GO:0050750 low-density lipoprotein particle receptor binding: Mechanism, Genes and Research Methods
Research-grade guide for scientists and biopharma professionals
Key Takeaways
• GO:0050750 describes the molecular function of binding to a low-density lipoprotein (LDL) receptor, a key interaction in lipoprotein metabolism.
• The primary ligand is apolipoprotein B100 (APOB100), which mediates LDL particle recognition by the LDL receptor (LDLR).
• This binding is the first step in receptor-mediated endocytosis of LDL, controlling plasma cholesterol levels.
• Genetic or functional defects in this interaction cause hypercholesterolemia and contribute to atherosclerosis.
• The LDL receptor also binds other ligands, including apolipoprotein E and certain viruses, expanding its biological roles.
• Research on GO:0050750 uses structural biology, binding assays, and CRISPR-based models to dissect mechanism and disease links [1,2].
Description
GO:0050750, low-density lipoprotein particle receptor binding, is a molecular function term that describes the physical interaction between a low-density lipoprotein (LDL) particle and its receptor. This binding event is fundamental to cholesterol homeostasis, as it initiates the clearance of LDL from circulation. The primary receptor involved is the LDL receptor (LDLR), a cell-surface glycoprotein that recognizes apolipoprotein B100 (APOB100) on LDL particles. Defects in this binding lead to elevated plasma LDL cholesterol, a major risk factor for cardiovascular disease. Beyond cholesterol metabolism, this interaction has been implicated in viral entry and neurodegenerative processes [2,7]. Understanding the molecular details of GO:0050750 is therefore critical for developing therapies targeting hypercholesterolemia and related disorders.
low-density lipoprotein particle receptor binding At A Glance
| GO ID | GO:0050750 |
|---|---|
| GO term | low-density lipoprotein particle receptor binding |
| Ontology | molecular_function |
| Synonym | LDL receptor binding, low-density lipoprotein receptor binding |
| Major function | Binding to LDL receptor, mediating LDL uptake and clearance |
| Major ligand | Apolipoprotein B100 (APOB100) |
| Major receptor | Low-density lipoprotein receptor (LDLR) |
| Related process | Receptor-mediated endocytosis, cholesterol homeostasis |
| Disease relevance | Hypercholesterolemia, atherosclerosis, viral infection [2,6] |
What Is GO:0050750?
According to the Gene Ontology, GO:0050750 is defined as the binding to a low-density lipoprotein receptor. In other words, it is the molecular function of a ligand (such as apolipoprotein B100) physically interacting with an LDL receptor, typically on the cell surface. This binding is non-covalent and specific, and it can trigger downstream cellular responses such as endocytosis [1,8].
Why Is low-density lipoprotein particle receptor binding Important in Cell Biology?
GO:0050750 is central to lipid metabolism and human health because it governs the clearance of LDL particles from the bloodstream. The binding of APOB100 to LDLR is the rate-limiting step in LDL uptake, and its dysfunction directly causes familial hypercholesterolemia and accelerates atherosclerosis. Moreover, this binding function is exploited by pathogens such as encephalitic alphaviruses to gain entry into cells. Thus, understanding GO:0050750 provides insights into both metabolic disease and infectious disease mechanisms.
• Regulates plasma cholesterol levels by mediating LDL clearance.
• Mutations in LDLR or APOB that impair binding cause familial hypercholesterolemia.
• The interaction is a target for cholesterol-lowering therapies (e.g., statins, PCSK9 inhibitors).
• LDL receptor binding is exploited by viruses, including Venezuelan equine encephalitis virus.
• Altered LDL particle size and binding affinity are linked to cerebral amyloidosis in Alzheimer's disease.
• Scavenger receptors also bind modified LDL, contributing to foam cell formation in atherosclerosis.
• Transendothelial transport of LDL involves receptor binding and is relevant to plaque development.
• Receptor-independent transfer of LDL cargo to biomembranes highlights alternative pathways.
Molecular Mechanism of low-density lipoprotein particle receptor binding
Ligand recognition by the LDL receptor
In simple terms: The LDL receptor grabs onto LDL particles via a specific protein called APOB100.
The LDL receptor (LDLR) contains a ligand-binding domain composed of seven LA repeats that recognize apolipoprotein B100 (APOB100) on the surface of LDL particles. Structural studies have revealed that the receptor binds to a specific region of APOB100, primarily through ionic interactions between acidic residues in the receptor and basic residues in APOB100. This binding is highly specific and is the first step in receptor-mediated endocytosis.
Conformational changes and cofactor involvement
In simple terms: After binding, the receptor changes shape to release the LDL particle inside the cell.
