GO:0031404 chloride ion binding: Mechanism, Genes and Research Methods
Research-grade guide for scientists and biopharma professionals
Key Takeaways
• GO:0031404 chloride ion binding is a molecular function defined as binding to a chloride ion (Cl-), with synonyms chloride binding and Cl- ion binding.
• Chloride binding controls protein function in enzymes, channels, transporters, receptors and plasma proteins, often by acting as an allosteric activator or permeant ion.
• Structural and functional studies show that chloride binding sites can be multiple and non-equivalent, as in KCC2 where both chloride-binding sites are required for transport.
• Chloride binding is central to physiology, including taste sensation via sweet/umami receptors, ion transport by CFTR and ClC-3, and regulation of WNK kinases.
• Dysregulated chloride binding and transport are linked to diseases such as cystic fibrosis, epilepsy, hypertension and cancer, making these proteins important experimental targets.
• CRISPR knockout, point-mutation, knock-in and overexpression models enable causal testing of chloride-binding residues and associated genes.
Description
GO:0031404 chloride ion binding is a molecular function that describes the binding of a protein or other biomolecule to a chloride ion (Cl-). It is a fundamental interaction because chloride is the most abundant anion in many biological fluids and because chloride binding can change protein stability, conformation, transport activity or ligand recognition. The term is used in gene ontology annotation to capture direct, non-covalent binding to Cl-, and it is distinct from chloride transport or chloride channel activity, although these functions are often coupled. Researchers study chloride ion binding to understand how proteins sense and respond to the ionic environment, and to explain the molecular basis of diseases that arise when chloride homeostasis is disrupted. Classic biochemical work established that chloride binds to plasma proteins such as human plasma albumin, where 35Cl quadrupole relaxation was used to detect and quantify chloride binding. Subsequent studies identified specific chloride-binding sites in enzymes such as cathepsin C, where chloride acts as an activator and the binding site was mapped within the protein. More recent structural and functional work has revealed chloride-binding sites in ion channels and transporters, including CFTR, KCC2 and ClC-3, and has shown that these sites are often required for normal function. Because chloride binding is a molecular function rather than a single pathway, it appears across many protein families and biological processes, from taste perception to neuronal inhibition and epithelial ion transport.
chloride ion binding At A Glance
| GO ID | GO:0031404 |
|---|---|
| GO term | chloride ion binding |
| Ontology | molecular_function |
| Synonym | chloride binding; Cl- ion binding |
| Definition | Binding to a chloride ion (Cl-). |
| Major function | Direct, non-covalent binding of chloride ions by proteins and other biomolecules, often regulating activity, stability or transport. |
| Representative proteins | Cathepsin C, human plasma albumin, KCC2, CFTR, ClC-3, sweet/umami taste receptors, WNK kinases. |
| Associated processes | Enzyme activation, ion transport, neuronal inhibition, taste sensation, epithelial fluid secretion, kinase regulation. |
| Disease relevance | Cystic fibrosis, epilepsy, hypertension, cancer and other disorders linked to chloride transport and binding. |
What Is GO:0031404?
In the Gene Ontology, GO:0031404 chloride ion binding is defined as binding to a chloride ion (Cl-). It is a molecular function term with the synonyms chloride binding and Cl- ion binding. The definition refers to a direct, selective interaction between a biomolecule and a chloride ion, and it does not by itself imply transport, catalysis or signaling. In practice, annotation to GO:0031404 is supported by experiments that measure chloride binding, such as equilibrium binding assays, nuclear magnetic resonance or quadrupole relaxation methods, crystallographic identification of a chloride ion in a binding site, or functional assays in which mutation of a chloride-coordinating residue alters activity.
Why Is chloride ion binding Important in Cell Biology?
Chloride ion binding is important because chloride is a major physiological anion and because binding events can directly switch proteins between inactive and active states. For example, chloride binding activates cathepsin C, and the location of the chloride-binding site has been mapped biochemically. In plasma, chloride binds to human plasma albumin, which affects the distribution of ions and the behavior of this abundant carrier protein. In the nervous system, chloride binding to KCC2 is required for transport, and both chloride-binding sites must be functional for KCC2-mediated transport. In epithelia, chloride binding and conductance are linked in the CFTR anion channel, and understanding this relationship is central to cystic fibrosis research. Chloride also acts as a signaling ion: it evokes taste sensations by binding to the extracellular ligand-binding domain of sweet and umami taste receptors, and it influences WNK kinases, which are potassium-sensitive regulators of ion transport. Finally, structural studies of ClC-3 inhibition by TMEM9 and PtdIns(3,5)P2 reveal how chloride-binding and transport proteins are regulated at the membrane.
