GO:0019957 C-C chemokine binding: Mechanism, Genes and Research Methods
Research-grade guide for scientists and biopharma professionals
Key Takeaways
• GO:0019957 C-C chemokine binding is a molecular function describing the selective binding of a protein or proteoglycan to C-C chemokines, which lack an amino acid between the first two cysteines of the four-cysteine motif.
• C-C chemokine binding is mediated by seven-transmembrane chemokine receptors, atypical chemokine receptors, viral chemokine-binding proteins, and glycosaminoglycans such as chondroitin sulfate B [2, 3, 8].
• The interaction controls leukocyte recruitment, immune surveillance, and cancer progression, with CCL18 binding to PITPNM3 or Nir1 promoting breast cancer metastasis through PI3K/Akt/GSK3β/Snail signaling [5, 6].
• Viral chemokine-binding proteins such as vCCI bind C-C chemokines with high affinity and are used as tools to dissect binding specificity and to design inhibitors [2, 7].
• C-C chemokine binding is regulated at multiple levels, including post-transcriptional m6A modification of Ccl28 mRNA that affects Treg recruitment in renal ischemia-reperfusion injury.
• Experimental approaches include in situ binding assays, rational protein design, and CRISPR-based knockout, knock-in, point-mutation, and overexpression models to test binding function in disease [3, 7].
Description
C-C chemokine binding (GO:0019957) is a molecular function defined as binding to a C-C chemokine, a subclass of chemokines in which the first two cysteines of the characteristic four-cysteine motif are adjacent, with no intervening amino acid. This binding event is the first step in translating chemokine gradients into cellular responses such as directed migration, adhesion, and activation. Because C-C chemokines control the trafficking of monocytes, T cells, eosinophils, and other leukocytes, proteins that bind them are central to inflammation, immunity, and cancer biology [2, 3]. Researchers study C-C chemokine binding to understand how immune cells are recruited to tissues, how pathogens evade immune surveillance, and how malignant cells co-opt chemokine networks for metastasis [2, 5, 6]. The function is not limited to classical G-protein-coupled receptors; it also includes atypical receptors, soluble decoy proteins, viral chemokine-binding proteins, and extracellular matrix glycosaminoglycans that sequester or present chemokines [2, 3, 8]. In situ binding assays have been developed to measure chemokine interactions with endothelial cells, providing a quantitative framework for studying this function in native tissue contexts. The growing list of C-C chemokine-binding proteins and their roles in disease makes GO:0019957 a high-value target for functional genomics and therapeutic discovery [4, 5, 6].
C-C chemokine binding At A Glance
| GO ID | GO:0019957 |
|---|---|
| GO term | C-C chemokine binding |
| Ontology | molecular_function |
| Synonym | None |
| Major function | Binding to C-C chemokines, which lack an amino acid between the first two cysteines of the four-cysteine motif |
| Example binders | CCR5, CCR2, ACKR1, ACKR2, vCCI, chondroitin sulfate B |
| Biological context | Leukocyte trafficking, inflammation, cancer metastasis, viral immune evasion |
| Experimental assay | In situ binding assay, surface plasmon resonance, rational design [3, 7] |
What Is GO:0019957?
In simple terms, GO:0019957 C-C chemokine binding describes the ability of a protein or molecule to physically attach to a C-C chemokine. The QuickGO definition states that this is binding to a C-C chemokine, and C-C chemokines are defined by the absence of an amino acid between the first two cysteines of the characteristic four-cysteine motif. This function is a molecular activity that can be carried out by chemokine receptors, decoy receptors, viral proteins, or extracellular matrix components, and it is the initial molecular recognition event that underlies chemokine-mediated signaling and gradient formation [2, 3, 8].
Why Is C-C chemokine binding Important in Cell Biology?
C-C chemokine binding is important because it determines how chemokine signals are interpreted in health and disease. The binding event initiates receptor activation, shapes chemokine gradients, and can be subverted by pathogens or tumors. For example, viral chemokine-binding proteins such as vCCI bind C-C chemokines to block immune cell recruitment, and understanding this interaction has guided the rational design of high-affinity binders [2, 7]. In cancer, CCL18 binding to PITPNM3 or Nir1 promotes breast cancer metastasis through PI3K/Akt/GSK3β/Snail signaling, making this function a potential therapeutic target [5, 6]. In renal ischemia-reperfusion injury, m6A modification of Ccl28 mRNA regulates Treg recruitment, linking C-C chemokine binding to post-transcriptional control. Glycosaminoglycans such as chondroitin sulfate B can bind the C-terminus of SLC (CCL21) and inhibit its function, showing that C-C chemokine binding extends beyond classical receptors. Thus, GO:0019957 is a nexus for immunology, oncology, virology, and matrix biology.
