GO:0031729 CCR4 chemokine receptor binding: Mechanism, Genes and Research Methods
Research-grade guide for scientists and biopharma professionals
Key Takeaways
• GO:0031729 (CCR4 chemokine receptor binding) is a molecular function describing the binding of a ligand to the CCR4 chemokine receptor.
• CCR4 is a G-protein-coupled receptor that binds chemokines such as CCL22 and CCL17, and also non-chemokine ligands like CKLF1 [2, 4, 6].
• Ligand binding to CCR4 can trigger receptor internalization and downstream signaling, which is relevant for immune cell migration and activation.
• CCR4 and its ligands are implicated in allergy, cancer, and cardiovascular disease, making this interaction a therapeutic target [2, 3, 4].
• Experimental approaches to study CCR4 binding include binding assays, internalization assays, and structural modeling [5, 7].
• EDITGENE provides CRISPR services to create knockout, point-mutation, knock-in, and overexpression models for studying CCR4 chemokine receptor binding.
Description
GO:0031729, CCR4 chemokine receptor binding, is a molecular function term that describes the binding of a ligand to the CCR4 chemokine receptor. CCR4 is a seven-transmembrane G-protein-coupled receptor that is expressed on various immune cells, including T helper 2 cells and regulatory T cells. The binding of chemokines such as CCL22 and CCL17 to CCR4 plays a critical role in immune cell trafficking and activation. This term is essential for understanding how extracellular signals are translated into cellular responses, particularly in the context of inflammation and immunity. Researchers study CCR4 chemokine receptor binding to elucidate mechanisms of allergic diseases, cancer progression, and cardiovascular repair [2, 3, 4]. The interaction is also targeted by small molecule antagonists and modified chemokines, highlighting its therapeutic potential [5, 8]. In this article, we provide a comprehensive overview of the ontology, mechanisms, key genes, and research methods associated with GO:0031729.
CCR4 chemokine receptor binding At A Glance
| GO ID | GO:0031729 |
|---|---|
| GO term | CCR4 chemokine receptor binding |
| Ontology | molecular_function |
| Synonym | CCR4 chemokine receptor ligand |
| Major function | Binding to CCR4 chemokine receptor, initiating signaling and cellular responses |
| Related ligands | CCL22, CCL17, CKLF1 |
| Related receptor | CCR4 (C-C chemokine receptor type 4) |
| Associated processes | Immune cell migration, allergic inflammation, cancer metastasis |
What Is GO:0031729?
CCR4 chemokine receptor binding (GO:0031729) is defined as the binding to a CCR4 chemokine receptor. This molecular function encompasses the interaction between a ligand, such as a chemokine or a non-chemokine protein, and the CCR4 receptor. It is a critical step in initiating receptor-mediated signaling events that regulate cell migration, adhesion, and activation. The term is used to annotate gene products that physically interact with CCR4, including chemokines like CCL22 and CCL17, and other ligands such as CKLF1 [4, 6].
Why Is CCR4 chemokine receptor binding Important in Cell Biology?
CCR4 chemokine receptor binding is important because it governs fundamental immune cell behaviors, including chemotaxis and activation, which are central to host defense and inflammatory diseases. Dysregulation of this interaction contributes to allergy, asthma, and cancer progression, as CCR4 is often overexpressed on malignant T cells and regulatory T cells that suppress anti-tumor immunity [2, 4]. Moreover, CCR4 binding by ligands such as CKLF1 has been implicated in cardiovascular repair and stroke [1, 3]. Understanding this molecular function is therefore critical for developing targeted therapies, including small molecule antagonists and biologics [5, 8].
• CCR4 binding mediates recruitment of immune cells to sites of inflammation, affecting allergy and asthma.
• CCR4 is a marker of Th2 and regulatory T cells, influencing immune tolerance and tumor immunity.
• Ligand binding to CCR4 can trigger receptor internalization, a process targeted by antagonists.
• CCR4 and its ligands are involved in cardiovascular repair after myocardial infarction.
• CKLF1 binding to CCR4 contributes to microglial efferocytosis disruption in ischemic stroke.
• CCR4 antagonists are explored for treating allergic diseases and lymphomas.
• Structural studies of CCR4 binding inform drug design.