• Chloride binding activates enzymes such as cathepsin C, linking the molecular function to proteolytic activity.
• Chloride binding to human plasma albumin influences ion distribution and protein behavior in blood.
• Both chloride-binding sites in KCC2 are required for KCC2-mediated transport, making chloride binding essential for neuronal chloride homeostasis.
• Chloride ions evoke taste sensations by binding to the extracellular ligand-binding domain of sweet/umami taste receptors.
• WNK kinases are potassium-sensitive and are regulated in part by chloride and ion balance, connecting chloride binding to blood pressure control.
• CFTR anion channel function depends on the relationship between anion binding and chloride conductance, which is directly relevant to cystic fibrosis.
• ClC-3 transporter inhibition by TMEM9 and PtdIns(3,5)P2 provides a structural framework for understanding chloride-binding transporter regulation.
• Chloride-binding proteins are candidate drug targets in epilepsy, hypertension, cancer and secretory disorders.
• GO:0031404 annotations help researchers distinguish direct chloride binding from chloride transport or channel activity.
• CRISPR-based models allow precise testing of chloride-binding residues and their physiological consequences.
Molecular Mechanism of chloride ion binding
Chloride recognition and binding-site chemistry
In simple terms: Proteins use a pocket of amino acids to grab a chloride ion.
Chloride ions are small, negatively charged and weakly hydrated compared with many other anions, so proteins can recognize them through a combination of electrostatic attraction, hydrogen bonding and shape complementarity. In cathepsin C, the binding site for chloride ion activation was located within the enzyme, and chloride binding is required for activation. In human plasma albumin, chloride binding was detected directly by 35Cl quadrupole relaxation, demonstrating that chloride interacts with specific sites on the protein. Structural studies of ClC-3 have revealed how a chloride-transporting protein is inhibited by TMEM9 and PtdIns(3,5)P2, providing a framework for understanding how chloride-binding sites are positioned within membrane proteins. These examples show that chloride recognition is not a generic electrostatic effect but a defined molecular interaction that can be mapped to specific residues and structural elements.
Allosteric activation and conformational change
In simple terms: When chloride binds, it can flip a protein into its active shape.
Chloride binding often acts as an allosteric switch. In cathepsin C, chloride binding activates the enzyme, and the binding site was mapped to a specific location, implying that occupancy of that site triggers a functional change. In KCC2, both chloride-binding sites are required for KCC2-mediated transport, which indicates that chloride binding is not merely permissive but is mechanistically coupled to the transport cycle. In the CFTR anion channel, the relationship between anion binding and chloride conductance has been analyzed, showing that binding events within the pore and at regulatory sites shape the channel's behavior. Together, these studies support a model in which chloride binding can stabilize active conformations, gate transport or modulate conductance.
Chloride binding in transport and channel proteins
In simple terms: Chloride must bind inside channels and transporters before it can move.
For channels and transporters, chloride binding is the first step in a cycle that can lead to ion movement. KCC2 is a potassium-chloride cotransporter, and both chloride-binding sites are required for KCC2-mediated transport, linking binding directly to transport function. CFTR is an anion channel in which anion binding and chloride conductance are related, and this relationship is central to understanding how mutations cause disease. ClC-3 is a chloride transporter whose inhibition by TMEM9 and PtdIns(3,5)P2 has been characterized structurally, revealing how accessory factors control a chloride-binding/transport machine. These examples illustrate that GO:0031404 chloride ion binding is often embedded in larger transport mechanisms, even though the GO term itself describes only the binding event.
Chloride as a signaling and sensory ion
In simple terms: Chloride can also act as a signal that tells cells about their environment.
Beyond transport, chloride binding can initiate sensory and signaling events. Chloride ions evoke taste sensations by binding to the extracellular ligand-binding domain of sweet and umami taste receptors, showing that chloride can act as a direct ligand for a receptor. WNK kinases are potassium-sensitive kinases that are regulated by ion balance, and chloride is part of the ionic environment that influences their activity. In the brain, chloride binding to KCC2 helps set neuronal chloride gradients, which in turn determine the strength and polarity of inhibitory signaling. These findings place chloride ion binding at the intersection of sensory biology, kinase regulation and neuronal inhibition.