• Controls leukocyte recruitment and immune surveillance by mediating chemokine gradient sensing [2, 3].
• Enables viral immune evasion through chemokine-binding proteins such as vCCI [2, 7].
• Promotes cancer progression and metastasis via CCL18 binding to PITPNM3 or Nir1 [5, 6].
• Regulates Treg recruitment in renal ischemia-reperfusion injury through Ccl28 m6A modification.
• Involves glycosaminoglycans like chondroitin sulfate B that bind and inhibit CCL21/SLC.
• Provides targets for anti-inflammatory and anti-metastatic drug discovery [4, 5, 6].
• Serves as a model for studying protein-protein interaction specificity and affinity.
• Links post-transcriptional regulation (m6A) to chemokine function.
• Underpins in situ binding assays for endothelial chemokine presentation.
• Guides rational design of high-affinity binding proteins for research and therapy.
Molecular Mechanism of C-C chemokine binding
Chemokine Recognition and Binding Interface
In simple terms: The binder must first recognize the C-C chemokine surface and form a stable contact.
C-C chemokines share a conserved four-cysteine motif with adjacent first two cysteines, which defines the subclass and presents a distinct surface for binding. Classical chemokine receptors engage the chemokine N-terminus and core, while viral chemokine-binding proteins such as vCCI can bind with high affinity and broad specificity [2, 7]. Rational design studies have shown that the vCCI-CCL17 interface can be engineered for higher affinity, revealing key contact residues. In situ binding assays with endothelial cells demonstrate that chemokines can be presented on cell surfaces, adding another layer of recognition.
Receptor Activation and Signaling
In simple terms: Once bound, the chemokine can trigger signals inside the cell.
For seven-transmembrane receptors, C-C chemokine binding induces conformational changes that activate G proteins and downstream cascades, leading to migration and adhesion. In cancer cells, CCL18 binding to PITPNM3 activates PI3K/Akt/GSK3β/Snail signaling to promote metastasis. Nir1 also binds CCL18 and promotes breast cancer cell invasion through the same pathway. These examples show that the binding event is coupled to specific intracellular signaling programs.
Atypical and Decoy Binding
In simple terms: Some binders sequester chemokines without triggering classical signaling.
Atypical chemokine receptors and viral chemokine-binding proteins can act as decoys or scavengers, internalizing or neutralizing C-C chemokines to shape gradients. Viral proteins such as vCCI bind C-C chemokines and inhibit leukocyte recruitment, representing a pathogen strategy to evade immunity [2, 7]. These non-signaling binders are valuable tools for probing chemokine function and for therapeutic design.
Glycosaminoglycan and Matrix Interactions
In simple terms: Extracellular matrix molecules can also bind C-C chemokines and change their activity.
Chondroitin sulfate B binds the C-terminus of secondary lymphoid tissue chemokine (SLC/CCL21) and inhibits its function, demonstrating that glycosaminoglycans participate in C-C chemokine binding. Such interactions can immobilize chemokines on endothelial surfaces and modulate gradient formation, as studied by in situ binding assays. This broadens the definition of C-C chemokine binding beyond protein receptors.
Regulation by Post-Transcriptional Modifications
In simple terms: The amount of chemokine available for binding can be controlled by RNA modifications.
In renal ischemia-reperfusion injury, inhibition of ALKBH5 promotes Ccl28 m6A modification and increases Treg recruitment, linking post-transcriptional regulation to C-C chemokine availability and binding. This shows that C-C chemokine binding is not only a biophysical event but also a regulated process at the level of chemokine expression and modification.
Key Genes Involved in GO:0019957 C-C chemokine binding
The following genes and proteins are directly implicated in C-C chemokine binding or its functional consequences, based on the verified literature.
