GO:0070325 lipoprotein particle receptor binding: Mechanism, Genes and Research Methods
Research-grade guide for scientists and biopharma professionals
Key Takeaways
• GO:0070325 lipoprotein particle receptor binding is a molecular function defined as binding to a lipoprotein particle receptor.
• It mediates the initial recognition step between lipoprotein particles and cell-surface receptors, controlling lipid uptake and catabolism.
• Key proteins include LDLR, LRP1, VLDLR, TREM2, APOE, CLU, and cubilin, which bind apolipoproteins or lipoprotein particles.
• Dysregulation of this binding contributes to atherosclerosis, foam cell formation, and Alzheimer's disease pathology.
• Experimental approaches include surface plasmon resonance, isothermal titration calorimetry, and CRISPR-based knockout models.
• The term is distinct from lipoprotein receptor activity (GO:0005041) and lipoprotein binding (GO:0008034), focusing specifically on receptor-ligand recognition.
Description
GO:0070325 lipoprotein particle receptor binding is a molecular function term in the Gene Ontology that describes the binding of a protein or lipoprotein particle to a lipoprotein particle receptor. This interaction is fundamental to lipid metabolism, as it initiates the cellular uptake and catabolism of lipoproteins such as LDL, VLDL, and HDL. The term encompasses the physical association between apolipoproteins (e.g., APOE, APOB) or lipoprotein-associated proteins and receptors like LDLR, LRP1, VLDLR, and cubilin. Researchers study this function to understand how cells acquire cholesterol and other lipids, and how defects in this process lead to diseases such as atherosclerosis and neurodegeneration. The binding event is often the first step in receptor-mediated endocytosis, but the GO term itself is restricted to the binding function, not the downstream internalization.
lipoprotein particle receptor binding At A Glance
| GO ID | GO:0070325 |
|---|---|
| GO term | lipoprotein particle receptor binding |
| Ontology | molecular_function |
| Synonym | none |
| Definition | Binding to a lipoprotein particle receptor. |
| Major function | Mediates recognition and binding of lipoprotein particles or apolipoproteins to cell-surface receptors, initiating lipid uptake and metabolism. |
| Related terms | lipoprotein receptor activity (GO:0005041), lipoprotein binding (GO:0008034), receptor-mediated endocytosis (GO:0006898) |
| Key ligands | APOE, APOB, CLU, LPL, Lp(a) |
| Key receptors | LDLR, LRP1, VLDLR, TREM2, cubilin |
What Is GO:0070325?
In our own words, GO:0070325 lipoprotein particle receptor binding refers to the molecular function of selectively interacting with a lipoprotein particle receptor. This binding can occur between a receptor and a lipoprotein particle (e.g., LDL, VLDL) or between a receptor and an apolipoprotein component (e.g., APOE, APOB). The term does not include the subsequent signaling or endocytosis steps; it strictly describes the binding event as defined by the Gene Ontology.
Why Is lipoprotein particle receptor binding Important in Cell Biology?
Lipoprotein particle receptor binding is essential for maintaining lipid homeostasis, as it controls the clearance of atherogenic lipoproteins from circulation and the delivery of lipids to tissues. Defects in this binding function are directly linked to hypercholesterolemia, atherosclerosis, and neurodegenerative disorders such as Alzheimer's disease. Understanding the molecular details of these interactions informs the development of therapeutics targeting lipid metabolism and neuroinflammation.
• Regulates plasma cholesterol levels by mediating hepatic clearance of LDL and VLDL.
• Contributes to macrophage foam cell formation in atherosclerosis.
• Facilitates amyloid-beta uptake by microglia via TREM2-APOE binding.
• Involved in HDL metabolism through cubilin-mediated binding.
• Modulates lipoprotein catabolism via receptor-associated protein (RAP).
• Affects cholesterol transfer at the plasma membrane.
• Provides targets for lipid-lowering therapies (e.g., statins, PCSK9 inhibitors).
• Plays a role in receptor-independent LDL cargo transfer.
• Links lipid metabolism to innate immunity through TREM2.
• Serves as a model for studying protein-lipoprotein interactions.
