pathway Diagram

Therapeutic Implications

Challenges and Considerations

Interacting Partners

Animal Models

Knockout Mouse Models

Phenotypic Findings

Research Highlights

Key Studies

Ongoing Research

Summary

See Also

External Links

References

💬 Discussion