• CCR4 binding is a model for understanding GPCR-ligand interactions.
What Happens During CCR4 chemokine receptor binding?
Ligand recognition and binding
In simple terms: A ligand molecule docks onto the CCR4 receptor on the cell surface.
The binding of ligands such as CCL22 or CCL17 to CCR4 involves specific interactions with the receptor's extracellular loops and N-terminus. This recognition is highly specific and can be influenced by the ligand's conformation. Non-chemokine ligands like CKLF1 also bind CCR4 through distinct peptide regions.
Receptor conformational changes
In simple terms: Upon binding, the receptor changes shape to transmit a signal inside the cell.
Ligand binding induces conformational changes in CCR4, particularly in the transmembrane helices, leading to activation of associated G-proteins. Distinct conformations of CCR4 have been observed, which may dictate differential signaling outcomes.
Receptor internalization
In simple terms: After binding, the receptor can be pulled into the cell, turning off the signal.
Internalization of CCR4 can be evoked by both orthosteric and allosteric antagonists, as well as by natural ligands. This process regulates receptor availability and signaling duration.
Downstream signaling
In simple terms: The signal from the receptor triggers a cascade of events inside the cell.
Activated CCR4 couples to G-proteins, leading to downstream pathways such as calcium flux and chemotaxis. These signaling events are critical for immune cell migration and function.
Key Genes Involved in GO:0031729 CCR4 chemokine receptor binding
The following genes and proteins are key players in CCR4 chemokine receptor binding and its associated functions.
| Gene | Major Role | Research Relevance |
|---|---|---|
| CCR4 | Receptor for chemokines; mediates signaling | Target for allergy and cancer therapy |
| CCL22 | Chemokine ligand for CCR4 | Promotes positive selection in germinal centers |
| CCL17 | Chemokine ligand for CCR4 | Involved in Th2-mediated inflammation |
| CKLF1 | Non-chemokine ligand for CCR4 | Disrupts microglial efferocytosis in stroke |
| CCR4 antagonists | Small molecules that block CCR4 | Therapeutic potential in allergy |
| GNAI | G-protein subunit coupled to CCR4 | Mediates downstream signaling |
| ARRB1 | Beta-arrestin, involved in internalization | Regulates receptor desensitization |
| GRK2 | G-protein-coupled receptor kinase | Phosphorylates activated CCR4 |
| PIK3CD | Phosphoinositide 3-kinase | Downstream of CCR4 in immune cells |
| AKT1 | Serine/threonine kinase | Survival signaling downstream of CCR4 |
| MAPK1 | Mitogen-activated protein kinase | Transmits signals from CCR4 |
| NFKB1 | Transcription factor | Activated by CCR4 signaling |
| CD4 | T cell co-receptor | Marks CCR4-expressing T cells |
| FOXP3 | Regulatory T cell marker | Co-expressed with CCR4 in Tregs |
| CCR4 ligands | Endogenous chemokines | Studied for binding affinity |
| CKLF | Chemokine-like factor | Binds CCR4 and modulates inflammation |
| PS | Phosphatidylserine | Interacts with CKLF1 in efferocytosis |
How Is CCR4 chemokine receptor binding Regulated?
The binding of ligands to CCR4 is regulated at multiple levels. Receptor expression levels on the cell surface are controlled by transcriptional and post-transcriptional mechanisms. Ligand availability is influenced by secretion from various cell types, including dendritic cells and macrophages. Additionally, receptor desensitization and internalization, mediated by GRK2 and beta-arrestin, modulate the duration of signaling. Allosteric modulators can also affect binding affinity and efficacy.
CCR4 chemokine receptor binding and Human Disease
| Gene | Disease / Biology | Potential Experimental Model |
|---|---|---|
| CCR4 | Allergic asthma | CCR4 knockout mouse |
| CCL22 | Germinal center reactions | CCL22 knock-in mouse |
| CKLF1 | Ischemic stroke | CKLF1 overexpression in microglia |
| CCR4 | Cutaneous T-cell lymphoma | CCR4-overexpressing cell line |
| CCR4 | Myocardial infarction | CCR4 antagonist treatment in mice |
Allergic inflammation and asthma
CCR4 and its ligands CCL22 and CCL17 are key mediators of Th2-driven allergic inflammation. Binding of these chemokines to CCR4 on Th2 cells promotes their recruitment to the lungs, contributing to asthma pathogenesis. Antagonists targeting CCR4 binding are being developed for therapeutic intervention.