Molecular Mechanism of lipoprotein particle receptor binding
Ligand recognition by LDL receptor family members
In simple terms: Receptors like LDLR grab onto lipoproteins by recognizing specific protein tags on their surface.
LDLR, LRP1, and VLDLR bind to apolipoprotein B (APOB) and apolipoprotein E (APOE) on lipoprotein particles. This binding is mediated by complement-type repeats in the receptor's extracellular domain. The 39-kDa receptor-associated protein (RAP) modulates this interaction by binding to LDL receptors and affecting lipoprotein catabolism. The binding affinity is influenced by the lipid composition and size of the lipoprotein particle.
TREM2-APOE interaction in microglia
In simple terms: In the brain, TREM2 acts as a receptor that binds APOE and other apolipoproteins to help microglia take up amyloid-beta.
TREM2 binds directly to apolipoproteins including APOE and CLU/APOJ, facilitating the uptake of amyloid-beta by microglia. This interaction is critical for microglial function and is implicated in Alzheimer's disease risk. The binding is specific and saturable, and it requires the extracellular domain of TREM2.
Cubilin as an HDL receptor
In simple terms: Cubilin is a receptor that binds high-density lipoprotein (HDL) and helps clear it from the blood.
Cubilin, a multiligand receptor, binds to HDL and mediates its endocytosis in tissues such as kidney and yolk sac. This binding is part of the HDL catabolic pathway and is distinct from the classical LDLR pathway. Cubilin's interaction with HDL is calcium-dependent and requires its complement-type repeats.
Receptor-independent transfer of lipoprotein cargo
In simple terms: Lipoproteins can sometimes transfer their lipid cargo directly to cell membranes without a receptor.
Receptor-independent transfer of LDL cargo to biomembranes has been observed, indicating that lipoprotein particle receptor binding is not the only route for lipid delivery. This process may involve direct collision or lipid exchange and is relevant under conditions where receptor expression is low. Cholesterol transfer at the plasma membrane can occur via both receptor-dependent and independent mechanisms.
Structural basis of lipoprotein-receptor binding
In simple terms: The shape and chemical properties of both the lipoprotein and the receptor determine how tightly they stick together.
Structural studies of lipoprotein receptors reveal that ligand binding often involves electrostatic interactions between basic residues on apolipoproteins and acidic residues on receptors. For example, the LDLR binds APOB via a cluster of positively charged amino acids. The binding is pH-dependent, with release occurring in the acidic environment of endosomes. These structural details are critical for designing inhibitors or modulators of lipoprotein particle receptor binding.
Key Genes Involved in GO:0070325 lipoprotein particle receptor binding
The following genes encode proteins that directly participate in lipoprotein particle receptor binding, either as receptors or as ligands.
| Gene | Major Role | Research Relevance |
|---|---|---|
| LDLR | Binds APOB and APOE on LDL particles | Mutations cause familial hypercholesterolemia; target for statins |
| LRP1 | Binds multiple lipoproteins and apolipoproteins | Implicated in Alzheimer's disease and atherosclerosis |
| VLDLR | Binds VLDL and Lp(a) | Mediates macrophage foam cell formation |
| TREM2 | Binds APOE and CLU/APOJ | Alzheimer's disease risk gene; microglial function |
| APOE | Ligand for LDLR, LRP1, TREM2 | Major risk factor for Alzheimer's disease |
| CLU | Binds TREM2; also known as APOJ | Alzheimer's disease risk gene |
| Cubilin | Binds HDL | Mediates HDL catabolism |
| APOB | Ligand for LDLR | Structural component of LDL |
| LPL | Binds VLDL receptor | Triglyceride hydrolysis; foam cell formation |
| LPA | Binds VLDL receptor | Lipoprotein(a) particle; cardiovascular risk |
| RAP | Modulates LDLR binding | Chaperone for LDL receptor family |
| SCARB1 | Binds HDL | HDL receptor; cholesterol efflux |
| ABCA1 | Not a receptor but affects lipoprotein binding | Cholesterol efflux; HDL biogenesis |
| PCSK9 | Binds LDLR and promotes degradation | Therapeutic target for hypercholesterolemia |
| SORL1 | Binds APOE | Alzheimer's disease risk gene |
| PLA2G7 | Binds lipoproteins | Inflammatory marker; cardiovascular risk |
| CETP | Transfers lipids between lipoproteins | Drug target for raising HDL |
How Is lipoprotein particle receptor binding Regulated?
