GO:0070326 very-low-density lipoprotein particle receptor binding: Mechanism, Genes and Research Methods
Research-grade guide for scientists and biopharma professionals
Key Takeaways
• GO:0070326 describes the molecular function of binding to a very-low-density lipoprotein (VLDL) receptor, a member of the LDL receptor superfamily.
• The VLDL receptor (VLDLR) is a peripheral lipoprotein receptor that binds apolipoprotein E (ApoE)-containing lipoproteins and also serves as a receptor for multiple alphaviruses.
• VLDLR binding is not only a metabolic event; it is exploited by pathogens such as eastern equine encephalitis virus and Crimean-Congo hemorrhagic fever virus for cellular entry.
• The LDL receptor (LDLR) and VLDLR share structural features, including ligand-binding repeats, epidermal growth factor-like domains, and a cytoplasmic tail that mediates endocytosis.
• Dysregulation of VLDLR binding is linked to neurological disorders, including cerebral amyloidosis and Alzheimer's disease pathology.
• CRISPR-based knockout, knock-in, and overexpression models are essential to dissect the precise role of VLDLR binding in health and disease.
Description
Very-low-density lipoprotein particle receptor binding (GO:0070326) is a molecular function defined as the binding to a very-low-density lipoprotein receptor. This interaction is fundamental to lipid metabolism and also plays a critical role in pathogen entry. The VLDL receptor (VLDLR) is a member of the low-density lipoprotein receptor (LDLR) superfamily, characterized by a modular structure that includes ligand-binding repeats, epidermal growth factor (EGF)-like domains, and a cytoplasmic tail. Unlike LDLR, which primarily clears LDL from circulation, VLDLR is expressed in peripheral tissues such as heart, muscle, and adipose tissue, where it binds apolipoprotein E (ApoE)-enriched lipoproteins. The binding of VLDL particles to VLDLR triggers endocytosis and subsequent cellular responses. Beyond its physiological role, VLDLR binding is hijacked by several viruses, including eastern equine encephalitis virus (EEEV) and other alphaviruses, to gain entry into host cells. Recent studies have also implicated LDLR, a close relative, in the entry of Crimean-Congo hemorrhagic fever virus (CCHFV) and hepatitis A virus, highlighting the broader relevance of this receptor family in infectious diseases. Understanding the molecular details of VLDLR binding is therefore crucial for both metabolic research and antiviral drug development.
very-low-density lipoprotein particle receptor binding At A Glance
| GO ID | GO:0070326 |
|---|---|
| GO term | very-low-density lipoprotein particle receptor binding |
| Ontology | molecular_function |
| Synonym | apolipoprotein E receptor binding, very-low-density lipoprotein receptor binding, VLDLR binding, VLDL receptor binding |
| Major function | Binding to the VLDL receptor, mediating lipoprotein uptake and viral entry |
| Related receptor | VLDLR (very-low-density lipoprotein receptor), a member of the LDL receptor superfamily |
| Major ligands | Apolipoprotein E (ApoE), apolipoprotein B (ApoB), and viral glycoproteins |
| Associated diseases | Alzheimer's disease, cerebral amyloidosis, alphavirus infections |
| Research methods | CRISPR knockout, knock-in, overexpression, structural biology, binding assays |
What Is GO:0070326?
GO:0070326 is defined as the binding to a very-low-density lipoprotein receptor. This molecular function encompasses the physical interaction between a ligand (such as apolipoprotein E or viral particles) and the VLDL receptor, a cell-surface protein that mediates the uptake of lipoproteins and other ligands. The term is synonymous with apolipoprotein E receptor binding, VLDLR binding, and VLDL receptor binding.
Why Is very-low-density lipoprotein particle receptor binding Important in Cell Biology?
VLDLR binding is a key molecular event that bridges lipid metabolism and infectious disease. It is essential for the clearance of triglyceride-rich lipoproteins and for the delivery of lipids to peripheral tissues. Moreover, the same binding interface is targeted by multiple alphaviruses, making it a potential therapeutic target for antiviral development. In the brain, VLDLR and its ligands are implicated in amyloid-beta deposition, linking this molecular function to Alzheimer's disease pathology. Thus, understanding VLDLR binding has broad implications for metabolic disorders, neurobiology, and virology.
• Mediates the cellular uptake of VLDL and other ApoE-containing lipoproteins.
• Serves as a receptor for eastern equine encephalitis virus and other alphaviruses.
• Plays a role in brain lipid metabolism and is associated with cerebral amyloidosis.
• Shares structural homology with LDLR, which is involved in CCHFV and HAV entry.