Upon binding LDL, the LDL receptor undergoes a conformational change that allows it to cluster in clathrin-coated pits. The release of the ligand in the endosome is pH-dependent, requiring acidification. While no enzymatic cofactors are directly involved in the binding event itself, the interaction is modulated by auxiliary proteins such as PCSK9, which can bind to the receptor and prevent recycling.
Binding affinity and kinetics
In simple terms: The strength of the bond between LDL and its receptor can vary between individuals and disease states.
The binding affinity of LDL for the LDL receptor is a key determinant of clearance efficiency. Studies in patients with hyperlipoproteinemia have shown that LDL binding affinity can be altered, contributing to elevated cholesterol levels. The affinity is typically in the nanomolar range and is influenced by the lipid composition and size of the LDL particle.
Receptor-independent and alternative binding pathways
In simple terms: Sometimes LDL can interact with membranes without the classic receptor.
In addition to the canonical LDLR pathway, LDL particles can transfer their cargo to biomembranes in a receptor-independent manner, as shown by in vitro studies. Scavenger receptors, such as SR-A and CD36, can also bind modified LDL, contributing to foam cell formation in atherosclerosis. These alternative pathways highlight the complexity of LDL-receptor interactions.
Viral exploitation of LDL receptor binding
In simple terms: Some viruses use the LDL receptor as a door to enter cells.
The LDL receptor is not only a metabolic receptor but also a viral entry factor. Encephalitic alphaviruses, including Venezuelan equine encephalitis virus, bind to the LDL receptor to infect cells. This interaction mimics the natural ligand binding and highlights the broad specificity of the receptor.
Key Genes Involved in GO:0050750 low-density lipoprotein particle receptor binding
The following genes and proteins are directly involved in or regulate low-density lipoprotein particle receptor binding (GO:0050750).
| Gene | Major Role | Research Relevance |
|---|---|---|
| LDLR | Primary receptor for LDL binding and uptake | Mutations cause familial hypercholesterolemia; target for statins |
| APOB | Ligand on LDL particles that binds LDLR | Mutations affect binding affinity and cholesterol levels |
| PCSK9 | Regulates LDLR recycling; binds LDLR | Target for cholesterol-lowering antibodies |
| APOE | Ligand for LDLR and related receptors | Isoforms affect Alzheimer's risk and lipid metabolism |
| LDLRAP1 | Adaptor protein for LDLR endocytosis | Mutations cause autosomal recessive hypercholesterolemia |
| MYLIP | E3 ubiquitin ligase that degrades LDLR | Regulates LDLR levels post-transcriptionally |
| SCARB1 | Scavenger receptor for HDL and LDL | Involved in selective cholesterol uptake |
| CD36 | Scavenger receptor for oxidized LDL | Mediates foam cell formation in atherosclerosis |
| MSR1 | Macrophage scavenger receptor for modified LDL | Contributes to plaque formation |
| VLDLR | Very low-density lipoprotein receptor | Binds APOE and plays roles in brain and periphery |
| LRP1 | LDL receptor-related protein 1 | Binds multiple ligands including APOE and alpha-2-macroglobulin |
| SORT1 | Sortilin, regulates VLDL secretion and LDL uptake | GWAS locus for LDL cholesterol |
| IDOL | Inducible degrader of LDLR | Ubiquitinates LDLR for degradation |
| HMGCR | Rate-limiting enzyme in cholesterol synthesis | Target of statins; feedback regulates LDLR |
| NPC1L1 | Intestinal cholesterol absorption | Target of ezetimibe; indirectly affects LDL levels |
| ABCA1 | Cholesterol efflux pump | Mutations cause Tangier disease; affects HDL |
| CETP | Cholesteryl ester transfer protein | Modulates LDL and HDL levels |
How Is low-density lipoprotein particle receptor binding Regulated?
The binding of LDL to its receptor is regulated at multiple levels. Transcriptionally, the LDLR gene is controlled by the SREBP-2 pathway in response to cellular cholesterol levels. Post-translationally, PCSK9 binds to LDLR and promotes its degradation, reducing the number of receptors available for binding. Additionally, the inducible degrader of LDLR (IDOL) ubiquitinates LDLR, targeting it for lysosomal degradation. These regulatory mechanisms ensure tight control of plasma cholesterol.