| Gene | Major Role | Research Relevance |
|---|---|---|
| CCL18 | C-C chemokine ligand that binds PITPNM3 and Nir1 | Promotes breast cancer metastasis via PI3K/Akt/GSK3β/Snail [5, 6] |
| PITPNM3 | Receptor for CCL18 | Mediates CCL18-induced breast cancer metastasis |
| Nir1 | CCL18-binding protein | Promotes breast cancer invasion through PI3K/Akt/GSK3β/Snail |
| CCL28 | C-C chemokine regulated by m6A | Influences Treg recruitment in renal ischemia-reperfusion injury |
| ALKBH5 | m6A demethylase | Inhibition increases Ccl28 m6A and Treg recruitment |
| CCL17 | C-C chemokine ligand for vCCI | Used in rational design of high-affinity vCCI binders |
| vCCI | Viral chemokine-binding protein | Binds C-C chemokines to evade immunity; engineered for affinity [2, 7] |
| CCL21/SLC | C-C chemokine bound by chondroitin sulfate B | Inhibited by glycosaminoglycan binding to its C-terminus |
| ACKR1 | Atypical chemokine receptor | Decoy and scavenging functions for C-C chemokines |
| ACKR2 | Atypical chemokine receptor | Decoy and scavenging functions for C-C chemokines |
| CCR5 | Classical C-C chemokine receptor | Mediates leukocyte migration and activation |
| CCR2 | Classical C-C chemokine receptor | Mediates monocyte recruitment |
| Chondroitin sulfate B | Glycosaminoglycan binder | Binds CCL21 C-terminus and inhibits function |
| Endothelial cells | Present chemokines for in situ binding | Used in in situ binding assays |
| Tregs | Respond to CCL28 gradient | Recruited in renal ischemia-reperfusion injury |
| Tumor-associated macrophages | Source of CCL18 | Promote breast cancer metastasis |
How Is C-C chemokine binding Regulated?
C-C chemokine binding is regulated at multiple levels. Post-transcriptional modification of Ccl28 mRNA by m6A affects chemokine availability and Treg recruitment in renal ischemia-reperfusion injury, and inhibition of ALKBH5 increases this modification. Viral chemokine-binding proteins such as vCCI can be engineered for altered affinity, indicating that binding strength is tunable. Glycosaminoglycans like chondroitin sulfate B can bind and inhibit CCL21, providing extracellular regulation. In situ binding assays show that endothelial cells can present chemokines, which influences binding accessibility.
C-C chemokine binding and Human Disease
| Gene | Disease / Biology | Potential Experimental Model |
|---|---|---|
| CCL18 | Breast cancer metastasis | Knockout or overexpression in breast cancer cell lines [5, 6] |
| PITPNM3 | Breast cancer metastasis | Point mutation or knockout in cancer cells |
| Nir1 | Breast cancer invasion | Knockdown or knockout in breast cancer cells |
| ALKBH5 | Renal ischemia-reperfusion injury | Knockout mice with I/R injury model |
| CCL28 | Treg recruitment in kidney injury | Knock-in of m6A site mutations |
Cancer Metastasis
CCL18 binding to PITPNM3 or Nir1 promotes breast cancer metastasis through PI3K/Akt/GSK3β/Snail signaling, making C-C chemokine binding a driver of tumor progression [5, 6]. CCL18 is also implicated in the progression of multiple cancers, highlighting its broad relevance.
Renal Ischemia-Reperfusion Injury
Inhibition of ALKBH5 attenuates ischemia-reperfusion-induced renal injury by promoting Ccl28 m6A modification and increasing Treg recruitment, linking C-C chemokine binding to kidney inflammation and repair.
Viral Immune Evasion
Viral chemokine-binding proteins such as vCCI bind C-C chemokines to block leukocyte recruitment, representing a pathogen strategy that exploits C-C chemokine binding [2, 7].
Inflammatory and Matrix Remodeling
Chondroitin sulfate B binds the C-terminus of CCL21/SLC and inhibits its function, suggesting that glycosaminoglycan-chemokine interactions modulate inflammation and lymphoid tissue organization.
From C-C chemokine binding-Related Genes to Experimental Models
| Research Question | Suitable Model |
|---|---|
| Does loss of a candidate receptor abolish CCL18 binding? | CRISPR knockout of PITPNM3 or Nir1 in breast cancer cells [5, 6] |
| Does a specific point mutation alter chemokine binding affinity? | Point-mutation knock-in of binding interface residues |
| Can a tagged chemokine be tracked in live cells? | Knock-in of fluorescent or epitope tag on CCL18 or CCL28 |
| Does overexpression of a decoy receptor reduce metastasis? | Overexpression of ACKR1/ACKR2 in cancer models |
| Does m6A modification of Ccl28 affect Treg recruitment? | Knock-in of m6A site mutations in mice |
| Can engineered vCCI variants bind CCL17 with higher affinity? | Rational design and overexpression of vCCI variants |
How to Study the C-C chemokine binding Process
| Method | What It Measures | Typical Application |
|---|---|---|
| In situ binding assay | Chemokine binding to endothelial cells | Studying native chemokine presentation |
| Surface plasmon resonance | Binding affinity and kinetics | Engineering vCCI-CCL17 interaction |
| CRISPR knockout | Loss-of-function of candidate binders | Testing PITPNM3 or Nir1 in metastasis [5, 6] |
| Point-mutation knock-in | Effect of specific residues on binding | Mapping binding interfaces |
| Overexpression | Gain-of-function of chemokine or receptor | Modeling CCL18-driven metastasis |
| m6A RNA immunoprecipitation | Post-transcriptional modification of Ccl28 | Linking ALKBH5 to Treg recruitment |
| Glycosaminoglycan binding assay | Interaction of chondroitin sulfate B with CCL21 | Matrix-chemokine regulation |
| Viral chemokine-binding protein assay | Inhibition of leukocyte recruitment | Viral immune evasion studies |
In Situ Binding Assays
In situ binding assays measure chemokine interactions with endothelial cells and other tissue components, providing spatial information about C-C chemokine binding in native contexts.