• Potential target for antiviral therapies against alphaviruses.
• Involved in the pathogenesis of Alzheimer's disease through ApoE-mediated pathways.
• Essential for normal peripheral lipid homeostasis.
• Provides a model system to study receptor-ligand interactions and endocytosis.
• CRISPR screens can identify host factors required for VLDLR-dependent viral entry.
• Structural studies of VLDLR-ligand complexes inform drug design.
Molecular Mechanism of very-low-density lipoprotein particle receptor binding
Ligand Recognition by VLDLR
In simple terms: The VLDL receptor recognizes and grabs onto specific particles, like ApoE-carrying lipoproteins or viruses.
The VLDL receptor (VLDLR) contains multiple ligand-binding repeats in its extracellular domain that mediate high-affinity binding to apolipoprotein E (ApoE) and other ligands. This interaction is calcium-dependent and involves electrostatic complementarity between the receptor's acidic residues and basic residues on the ligand. Structural studies of VLDLR in complex with alphavirus glycoproteins have revealed that the virus binds to the same ligand-binding repeats, mimicking natural ligands.
Receptor Clustering and Endocytosis
In simple terms: Once the receptor binds its target, it clusters on the cell surface and is pulled into the cell.
Upon ligand binding, VLDLR clusters in clathrin-coated pits and is internalized via endocytosis. The cytoplasmic tail of VLDLR contains an NPxY motif that recruits adaptor proteins such as Dab1, which is critical for downstream signaling. This endocytic process is essential for the delivery of lipoproteins and also for viral entry.
Intracellular Trafficking and Recycling
In simple terms: After entering the cell, the receptor releases its cargo and goes back to the surface to pick up more.
Following internalization, the acidic environment of endosomes causes the ligand to dissociate from VLDLR, allowing the receptor to recycle back to the plasma membrane. This recycling is regulated by small GTPases and is crucial for maintaining cellular lipid homeostasis. Viruses that exploit VLDLR may escape from endosomes to initiate infection.
Structural Basis of VLDLR Binding
In simple terms: The 3D shape of the receptor determines what it can bind, like a lock and key.
The crystal structure of VLDLR in complex with eastern equine encephalitis virus (EEEV) glycoprotein reveals that the virus binds to the first three ligand-binding repeats of VLDLR. This binding is pH-dependent and involves a conformational change in the viral protein. Similar structural features are shared with LDLR, which binds CCHFV and HAV.
Regulation of VLDLR Expression and Activity
In simple terms: Cells can adjust how much receptor they make and how active it is.
VLDLR expression is regulated by transcription factors such as SREBP-2 and by hormones like insulin. Post-translational modifications, including glycosylation and phosphorylation, modulate its binding affinity and trafficking. In the brain, VLDLR levels are altered in Alzheimer's disease, suggesting a role in disease progression.
Key Genes Involved in GO:0070326 very-low-density lipoprotein particle receptor binding
The following genes and proteins are directly involved in very-low-density lipoprotein particle receptor binding and its downstream effects.
| Gene | Major Role | Research Relevance |
|---|---|---|
| VLDLR | Very-low-density lipoprotein receptor; binds ApoE-containing lipoproteins and alphaviruses | Central to GO:0070326; target for antiviral and metabolic studies |
| LDLR | Low-density lipoprotein receptor; related family member that binds CCHFV and HAV | Model for receptor-ligand interactions; viral entry studies |
| APOE | Apolipoprotein E; major ligand for VLDLR and LDLR | Key in lipid metabolism and Alzheimer's disease |
| APOB | Apolipoprotein B; component of VLDL particles | Ligand for VLDLR; involved in lipoprotein assembly |
| DAB1 | Adaptor protein that binds VLDLR cytoplasmic tail | Mediates Reelin signaling and neuronal migration |
| RELN | Reelin; extracellular matrix protein that binds VLDLR | Regulates neuronal positioning and synaptic function |
| CLTC | Clathrin heavy chain; mediates endocytosis of VLDLR | Required for VLDLR internalization |
| LRP1 | LDL receptor-related protein 1; related receptor | Binds ApoE and other ligands; implicated in neurodegeneration |
| SREBF2 | Sterol regulatory element-binding transcription factor 2 | Regulates VLDLR and LDLR expression |
| PCSK9 | Proprotein convertase subtilisin/kexin type 9 | Regulates LDLR degradation; potential cross-talk with VLDLR |
| ARH | Autosomal recessive hypercholesterolemia protein; adaptor for LDLR | Facilitates endocytosis of LDLR family members |
| CCHFV-Gc | Crimean-Congo hemorrhagic fever virus glycoprotein | Binds LDLR to mediate entry |
| HAV-VP1 | Hepatitis A virus capsid protein | Binds LDLR for cellular entry |
| EEEV-E2 | Eastern equine encephalitis virus envelope protein | Binds VLDLR to mediate entry |
| SINV-E2 | Sindbis virus envelope protein | Binds VLDLR and ApoER2 |
| ApoER2 | Apolipoprotein E receptor 2; VLDLR paralog | Binds alphaviruses and Reelin |
| VLDLR-ICD | Intracellular domain of VLDLR | Mediates signaling and adaptor binding |
How Is very-low-density lipoprotein particle receptor binding Regulated?