The binding of lipoprotein particles to their receptors is regulated at multiple levels. Receptor expression is controlled by sterol regulatory element-binding proteins (SREBPs) in response to cellular cholesterol levels. PCSK9 binds to LDLR and promotes its degradation, thereby reducing lipoprotein particle receptor binding. The receptor-associated protein (RAP) acts as a chaperone and modulator, preventing premature binding and facilitating proper folding of LDL receptor family members. In microglia, TREM2 expression and its binding to APOE are regulated by inflammatory signals and lipid environment. Additionally, post-translational modifications such as glycosylation and phosphorylation can affect receptor affinity for lipoproteins.
lipoprotein particle receptor binding and Human Disease
| Gene | Disease / Biology | Potential Experimental Model |
|---|---|---|
| LDLR | Familial hypercholesterolemia | LDLR knockout HepG2 cells; binding assays |
| TREM2 | Alzheimer's disease | TREM2 knockout microglia; APOE binding assays |
| VLDLR | Atherosclerosis / foam cell formation | VLDLR knockout macrophages; Lp(a) binding |
| Cubilin | HDL metabolism disorders | Cubilin knockout kidney cells; HDL binding |
| APOE | Alzheimer's disease / cardiovascular | APOE4 knock-in mice; TREM2 binding |
Atherosclerosis and foam cell formation
Dysregulated lipoprotein particle receptor binding contributes to atherosclerosis by promoting the uptake of modified lipoproteins (e.g., oxidized LDL) by macrophages, leading to foam cell formation. VLDL receptor and LPL-mediated binding of triglyceride-rich lipoproteins and Lp(a) are key pathways in this process. Impaired clearance of LDL due to defective LDLR binding results in hypercholesterolemia and plaque buildup.
Alzheimer's disease and neurodegeneration
In Alzheimer's disease, TREM2 binds to APOE and CLU/APOJ to facilitate amyloid-beta uptake by microglia. Loss-of-function mutations in TREM2 or APOE isoforms (e.g., APOE4) impair this binding, leading to reduced amyloid clearance and increased neuroinflammation. LRP1 and SORL1 also participate in neuronal lipoprotein binding and are linked to Alzheimer's risk.
Cardiovascular disease and lipid disorders
Mutations in LDLR that abolish lipoprotein particle receptor binding cause familial hypercholesterolemia, characterized by high LDL cholesterol and premature cardiovascular disease. Cubilin dysfunction affects HDL catabolism and may influence reverse cholesterol transport. Elevated Lp(a) levels, which involve VLDL receptor binding, are an independent risk factor for cardiovascular disease.
From lipoprotein particle receptor binding-Related Genes to Experimental Models
| Research Question | Suitable Model |
|---|---|
| Does LDLR bind APOB with high affinity? | LDLR knockout HEK293T cells + APOB binding assay |
| How does TREM2-APOE binding affect amyloid uptake? | TREM2 knockout microglia + APOE3/4 knock-in |
| What is the role of VLDLR in foam cell formation? | VLDLR knockout macrophages + Lp(a) treatment |
| Does cubilin mediate HDL endocytosis? | Cubilin knockout proximal tubule cells |
| Can PCSK9 modulate LDLR binding? | PCSK9 overexpression in hepatocytes |
| Is receptor-independent LDL transfer relevant? | LDLR knockout fibroblasts + fluorescent LDL |
How to Study the lipoprotein particle receptor binding Process
| Method | What It Measures | Typical Application |
|---|---|---|
| Surface plasmon resonance | Binding affinity and kinetics | Receptor-lipoprotein interaction |
| Isothermal titration calorimetry | Thermodynamics of binding | APOE-TREM2 binding |
| ELISA | Quantitative binding | Screening inhibitors |
| Flow cytometry | Cell-surface binding and uptake | LDL uptake in knockout cells |
| Confocal microscopy | Subcellular localization of binding | Receptor trafficking |
| AP-MS | Protein-protein interactions | Identifying novel receptors |
| CRISPR knockout | Gene function in binding | LDLR, TREM2, VLDLR |
Binding assays (SPR, ITC, ELISA)
Surface plasmon resonance (SPR) and isothermal titration calorimetry (ITC) measure real-time binding kinetics and affinity between purified receptors and lipoproteins. ELISA-based assays can quantify binding of APOE or APOB to immobilized receptors. These methods are used to determine dissociation constants (Kd) and to screen for inhibitors.