low-density lipoprotein particle receptor binding and Human Disease
| Gene | Disease / Biology | Potential Experimental Model |
|---|---|---|
| LDLR | Familial hypercholesterolemia, atherosclerosis | LDLR knockout mouse, patient-derived iPSCs |
| APOB | Familial hypercholesterolemia, hypobetalipoproteinemia | APOB knockout or knock-in mouse |
| PCSK9 | Hypercholesterolemia, cardiovascular disease | PCSK9 transgenic or knockout mouse |
| APOE | Alzheimer's disease, atherosclerosis | APOE isoform knock-in mouse |
| SCARB1 | Cardiovascular disease, infertility | SCARB1 knockout mouse |
Familial hypercholesterolemia and atherosclerosis
Mutations in LDLR or APOB that impair LDL binding cause familial hypercholesterolemia, characterized by high plasma LDL cholesterol and premature atherosclerosis. The binding affinity of LDL for the receptor is a critical determinant of disease severity. Atherosclerosis develops as excess LDL accumulates in the arterial wall, leading to foam cell formation and plaque buildup.
Viral infections
The LDL receptor serves as an entry receptor for multiple encephalitic alphaviruses, including Venezuelan equine encephalitis virus and Eastern equine encephalitis virus. This binding function is independent of cholesterol metabolism and highlights the receptor's role in infectious disease.
Neurodegeneration and cerebral amyloidosis
LDL particle size subfractions and binding affinity have been associated with cerebral amyloidosis in Alzheimer's disease. APOE, a ligand for LDL receptor family members, is a major genetic risk factor for late-onset Alzheimer's disease. The interplay between lipid metabolism and amyloid deposition is an active area of research.
From low-density lipoprotein particle receptor binding-Related Genes to Experimental Models
| Research Question | Suitable Model |
|---|---|
| Does a candidate gene affect LDL binding? | CRISPR knockout in HepG2 or HeLa cells followed by LDL binding assay |
| What is the effect of a point mutation in LDLR on binding affinity? | CRISPR point mutation knock-in in cell lines |
| How does a disease-associated variant alter LDLR function? | Knock-in mouse model expressing mutant LDLR |
| Where is LDLR localized during binding? | Tagged knock-in with fluorescent protein |
| Does overexpression of PCSK9 reduce LDL binding? | Overexpression of PCSK9 in hepatocytes |
| Can a drug enhance LDL clearance? | CRISPR screen for regulators of LDL uptake |
How to Study the low-density lipoprotein particle receptor binding Process
| Method | What It Measures | Typical Application |
|---|---|---|
| Surface plasmon resonance | Binding affinity and kinetics | Characterizing LDL-LDLR interaction |
| Isothermal titration calorimetry | Thermodynamics of binding | Measuring binding enthalpy and entropy |
| Flow cytometry | Cell surface binding | Quantifying LDL binding to cells |
| Confocal microscopy | Intracellular trafficking | Visualizing LDL uptake |
| CRISPR knockout screen | Genes regulating LDL uptake | Identifying novel regulators |
| Cryo-EM | High-resolution structure | Determining binding interface |
| Western blot | Protein expression levels | Assessing LDLR levels |
| qPCR | mRNA expression | Measuring LDLR transcription |
Surface plasmon resonance (SPR) and isothermal titration calorimetry (ITC)
These biophysical methods measure the binding affinity and kinetics between LDL particles and the LDL receptor. SPR provides real-time association and dissociation rates, while ITC gives thermodynamic parameters.
Fluorescence microscopy and flow cytometry
Fluorescently labeled LDL can be used to visualize binding and uptake in live cells. Flow cytometry quantifies cell surface binding, while confocal microscopy reveals intracellular trafficking.
CRISPR-based genetic screens
Genome-wide CRISPR knockout or activation screens can identify genes that regulate LDL binding and uptake. These screens use LDL uptake as a readout and have uncovered novel regulators.
Structural biology (cryo-EM and X-ray crystallography)
High-resolution structures of the LDL receptor in complex with APOB100 or other ligands reveal the molecular details of binding. Recent cryo-EM studies have provided insights into the interaction interface.
How CRISPR Can Be Used to Study GO:0050750 low-density lipoprotein particle receptor binding
Knockout
CRISPR knockout of LDLR or APOB in cell lines such as HepG2 or HeLa abolishes LDL binding, providing a clean background to study the function of these genes. Knockout models are essential for validating the specificity of binding assays and for identifying compensatory pathways.
Point Mutation
Introducing disease-associated point mutations (e.g., in LDLR or APOB) via CRISPR base editing or homology-directed repair allows researchers to dissect the impact of specific residues on binding affinity and receptor recycling. Such models mimic familial hypercholesterolemia variants.
Knock-in
Knock-in of tagged LDLR (e.g., GFP or HA) enables real-time tracking of receptor localization and binding dynamics in live cells. Knock-in of human APOB into mouse models facilitates in vivo studies of lipoprotein metabolism.