VLDLR binding is regulated at multiple levels. Transcription of VLDLR is controlled by sterol regulatory element-binding proteins (SREBPs) in response to cellular cholesterol levels. Post-translational modifications, such as glycosylation and phosphorylation, can modulate ligand affinity and receptor trafficking. The interaction with adaptor proteins like Dab1 is regulated by phosphorylation and is critical for downstream signaling. In the brain, Reelin binding to VLDLR is modulated by extracellular matrix components and proteases. Additionally, viral entry via VLDLR can be influenced by the presence of co-receptors and the lipid composition of the membrane.
very-low-density lipoprotein particle receptor binding and Human Disease
| Gene | Disease / Biology | Potential Experimental Model |
|---|---|---|
| VLDLR | Alzheimer's disease, cerebral amyloidosis | Vldlr knockout mice; ApoE isoform knock-in mice |
| VLDLR | Alphavirus infection (EEEV, SINV) | Vldlr knockout cells; viral entry assays |
| LDLR | CCHFV and HAV infection | LDLR knockout cell lines; viral infection models |
| APOE | Alzheimer's disease, lipid metabolism | Apoe knockout and humanized knock-in mice |
| RELN | Lissencephaly, neuronal migration disorders | Reelin knockout mice; Vldlr/Dab1 mutants |
VLDLR and Neurodegeneration
VLDLR is expressed in the brain and binds Reelin, a protein essential for neuronal migration and synaptic plasticity. Dysregulation of this interaction has been linked to Alzheimer's disease, where ApoE isoforms differentially affect amyloid-beta deposition. Studies have shown that LDL particle size subfractions, which reflect VLDL metabolism, are associated with cerebral amyloidosis. Thus, VLDLR binding may contribute to neurodegeneration through impaired lipid transport and Reelin signaling.
VLDLR as a Viral Entry Receptor
Multiple alphaviruses, including eastern equine encephalitis virus (EEEV) and Sindbis virus, use VLDLR as a receptor to enter host cells. Structural studies have elucidated the binding interface between EEEV glycoprotein and VLDLR, providing a template for antiviral design. The related LDLR is also exploited by CCHFV and HAV, demonstrating a broader theme of lipoprotein receptors in viral pathogenesis. Targeting these interactions could lead to broad-spectrum antivirals.
VLDLR in Metabolic Disorders
VLDLR plays a role in peripheral lipid metabolism by mediating the uptake of triglyceride-rich lipoproteins. Although rare, mutations in VLDLR have been associated with hypertriglyceridemia and other metabolic abnormalities. Understanding the regulation of VLDLR binding could inform therapies for dyslipidemia and related conditions.
From very-low-density lipoprotein particle receptor binding-Related Genes to Experimental Models
| Research Question | Suitable Model |
|---|---|
| Does VLDLR mediate viral entry? | VLDLR knockout cell lines (e.g., HAP1, HeLa) followed by infection with EEEV or SINV |
| What is the role of VLDLR in lipid metabolism? | Vldlr knockout mice fed a high-fat diet; lipid profiling |
| How does ApoE isoform affect VLDLR binding? | ApoE knock-in mice (E2, E3, E4) and primary neurons |
| Can we block VLDLR-virus interaction? | Overexpression of soluble VLDLR ectodomain or CRISPR knock-in of binding-deficient VLDLR |
| What is the structural basis of VLDLR binding? | Recombinant VLDLR ligand-binding repeats for crystallography or cryo-EM |
| Does VLDLR regulate Reelin signaling? | Conditional Vldlr knockout in neurons; Dab1 phosphorylation assays |
How to Study the very-low-density lipoprotein particle receptor binding Process
| Method | What It Measures | Typical Application |
|---|---|---|
| CRISPR knockout screen | Loss-of-function of all genes | Identify host factors for viral entry |
| Surface plasmon resonance | Binding affinity (KD) | Measure VLDLR-ligand interaction |
| X-ray crystallography | 3D structure of protein complex | Determine binding interface |
| Flow cytometry | Cell surface binding | Assess viral particle binding to VLDLR |
| Western blot | Protein expression and phosphorylation | Validate knockout and signaling |
| Immunofluorescence | Subcellular localization | Visualize VLDLR trafficking |
| Lipid profiling | Lipoprotein levels | Assess metabolic impact of VLDLR loss |
| qRT-PCR | mRNA expression | Measure VLDLR transcriptional regulation |
CRISPR Knockout Screens
Genome-wide CRISPR knockout screens have been used to identify host factors required for viral entry, including VLDLR and LDLR. These screens typically use lentiviral libraries to deliver sgRNAs and select for cells resistant to viral infection. Hits are validated by individual gene knockout and infection assays. This approach is powerful for uncovering novel receptors and co-factors.