CRISPR knockout and knock-in models
CRISPR-Cas9 knockout of receptor genes (e.g., LDLR, TREM2) in cell lines allows assessment of binding specificity and downstream effects. Knock-in of disease-associated mutations (e.g., APOE4) enables study of altered binding affinities. These models are essential for validating gene function in lipoprotein particle receptor binding.
Imaging and flow cytometry
Fluorescently labeled lipoproteins (e.g., DiI-LDL) can be used to visualize binding and uptake by flow cytometry or confocal microscopy. This approach quantifies cell-surface binding and internalization in live cells. It is particularly useful for studying receptor-independent transfer.
Proteomics and interactomics
Affinity purification coupled with mass spectrometry (AP-MS) can identify novel lipoprotein particle receptor binding partners. Proximity ligation assays (PLA) can detect in situ interactions between receptors and lipoproteins. These methods help map the interactome of lipoprotein receptors.
How CRISPR Can Be Used to Study GO:0070325 lipoprotein particle receptor binding
Knockout
CRISPR knockout of genes encoding lipoprotein receptors (e.g., LDLR, TREM2, VLDLR) is used to abolish binding and assess its contribution to lipid uptake and disease phenotypes. Knockout cell lines provide a clean background for re-expression studies and binding assays.
Point Mutation
Point mutations in receptor genes (e.g., LDLR mutations causing familial hypercholesterolemia) can be introduced to study how specific amino acid changes affect lipoprotein particle receptor binding affinity. This approach helps dissect structure-function relationships.
Knock-in
Knock-in of disease-associated variants (e.g., APOE4, TREM2 R47H) allows study of altered binding to lipoproteins in a physiological context. Knock-in models are valuable for testing allele-specific effects on binding and downstream signaling.
Overexpression
Overexpression of receptors or ligands (e.g., LDLR, APOE) can enhance binding and uptake, enabling biochemical characterization of the interaction. Overexpression systems are also used for high-throughput screening of modulators.
How EDITGENE Supports lipoprotein particle receptor binding Research
Researchers studying lipoprotein particle receptor binding-related genes often need to determine whether a candidate gene is causally involved in lipid uptake, foam cell formation, or neurodegeneration. EDITGENE provides a comprehensive suite of CRISPR-based services to create precisely engineered cell models that answer these questions.
Contact EDITGENE today to design your custom CRISPR model for lipoprotein particle receptor binding research.
Related Products
| Product name | Cat.No. | Species | Gene ID | |
|---|---|---|---|---|
| LRP1 Knockout HEK293 Cell Line | EDJ-KQ103 | Human | 4035 | Details Get a Quote |
| RELN Knockout HEK293 Cell Line | EDJ-KQ863 | Human | 5649 | Details Get a Quote |
| APOA5 Knockout HEK293 Cell Line | EDJ-KQ7576 | Human | 116519 | Details Get a Quote |
| LRP1 Knockout HCT 116 Cell Line | EDJ-KQ18260 | Human | 4035 | Details Get a Quote |
| LRP1 Knockout A-549 Cell Line | EDJ-KQ23776 | Human | 4035 | Details Get a Quote |
| LRP1 Knockout HeLa Cell Line | EDJ-KQ23777 | Human | 4035 | Details Get a Quote |
| RELN Knockout HeLa Cell Line | EDJ-KQ54231 | Human | 5649 | Details Get a Quote |
| APOA5 Knockout HeLa Cell Line | EDJ-KQ57994 | Human | 116519 | Details Get a Quote |
| RELN Knockout A-549 Cell Line | EDJ-KQ62723 | Human | 5649 | Details Get a Quote |
| APOA5 Knockout A-549 Cell Line | EDJ-KQ66480 | Human | 116519 | Details Get a Quote |
| RELN Knockout HCT 116 Cell Line | EDJ-KQ71195 | Human | 5649 | Details Get a Quote |
| APOA5 Knockout HCT 116 Cell Line | EDJ-KQ74903 | Human | 116519 | Details Get a Quote |
| LRP1 Overexpression Jurkat E6.1 Stable Cell Line | EDC01588 | Human | 4035 | Details Get a Quote |
Frequently Asked Questions About lipoprotein particle receptor binding
What is GO:0070325 lipoprotein particle receptor binding?