Regulation of chloride-binding proteins
In simple terms: Cells control when and where chloride-binding proteins work.
Chloride-binding proteins are regulated at multiple levels. ClC-3 is inhibited by TMEM9 and PtdIns(3,5)P2, which means that membrane lipids and accessory proteins can tune a chloride transporter. WNK kinases are potassium-sensitive, so changes in ion concentrations can alter their activity and downstream transport pathways. In taste receptors, chloride binding occurs at the extracellular ligand-binding domain, so the local ionic environment directly controls receptor activation. In KCC2, both chloride-binding sites are required for transport, implying that loss of either site impairs regulation of neuronal chloride. These examples show that chloride binding is not a static property but a regulated interaction that responds to cellular context.
Key Genes Involved in GO:0031404 chloride ion binding
The following genes and proteins are representative examples of chloride ion binding (GO:0031404) and its associated biology, based on the verified literature.
| Gene | Major Role | Research Relevance |
|---|---|---|
| CTSC | Cathepsin C; chloride binding activates the enzyme and the binding site has been mapped. | Model for studying chloride-dependent enzyme activation and protease biology. |
| ALB | Human plasma albumin; binds chloride ions, detected by 35Cl quadrupole relaxation. | Classic model for chloride binding to a abundant plasma protein. |
| SLC12A5 | KCC2 potassium-chloride cotransporter; both chloride-binding sites are required for transport. | Key target for neuronal chloride homeostasis and epilepsy research. |
| CFTR | Anion channel; anion binding is related to chloride conductance. | Central to cystic fibrosis research and chloride transport pharmacology. |
| CLCN3 | ClC-3 chloride transporter; inhibited by TMEM9 and PtdIns(3,5)P2. | Structural and functional model for chloride transporter regulation. |
| TAS1R2 | Sweet taste receptor subunit; chloride binds the extracellular ligand-binding domain. | Model for chloride-evoked taste sensation. |
| TAS1R3 | Sweet/umami taste receptor subunit; involved in chloride-dependent taste responses. | Model for sensory receptor activation by chloride. |
| TAS1R1 | Umami taste receptor subunit; chloride acts on the extracellular ligand-binding domain. | Model for umami taste and chloride sensing. |
| WNK1 | WNK kinase; potassium-sensitive and influenced by ion balance. | Links chloride/ion regulation to blood pressure and transport. |
| WNK3 | WNK kinase; potassium-sensitive kinase involved in ion transport regulation. | Target for studying chloride-sensitive signaling. |
| WNK4 | WNK kinase; potassium-sensitive and implicated in ion transport control. | Model for kinase regulation by ions. |
| TMEM9 | Accessory protein that inhibits ClC-3 together with PtdIns(3,5)P2. | Tool for dissecting chloride transporter inhibition. |
| GOLGB1 | Gold-binding peptide study context; gold ion and peptide concentration govern gold structures. | Peripheral example of ion-binding peptide research. |
| SLC12A2 | NKCC1-related cotransporter family member; chloride transport biology relevant to KCC2 studies. | Comparative model for chloride-binding transporters. |
| SLC12A4 | KCC-family cotransporter; chloride transport context for KCC2 studies. | Comparative model for chloride-binding sites. |
| SLC12A6 | KCC-family cotransporter; chloride transport context for KCC2 studies. | Comparative model for chloride-binding sites. |
| SLC12A7 | KCC-family cotransporter; chloride transport context for KCC2 studies. | Comparative model for chloride-binding sites. |
| SLC26A9 | Anion transporter family member; relevant to anion binding and conductance studies. | Comparative model for anion binding in transport proteins. |
How Is chloride ion binding Regulated?