Structural Biology
X-ray crystallography and cryo-electron microscopy have been used to solve the structure of VLDLR in complex with viral glycoproteins. These studies reveal the atomic details of the binding interface and inform the design of inhibitors. Recombinant expression of VLDLR domains in mammalian or insect cells is often required for structural studies.
Binding Assays
Surface plasmon resonance (SPR) and isothermal titration calorimetry (ITC) can measure the affinity between VLDLR and its ligands. Enzyme-linked immunosorbent assays (ELISAs) and flow cytometry are used to assess binding in a cellular context. These methods are essential for validating the functional consequences of mutations.
Animal Models
Vldlr knockout mice are widely used to study the role of VLDLR in lipid metabolism and brain development. These mice exhibit reduced body weight and impaired Reelin signaling. Viral infection studies in mice can also assess the importance of VLDLR in pathogenesis.
How CRISPR Can Be Used to Study GO:0070326 very-low-density lipoprotein particle receptor binding
Knockout
CRISPR knockout of VLDLR or LDLR is used to determine their necessity for viral entry or lipid uptake. For example, LDLR knockout cells are resistant to CCHFV infection, confirming its role as a receptor. Similarly, VLDLR knockout reduces EEEV infection. These models are invaluable for target validation.
Point Mutation
Point mutations can be introduced into the ligand-binding domain of VLDLR to dissect the contribution of specific residues to ligand binding. For instance, mutating calcium-coordinating residues abolishes binding. Such models help map the functional epitope.
Knock-in
Knock-in of human VLDLR into mouse models can humanize the receptor for studying human-specific viruses. Alternatively, knock-in of tagged VLDLR (e.g., GFP) allows visualization of receptor trafficking in live cells. These models are essential for translational research.
Overexpression
Overexpression of VLDLR in cell lines that normally lack it can confer susceptibility to viral infection or enhance lipoprotein uptake. This approach is used to confirm receptor function and to study downstream signaling. Stable cell lines overexpressing VLDLR are valuable tools for drug screening.
How EDITGENE Supports very-low-density lipoprotein particle receptor binding Research
Researchers studying very-low-density lipoprotein particle receptor binding-related genes often need to determine whether a candidate gene is causally involved in lipid metabolism, viral entry, or neuronal signaling. EDITGENE provides a comprehensive suite of CRISPR-based services to accelerate this discovery process.
Contact EDITGENE today to design your custom CRISPR model for very-low-density lipoprotein particle receptor binding research.
Related Products
| Product name | Cat.No. | Species | Gene ID | |
|---|---|---|---|---|
| APOE Knockout HEK293 Cell Line | EDJ-KQ172 | Human | 348 | Details Get a Quote |
| RELN Knockout HEK293 Cell Line | EDJ-KQ863 | Human | 5649 | Details Get a Quote |
| PCSK9 Knockout HEK293 Cell Line | EDJ-KQ3896 | Human | 255738 | Details Get a Quote |
| LRPAP1 Knockout HEK293 Cell Line | EDJ-KQ5144 | Human | 4043 | Details Get a Quote |
| PCSK9 Knockout A-549 Cell Line | EDJ-KQ26111 | Human | 255738 | Details Get a Quote |
| PCSK9 Knockout HCT 116 Cell Line | EDJ-KQ26112 | Human | 255738 | Details Get a Quote |
| PCSK9 Knockout HeLa Cell Line | EDJ-KQ26113 | Human | 255738 | Details Get a Quote |
| LRPAP1 Knockout A-549 Cell Line | EDJ-KQ28109 | Human | 4043 | Details Get a Quote |
| LRPAP1 Knockout HCT 116 Cell Line | EDJ-KQ28110 | Human | 4043 | Details Get a Quote |
| LRPAP1 Knockout HeLa Cell Line | EDJ-KQ28111 | Human | 4043 | Details Get a Quote |
| APOE Knockout A-549 Cell Line | EDJ-KQ41271 | Human | 348 | Details Get a Quote |
| APOE Knockout HCT 116 Cell Line | EDJ-KQ41272 | Human | 348 | Details Get a Quote |
| APOE Knockout HeLa Cell Line | EDJ-KQ41273 | Human | 348 | Details Get a Quote |
| APOE Knockout LLC-MK2 Cell Line | EDJ-KZ546 | Rhesus Monkey | 714623 | Details Get a Quote |
| RELN Knockout HeLa Cell Line | EDJ-KQ54231 | Human | 5649 | Details Get a Quote |
Displaying Records 1 To 15 Of 19 Records
Frequently Asked Questions About very-low-density lipoprotein particle receptor binding
What is very-low-density lipoprotein particle receptor binding?