Cancer and lymphoma
CCR4 is expressed on certain T-cell lymphomas and regulatory T cells that suppress anti-tumor immunity. Ligand binding promotes tumor cell survival and migration. Targeting CCR4 with antibodies or small molecules is a strategy for treating cutaneous T-cell lymphoma.
Cardiovascular disease and stroke
CKLF1, a ligand for CCR4, disrupts microglial efferocytosis after ischemic stroke, exacerbating brain injury. In myocardial infarction, CCR4-binding ligands influence macrophage function and wound healing. These findings highlight the role of CCR4 binding in cardiovascular repair.
From CCR4 chemokine receptor binding-Related Genes to Experimental Models
| Research Question | Suitable Model |
|---|---|
| Does CCR4 binding mediate Th2 recruitment? | CCR4 knockout mouse |
| What is the affinity of CCL22 for CCR4? | Point-mutated CCR4 in HEK293 cells |
| Can CKLF1 binding to CCR4 be blocked? | Knock-in of CKLF1 binding site mutations |
| How does CCR4 internalization affect signaling? | Tagged CCR4 knock-in for imaging |
| Does CCR4 overexpression drive lymphoma? | CCR4 overexpression in T cells |
| What is the role of CCR4 in wound healing? | Conditional CCR4 knockout in macrophages |
How to Study the CCR4 chemokine receptor binding Process
| Method | What It Measures | Typical Application |
|---|---|---|
| Radioligand binding | Affinity and kinetics of ligand binding | Characterizing CCR4 antagonists |
| Surface plasmon resonance | Real-time binding kinetics | Ligand-receptor interaction studies |
| Flow cytometry | Receptor internalization | Evaluating antagonist efficacy |
| Calcium flux assay | G-protein activation | Functional signaling assays |
| Chemotaxis assay | Cell migration | Immune cell recruitment studies |
| Molecular docking | Predicted binding poses | Virtual screening of inhibitors |
| Western blot | Protein phosphorylation | Downstream signaling analysis |
Binding assays
Radioligand binding assays and surface plasmon resonance (SPR) are used to measure the affinity and kinetics of ligand binding to CCR4. These methods help identify competitive antagonists and characterize binding modes.
Internalization assays
Flow cytometry and fluorescence microscopy can quantify CCR4 internalization following ligand or antagonist treatment. This reveals receptor trafficking and desensitization mechanisms.
Signaling assays
Calcium flux assays, cAMP inhibition, and chemotaxis assays measure downstream signaling events triggered by CCR4 binding. These are used to evaluate functional consequences of ligand-receptor interactions.
Structural modeling and docking
Homology modeling and molecular dynamics simulations provide insights into the binding modes of CCR4 inhibitors and ligands, guiding rational drug design.
How CRISPR Can Be Used to Study GO:0031729 CCR4 chemokine receptor binding
Knockout
CRISPR knockout of CCR4 or its ligands (e.g., CCL22, CKLF1) can abolish binding and downstream signaling, providing causal insights into their roles in immune responses and disease models [1, 2].
Point Mutation
Introducing point mutations in the CCR4 binding pocket or in ligand interaction domains can dissect specific residues critical for binding affinity and selectivity. This helps validate structural models and identify druggable sites.
Knock-in
Knock-in of tagged CCR4 (e.g., GFP or HA) allows real-time imaging of receptor trafficking and internalization upon ligand binding. Knock-in of disease-associated mutations can model altered binding in vivo.
Overexpression
Overexpression of CCR4 or its ligands in cell lines or primary cells can mimic pathological states such as lymphoma or chronic inflammation, enabling studies of binding-driven oncogenesis and immune evasion.
How EDITGENE Supports CCR4 chemokine receptor binding Research
Researchers studying CCR4 chemokine receptor binding-related genes often need to determine whether a candidate gene is causally involved in ligand-receptor interactions, signaling, or disease phenotypes. EDITGENE provides a comprehensive suite of CRISPR-based services to create precisely engineered cell models, enabling rigorous functional validation of genes implicated in GO:0031729.