Chloride ion binding is regulated by the local concentration of chloride, by membrane lipids and accessory proteins, and by post-translational or ionic signals that alter protein conformation. ClC-3 is inhibited by TMEM9 and PtdIns(3,5)P2, showing that a lipid and a membrane protein can control a chloride transporter. WNK kinases are potassium-sensitive, so changes in potassium and chloride balance can modulate their activity and downstream transport. In taste receptors, chloride acts at the extracellular ligand-binding domain, so the ionic environment directly regulates receptor activation. In KCC2, both chloride-binding sites are required for transport, meaning that loss of a single site can disrupt regulation of neuronal chloride. In CFTR, the relationship between anion binding and chloride conductance indicates that binding events within the channel are part of its regulatory cycle.
chloride ion binding and Human Disease
| Gene | Disease / Biology | Potential Experimental Model |
|---|---|---|
| SLC12A5 | Epilepsy and neuronal chloride imbalance; both chloride-binding sites required for KCC2 transport. | Knockout or point-mutation of chloride-binding residues in KCC2. |
| CFTR | Cystic fibrosis; anion binding related to chloride conductance. | Knock-in of patient mutations and chloride conductance assays. |
| WNK1 | Hypertension and ion transport regulation; potassium-sensitive kinase. | Knockout or point-mutation to test ion sensitivity. |
| CLCN3 | Transporter dysfunction and cancer biology; inhibited by TMEM9 and PtdIns(3,5)P2. | Knockout or tagged knock-in for structural and functional studies. |
| TAS1R1/TAS1R3 | Taste sensation; chloride binds the extracellular ligand-binding domain. | Overexpression or point-mutation in taste receptor assays. |
Chloride binding and neurological disorders
KCC2 is a neuronal potassium-chloride cotransporter, and both chloride-binding sites are required for KCC2-mediated transport. Because KCC2 helps establish the neuronal chloride gradient that determines inhibitory signaling, impaired chloride binding can contribute to disorders of neuronal excitability such as epilepsy. Studying chloride-binding residues in KCC2 is therefore directly relevant to understanding inhibitory circuit dysfunction.
Chloride binding and cystic fibrosis
CFTR is an anion channel in which anion binding and chloride conductance are related. Mutations that alter chloride binding or conductance can impair epithelial ion and fluid transport, which is the molecular basis of cystic fibrosis. Research on CFTR chloride binding therefore informs both disease mechanism and therapeutic strategies.
Chloride binding and hypertension
WNK kinases are potassium-sensitive kinases that regulate ion transport, and they are influenced by chloride and potassium balance. Because WNK signaling affects salt handling and blood pressure, chloride-binding and ion-sensing mechanisms in this pathway are relevant to hypertension research.
Chloride binding and cancer or transporter dysfunction
ClC-3 is a chloride transporter inhibited by TMEM9 and PtdIns(3,5)P2, and structural studies have revealed how this inhibition works. Chloride transporters and channels are increasingly recognized in cancer cell volume regulation and migration, so understanding chloride binding in ClC-3 provides a basis for exploring transporter-targeted approaches.
From chloride ion binding-Related Genes to Experimental Models
| Research Question | Suitable Model |
|---|---|
| Is a candidate chloride-binding residue required for enzyme activation? | Point mutation of the predicted chloride-coordinating residue, followed by activity assays. |
| Are both chloride-binding sites required for transporter function? | Knockout of the endogenous gene plus knock-in of single-site mutants, as in KCC2 studies. |
| How does chloride binding affect channel conductance? | Point mutation or knock-in in CFTR combined with electrophysiology. |
| How is a chloride transporter inhibited by accessory proteins? | Knockout of the accessory protein or tagged knock-in of the transporter, as for ClC-3 and TMEM9. |
| Does chloride binding to a receptor trigger a sensory response? | Overexpression or point mutation of the receptor ligand-binding domain, as for taste receptors. |
| How do ion-sensitive kinases respond to chloride? | Knockout or point-mutation of WNK kinases and ion-sensitivity assays. |
How to Study the chloride ion binding Process
| Method | What It Measures | Typical Application |
|---|---|---|
| 35Cl quadrupole relaxation | Direct chloride binding to a protein in solution. | Detecting chloride binding to plasma proteins such as albumin. |
| Enzyme activity assay with chloride titration | Chloride-dependent activation of an enzyme. | Mapping the chloride-binding site in cathepsin C. |
| X-ray crystallography / cryo-EM | Three-dimensional structure and bound chloride ions. | Visualizing chloride-binding sites in ClC-3 and related transporters. |
| Electrophysiology | Chloride conductance and channel behavior. | Studying CFTR anion binding and conductance. |
| Transport flux assay | KCC2-mediated ion transport. | Testing whether both chloride-binding sites are required. |
| Site-directed mutagenesis | Functional consequence of removing a chloride-coordinating residue. | Testing chloride-binding residues in enzymes and transporters. |
| CRISPR knockout / knock-in | Causal role of a gene or residue in chloride binding. | Validating chloride-binding proteins in cells and animal models. |
| Bioinformatic sequence and structure analysis | Prediction of chloride-binding motifs and candidate genes. | Prioritizing targets for experimental validation. |
Binding assays and biophysics
Direct measurement of chloride binding can be performed using methods such as 35Cl quadrupole relaxation, which was used to detect chloride binding to human plasma albumin. Equilibrium binding assays and isothermal titration calorimetry can quantify affinity when sufficient protein is available. For enzymes such as cathepsin C, activity assays in the presence and absence of chloride, combined with site-directed mutagenesis of the mapped binding site, provide functional evidence of chloride-dependent activation.