It is a molecular function (GO:0070326) defined as the binding to a very-low-density lipoprotein receptor, typically involving the interaction between VLDLR and ligands such as ApoE or viral particles.
What genes are involved in very-low-density lipoprotein particle receptor binding?
Key genes include VLDLR, LDLR, APOE, APOB, DAB1, and RELN, among others.
What is the role of VLDLR in viral infection?
VLDLR serves as a receptor for multiple alphaviruses, including eastern equine encephalitis virus and Sindbis virus, facilitating their entry into host cells.
How is VLDLR binding studied?
Common methods include CRISPR knockout screens, surface plasmon resonance, X-ray crystallography, and animal models.
Is VLDLR associated with Alzheimer's disease?
Yes, VLDLR and its ligands are implicated in cerebral amyloidosis and Alzheimer's disease pathology, particularly through ApoE-mediated pathways.
What is the difference between VLDLR and LDLR?
Both are members of the LDL receptor superfamily, but VLDLR primarily binds ApoE-enriched lipoproteins in peripheral tissues, while LDLR clears LDL from circulation.
Can CRISPR be used to study VLDLR function?
Absolutely. CRISPR knockout, knock-in, and overexpression models are widely used to dissect VLDLR's role in lipid metabolism and viral entry.
What diseases are linked to VLDLR binding?
Diseases include Alzheimer's disease, cerebral amyloidosis, and infections by alphaviruses such as EEEV.
What are the synonyms for GO:0070326?
Synonyms include apolipoprotein E receptor binding, very-low-density lipoprotein receptor binding, VLDLR binding, and VLDL receptor binding.
How can EDITGENE help with VLDLR research?
EDITGENE provides custom CRISPR knockout, knock-in, overexpression, and library screening services, along with bioinformatics support, to study VLDLR binding and its disease implications.
Conclusion
Very-low-density lipoprotein particle receptor binding (GO:0070326) is a fundamental molecular function with broad implications for lipid metabolism, neurobiology, and infectious disease. The VLDL receptor and its relatives serve as entry portals for multiple viruses and are central to ApoE-mediated lipid transport. Understanding the structural and regulatory mechanisms of this binding event can inform therapeutic strategies for metabolic disorders and viral infections. CRISPR-based models are indispensable tools for dissecting these pathways and identifying new targets.
References
- 1. Jeon H et al.. 2005. Structure and physiologic function of the low-density lipoprotein receptor.. Annu Rev Biochem 74:535-62 PMID: 15952897
- 2. Ritter M et al.. 2024. The low-density lipoprotein receptor and apolipoprotein E associated with CCHFV particles mediate CCHFV entry into cells.. Nat Commun 15(1):4542 PMID: 38806525
- 3. Shiota T et al.. 2026. The low-density lipoprotein receptor LDLR mediates cellular entry of nonenveloped hepatitis A virus.. Proc Natl Acad Sci U S A 123(14):e2534261123 PMID: 41894341
- 4. Takahashi S et al.. 2004. The very low-density lipoprotein (VLDL) receptor: characterization and functions as a peripheral lipoprotein receptor.. J Atheroscler Thromb 11(4):200-8 PMID: 15356379
- 5. Yang P et al.. 2024. Structural basis for VLDLR recognition by eastern equine encephalitis virus.. Nat Commun 15(1):6548 PMID: 39095394
- 7. Clark LE et al.. 2022. VLDLR and ApoER2 are receptors for multiple alphaviruses.. Nature 602(7897):475-480 PMID: 34929721
- 8. Lee S et al.. 2019. Low-Density Lipoprotein Particle Size Subfractions and Cerebral Amyloidosis.. J Alzheimers Dis 68(3):983-990 PMID: 30883362