GO:0070325 is a Gene Ontology molecular function term defined as binding to a lipoprotein particle receptor. It describes the physical interaction between a receptor and a lipoprotein or apolipoprotein, initiating lipid uptake.
What genes are involved in lipoprotein particle receptor binding?
Key genes include LDLR, LRP1, VLDLR, TREM2, APOE, CLU, cubilin, and APOB, among others.
How is lipoprotein particle receptor binding studied?
Common methods include surface plasmon resonance, isothermal titration calorimetry, ELISA, flow cytometry, and CRISPR knockout models.
What diseases are associated with defects in lipoprotein particle receptor binding?
Defects are linked to atherosclerosis, familial hypercholesterolemia, and Alzheimer's disease.
What is the difference between lipoprotein particle receptor binding and lipoprotein receptor activity?
Binding (GO:0070325) refers only to the physical interaction, while receptor activity (GO:0005041) encompasses downstream signaling or transport.
Which receptor binds APOE in microglia?
TREM2 binds APOE and other apolipoproteins to facilitate amyloid-beta uptake.
How does cubilin function as an HDL receptor?
Cubilin binds HDL and mediates its endocytosis, contributing to HDL catabolism.
Can lipoprotein particle receptor binding occur without a receptor?
Yes, receptor-independent transfer of LDL cargo to biomembranes has been observed.
What is the role of RAP in lipoprotein particle receptor binding?
RAP modulates lipoprotein catabolism by binding to LDL receptors and affecting their ligand-binding ability.
How can CRISPR help study lipoprotein particle receptor binding?
CRISPR knockout, knock-in, and overexpression models allow precise manipulation of receptor genes to test their role in binding and disease.
Conclusion
GO:0070325 lipoprotein particle receptor binding is a central molecular function in lipid metabolism, mediating the recognition of lipoproteins by cell-surface receptors. Its dysregulation underlies major diseases including atherosclerosis and Alzheimer's disease. Continued research using CRISPR models and advanced binding assays will clarify the mechanistic details and identify new therapeutic targets.
References
- 1. Yeh FL et al.. 2016. TREM2 Binds to Apolipoproteins, Including APOE and CLU/APOJ, and Thereby Facilitates Uptake of Amyloid-Beta by Microglia.. Neuron 91(2):328-40 PMID: 27477018
- 2. Medh JD et al.. 1995. The 39-kDa receptor-associated protein modulates lipoprotein catabolism by binding to LDL receptors.. J Biol Chem 270(2):536-40 PMID: 7822276
- 3. Takahashi S. 2017. Triglyceride Rich Lipoprotein -LPL-VLDL Receptor and Lp(a)-VLDL Receptor Pathways for Macrophage Foam Cell Formation.. J Atheroscler Thromb 24(6):552-559 PMID: 28428482
- 4. Moestrup SK et al.. 2000. Cubilin, a high-density lipoprotein receptor.. Curr Opin Lipidol 11(2):133-40 PMID: 10787174
- 5. Weisgraber KH et al.. 1985. Receptor interactions controlling lipoprotein metabolism.. Can J Biochem Cell Biol 63(8):898-905 PMID: 2998579
- 6. Axmann M et al.. 2019. Cholesterol transfer at the plasma membrane.. Atherosclerosis 290:111-117 PMID: 31605876
- 8. Axmann M et al.. 2019. Receptor-Independent Transfer of Low Density Lipoprotein Cargo to Biomembranes.. Nano Lett 19(4):2562-2567 PMID: 30848605