Rational Protein Design and Affinity Measurement
Rational design has been used to engineer high-affinity interaction between vCCI and CCL17, and binding affinities can be measured by biophysical methods such as surface plasmon resonance.
CRISPR Functional Genomics
CRISPR knockout, point mutation, knock-in, and overexpression models allow causal testing of genes involved in C-C chemokine binding, such as PITPNM3, Nir1, and ALKBH5 [1, 5, 6].
Post-Transcriptional Modification Analysis
m6A modification of Ccl28 mRNA can be studied by RNA immunoprecipitation and sequencing, linking post-transcriptional regulation to C-C chemokine binding and Treg recruitment.
How CRISPR Can Be Used to Study GO:0019957 C-C chemokine binding
Knockout
CRISPR knockout of genes encoding C-C chemokine binders such as PITPNM3 or Nir1 can abolish CCL18-induced signaling and metastasis, providing causal evidence for their role in C-C chemokine binding [5, 6]. Knockout of ALKBH5 in mice has been used to study Ccl28 m6A modification and Treg recruitment in renal injury.
Point Mutation
Point mutations in the binding interface of chemokine receptors or viral chemokine-binding proteins can be introduced to test which residues are required for C-C chemokine binding, as demonstrated by rational design studies of vCCI-CCL17.
Knock-in
Knock-in of tagged chemokines or m6A site mutations allows tracking of C-C chemokine binding in vivo and testing the functional impact of post-transcriptional modifications, such as Ccl28 m6A in Treg recruitment.
Overexpression
Overexpression of CCL18, PITPNM3, or decoy receptors such as ACKR1/ACKR2 can model gain-of-function states in cancer and inflammation, helping to dissect how increased C-C chemokine binding drives disease [2, 6].
How EDITGENE Supports C-C chemokine binding Research
Researchers studying C-C chemokine binding-related genes often need to determine whether a candidate gene is causally involved in chemokine recognition, signaling, or disease progression. EDITGENE provides CRISPR-based cell models and screening services to test these hypotheses with precision and reproducibility.
Contact EDITGENE today to design your custom CRISPR model for C-C chemokine binding research.
Related Products
| Product name | Cat.No. | Species | Gene ID | |
|---|---|---|---|---|
| CXCR2 Knockout HEK293 Cell Line | EDJ-KQ271 | Human | 3579 | Details Get a Quote |
| CCR2 Knockout HEK293 Cell Line | EDJ-KQ442 | Human | 729230 | Details Get a Quote |
| ZFP36 Knockout HEK293 Cell Line | EDJ-KQ1014 | Human | 7538 | Details Get a Quote |
| CXCR4 Knockout HEK293 Cell Line | EDJ-KQ1608 | Human | 7852 | Details Get a Quote |
| CXCR1 Knockout HEK293 Cell Line | EDJ-KQ1723 | Human | 3577 | Details Get a Quote |
| ACKR3 Knockout HEK293 Cell Line | EDJ-KQ2468 | Human | 57007 | Details Get a Quote |
| CCR4 Knockout HEK293 Cell Line | EDJ-KQ3206 | Human | 1233 | Details Get a Quote |
| CCR10 Knockout HEK293 Cell Line | EDJ-KQ3228 | Human | 2826 | Details Get a Quote |
| CCR8 Knockout HEK293 Cell Line | EDJ-KQ3618 | Human | 1237 | Details Get a Quote |
| CX3CR1 Knockout HEK293 Cell Line | EDJ-KQ3859 | Human | 1524 | Details Get a Quote |
| CCR3 Knockout HEK293 Cell Line | EDJ-KQ4298 | Human | 1232 | Details Get a Quote |
| ACKR2 Knockout HEK293 Cell Line | EDJ-KQ4299 | Human | 1238 | Details Get a Quote |
| CCR1 Knockout HEK293 Cell Line | EDJ-KQ4300 | Human | 1230 | Details Get a Quote |
| ACKR1 Knockout HEK293 Cell Line | EDJ-KQ4647 | Human | 2532 | Details Get a Quote |
| XCR1 Knockout HEK293 Cell Line | EDJ-KQ4756 | Human | 2829 | Details Get a Quote |
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Frequently Asked Questions About C-C chemokine binding
What is C-C chemokine binding?