Contact EDITGENE today to design your custom CRISPR model for CCR4 chemokine receptor binding research.
Frequently Asked Questions About CCR4 chemokine receptor binding
What is CCR4 chemokine receptor binding?
CCR4 chemokine receptor binding (GO:0031729) is a molecular function describing the binding of a ligand, such as a chemokine, to the CCR4 receptor, initiating signaling and cellular responses.
What genes are involved in CCR4 chemokine receptor binding?
Key genes include CCR4 itself, chemokines CCL22 and CCL17, and non-chemokine ligand CKLF1, as well as downstream signaling molecules like G-proteins and arrestins [4, 6].
What diseases are associated with CCR4 chemokine receptor binding?
It is linked to allergic asthma, cutaneous T-cell lymphoma, ischemic stroke, and myocardial infarction [1, 2, 3, 8].
How is CCR4 chemokine receptor binding studied?
Common methods include radioligand binding assays, internalization assays, calcium flux, and molecular docking [5, 7].
What is the role of CCL22 in CCR4 binding?
CCL22 is a high-affinity ligand for CCR4 that promotes positive selection in germinal centers and recruits Th2 cells.
Can CCR4 binding be blocked therapeutically?
Yes, small molecule antagonists and antibodies targeting CCR4 binding are in development for allergy and lymphoma [5, 8].
What is the difference between CCR4 and other chemokine receptors?
CCR4 is a G-protein-coupled receptor with distinct ligand specificity and expression patterns, particularly on Th2 and regulatory T cells.
How does CKLF1 interact with CCR4?
CKLF1 binds CCR4 through its C-terminal peptides, and this interaction disrupts microglial efferocytosis after stroke [1, 6].
What CRISPR models are available for CCR4 research?
EDITGENE offers knockout, point mutation, knock-in, and overexpression models for CCR4 and its ligands, as well as library screening.
Why is CCR4 chemokine receptor binding important for drug discovery?
It is a validated target for allergic and oncological diseases, and understanding binding mechanisms aids in designing effective antagonists [7, 8].
Conclusion
CCR4 chemokine receptor binding (GO:0031729) is a fundamental molecular function that orchestrates immune cell migration and activation. Its dysregulation contributes to allergy, cancer, and cardiovascular disease, making it a prime therapeutic target. Advances in structural biology and CRISPR-based models continue to unravel the intricacies of this interaction. EDITGENE's comprehensive services empower researchers to dissect CCR4 binding mechanisms and accelerate drug discovery.
References
- 1. Fan PL et al.. 2025. CKLF1 disrupts microglial efferocytosis following acute ischemic stroke by binding to phosphatidylserine.. Cell Death Differ 32(8):1499-1517 PMID: 40057593
- 2. Viney JM et al.. 2014. Distinct conformations of the chemokine receptor CCR4 with implications for its targeting in allergy.. J Immunol 192(7):3419-27 PMID: 24563252
- 3. Ismahil MA et al.. 2025. Splenic CD169(+)Tim4(+) Marginal Metallophilic Macrophages Are Essential for Wound Healing After Myocardial Infarction.. Circulation 151(24):1712-1729 PMID: 40289811
- 4. Liu B et al.. 2021. Affinity-coupled CCL22 promotes positive selection in germinal centres.. Nature 592(7852):133-137 PMID: 33597749
- 5. Ajram L et al.. 2014. Internalization of the chemokine receptor CCR4 can be evoked by orthosteric and allosteric receptor antagonists.. Eur J Pharmacol 729(100):75-85 PMID: 24534492
- 6. Wang Y et al.. 2008. Two C-terminal peptides of human CKLF1 interact with the chemokine receptor CCR4.. Int J Biochem Cell Biol 40(5):909-19 PMID: 18069042
- 7. Gadhe CG et al.. 2015. Insights into the binding modes of CC chemokine receptor 4 (CCR4) inhibitors: a combined approach involving homology modelling, docking, and molecular dynamics simulation studies.. Mol Biosyst 11(2):618-34 PMID: 25474265
- 8. DeSantis AJ et al.. 2021. Chemokine receptor antagonists with α(1)-adrenergic receptor blocker activity.. J Basic Clin Physiol Pharmacol 33(4):519-523 PMID: 34144642