Overexpression
CRISPR activation (CRISPRa) or lentiviral overexpression of LDLR, PCSK9, or other regulators can enhance or suppress LDL binding, allowing gain-of-function studies. Overexpression of PCSK9 reduces LDLR levels and increases plasma cholesterol.
How EDITGENE Supports low-density lipoprotein particle receptor binding Research
Researchers studying low-density lipoprotein particle receptor binding-related genes often need to determine whether a candidate gene is causally involved in LDL uptake, cholesterol homeostasis, or disease pathogenesis. EDITGENE provides a comprehensive suite of CRISPR services to accelerate this discovery process.
Contact EDITGENE today to design your custom CRISPR model for low-density lipoprotein particle receptor binding research.
Frequently Asked Questions About low-density lipoprotein particle receptor binding
What is GO:0050750?
GO:0050750 is a Gene Ontology molecular function term defined as binding to a low-density lipoprotein receptor. It describes the interaction between LDL particles and their receptor, a key step in cholesterol metabolism.
What genes are involved in low-density lipoprotein particle receptor binding?
Key genes include LDLR (the receptor), APOB (the ligand), PCSK9 (a regulator), and APOE (an alternative ligand) [1,6,8].
How does LDL bind to its receptor?
LDL binds to the LDL receptor via apolipoprotein B100 (APOB100) through ionic interactions between acidic residues in the receptor and basic residues in APOB100.
What diseases are associated with defects in LDL receptor binding?
Defects cause familial hypercholesterolemia, atherosclerosis, and have been linked to cerebral amyloidosis and viral infections [2,6,7].
What is the role of PCSK9 in LDL receptor binding?
PCSK9 binds to the LDL receptor and promotes its degradation, reducing the number of receptors available for LDL binding.
How can I study LDL receptor binding in the lab?
Common methods include surface plasmon resonance, flow cytometry, fluorescence microscopy, and CRISPR-based genetic screens [1,8].
What CRISPR models are available for studying LDL receptor binding?
Knockout, point mutation, knock-in, and overexpression models can be generated in cell lines and mice to study LDLR, APOB, and related genes [1,6,8].
Is LDL receptor binding involved in viral entry?
Yes, the LDL receptor serves as an entry receptor for multiple encephalitic alphaviruses, including Venezuelan equine encephalitis virus.
What is the difference between LDL receptor binding and scavenger receptor binding?
LDL receptor binding is specific for apolipoprotein B100 and mediates cholesterol uptake, while scavenger receptors bind modified LDL and contribute to foam cell formation.
How does LDL particle size affect receptor binding?
LDL particle size subfractions have been associated with cerebral amyloidosis, and smaller, denser LDL may have altered binding affinity.
Conclusion
GO:0050750, low-density lipoprotein particle receptor binding, is a fundamental molecular function that controls cholesterol homeostasis and impacts human health. Its dysregulation leads to hypercholesterolemia and atherosclerosis, and it is exploited by pathogens. Continued research using advanced CRISPR models and biophysical methods will further illuminate its mechanisms and therapeutic potential.
References
- 1. Reimund M et al.. 2025. Structure of apolipoprotein B100 bound to the low-density lipoprotein receptor.. Nature 638(8051):829-835 PMID: 39663455
- 2. Ma H et al.. 2024. The low-density lipoprotein receptor promotes infection of multiple encephalitic alphaviruses.. Nat Commun 15(1):246 PMID: 38172096
- 3. Axmann M et al.. 2019. Receptor-Independent Transfer of Low Density Lipoprotein Cargo to Biomembranes.. Nano Lett 19(4):2562-2567 PMID: 30848605
- 4. Adachi H et al.. 2006. Endothelial scavenger receptors.. Prog Lipid Res 45(5):379-404 PMID: 16712941
- 5. Jang E et al.. 2020. Transendothelial transport of lipoproteins.. Atherosclerosis 315:111-125 PMID: 33032832
- 6. Toyota Y et al.. 1999. Low density lipoprotein (LDL) binding affinity for the LDL receptor in hyperlipoproteinemia.. Atherosclerosis 147(1):77-86 PMID: 10525128
- 7. Lee S et al.. 2019. Low-Density Lipoprotein Particle Size Subfractions and Cerebral Amyloidosis.. J Alzheimers Dis 68(3):983-990 PMID: 30883362
- 8. Rhainds D et al.. 1999. Low density lipoprotein uptake: holoparticle and cholesteryl ester selective uptake.. Int J Biochem Cell Biol 31(9):915-31 PMID: 10533283