C-C chemokine binding (GO:0019957) is the molecular function of binding to a C-C chemokine, which lacks an amino acid between the first two cysteines of the four-cysteine motif.
What genes are involved in C-C chemokine binding?
Genes include CCL18, PITPNM3, Nir1, CCL28, ALKBH5, CCL17, vCCI, CCL21, ACKR1, ACKR2, CCR5, and CCR2 [1, 2, 5, 6, 7, 8].
How is C-C chemokine binding studied?
It is studied using in situ binding assays, surface plasmon resonance, rational design, and CRISPR knockout or knock-in models [1, 3, 7].
What diseases are linked to C-C chemokine binding?
It is linked to breast cancer metastasis, renal ischemia-reperfusion injury, viral immune evasion, and inflammatory matrix remodeling [1, 2, 5, 6, 8].
What is the role of CCL18 in cancer?
CCL18 binds PITPNM3 and Nir1 to promote breast cancer metastasis via PI3K/Akt/GSK3β/Snail signaling [5, 6].
How does vCCI bind C-C chemokines?
vCCI is a viral chemokine-binding protein that binds C-C chemokines with high affinity and can be engineered for improved binding [2, 7].
Can glycosaminoglycans bind C-C chemokines?
Yes, chondroitin sulfate B binds the C-terminus of CCL21/SLC and inhibits its function.
What is the role of m6A in C-C chemokine binding?
Inhibition of ALKBH5 promotes Ccl28 m6A modification and increases Treg recruitment in renal ischemia-reperfusion injury.
What assays measure C-C chemokine binding?
In situ binding assays and surface plasmon resonance are commonly used to measure binding to endothelial cells and purified proteins [3, 7].
How can CRISPR help study C-C chemokine binding?
CRISPR knockout, point mutation, knock-in, and overexpression models allow causal testing of genes such as PITPNM3, Nir1, and ALKBH5 in C-C chemokine binding and disease [1, 5, 6].
Conclusion
GO:0019957 C-C chemokine binding is a central molecular function that governs how C-C chemokines are recognized by receptors, decoy proteins, viral inhibitors, and extracellular matrix components. Its roles in leukocyte trafficking, cancer metastasis, renal injury, and viral immune evasion make it a high-priority area for functional genomics and therapeutic development [1, 2, 5, 6, 7, 8]. CRISPR-based models and bioinformatics screening provide powerful tools to dissect the causal genes and mechanisms underlying this function.
References
- 1. Chen J et al.. 2023. Inhibition of ALKBH5 attenuates I/R-induced renal injury in male mice by promoting Ccl28 m6A modification and increasing Treg recruitment.. Nat Commun 14(1):1161 PMID: 36859428
- 2. Seet BT et al.. 2002. Viral chemokine-binding proteins.. J Leukoc Biol 72(1):24-34 PMID: 12101259
- 3. Rot A. 2003. In situ binding assay for studying chemokine interactions with endothelial cells.. J Immunol Methods 273(1-2):63-71 PMID: 12535798
- 4. Korbecki J et al.. 2020. CCL18 in the Progression of Cancer.. Int J Mol Sci 21(21) PMID: 33114763
- 5. Zhang B et al.. 2013. Nir1 promotes invasion of breast cancer cells by binding to chemokine (C-C motif) ligand 18 through the PI3K/Akt/GSK3β/Snail signalling pathway.. Eur J Cancer 49(18):3900-13 PMID: 24001613
- 6. Chen J et al.. 2011. CCL18 from tumor-associated macrophages promotes breast cancer metastasis via PITPNM3.. Cancer Cell 19(4):541-55 PMID: 21481794
- 7. Guan W et al.. 2024. Rational Design of High Affinity Interaction Between CC Chemokine Binding Protein vCCI and CCL17/TARC.. Biochemistry 63(18):2235-2239 PMID: 39194151
- 8. Hirose J et al.. 2002. Chondroitin sulfate B exerts its inhibitory effect on secondary lymphoid tissue chemokine (SLC) by binding to the C-terminus of SLC.. Biochim Biophys Acta 1571(3):219-24 PMID: 12090936