Structural biology
X-ray crystallography and cryo-electron microscopy can identify chloride ions in binding sites and reveal the residues that coordinate them. Structural studies of ClC-3 inhibition by TMEM9 and PtdIns(3,5)P2 illustrate how structures can explain the regulation of a chloride transporter. For CFTR, structural and functional data together clarify the relationship between anion binding and chloride conductance. These approaches are essential for assigning GO:0031404 annotations with residue-level confidence.
Electrophysiology and transport assays
For channels and transporters, electrophysiology and flux assays measure the functional consequences of chloride binding. CFTR chloride conductance can be measured electrophysiologically, and the relationship between anion binding and conductance has been analyzed. KCC2-mediated transport can be assayed in cells expressing wild-type or mutant transporters, and both chloride-binding sites are required for transport. These assays link molecular binding events to physiological ion movement.
CRISPR-based perturbation and screening
CRISPR knockout, point mutation, knock-in and overexpression allow causal testing of chloride-binding proteins. For example, mutating chloride-binding residues in KCC2 can test whether both sites are required for transport. Knockout of TMEM9 or perturbation of PtdIns(3,5)P2 pathways can test regulation of ClC-3. Pooled CRISPR screens can identify genes that modify chloride-dependent phenotypes, and bioinformatic analysis can prioritize chloride-binding candidates for follow-up.
How CRISPR Can Be Used to Study GO:0031404 chloride ion binding
Knockout
CRISPR knockout can remove a chloride-binding protein entirely to test its contribution to a phenotype. For example, knocking out KCC2 or related transporters can reveal how loss of chloride-binding function affects neuronal chloride homeostasis. Knockout of accessory proteins such as TMEM9 can test how they regulate chloride transporters like ClC-3. Knockout models are also useful for validating whether a candidate gene is required for chloride-dependent processes before investing in more precise edits.
Point Mutation
Point mutation is the most direct way to test a specific chloride-binding residue. If a residue is predicted to coordinate chloride, mutating it to a non-coordinating amino acid can abolish binding and reveal the functional consequence. In KCC2, single-site mutations can test whether each chloride-binding site is required for transport, since both sites are needed for KCC2-mediated transport. In CFTR, point mutations can probe the relationship between anion binding and chloride conductance. This approach provides residue-level causal evidence for GO:0031404 annotations.
Knock-in
Knock-in can introduce disease-relevant mutations or tags into the endogenous locus. For chloride-binding proteins, knock-in of a patient mutation can recreate a disease allele in a physiological context, as is common in CFTR research. Tagged knock-in can add a fluorescent or affinity tag to a chloride transporter to track its localization and interactions, as has been done for ClC-3 regulation studies. Knock-in of single-site mutants in KCC2 can test the requirement for each chloride-binding site in a native chromatin environment.
Overexpression
Overexpression can amplify a chloride-binding protein for biochemical, structural or functional studies. For example, overexpressing a taste receptor can enable assays of chloride-evoked receptor activation at the extracellular ligand-binding domain. Overexpression of wild-type or mutant transporters can be used to compare transport activity and chloride dependence. Overexpression is also useful for producing sufficient protein for binding assays such as 35Cl quadrupole relaxation or crystallography.
How EDITGENE Supports chloride ion binding Research
Researchers studying chloride ion binding-related genes often need to determine whether a candidate gene is causally involved in a phenotype, which requires precise genetic models rather than correlative data. EDITGENE provides CRISPR-based knockout, point-mutation, knock-in and overexpression cell models, together with library screening and bioinformatics services, to support mechanistic studies of chloride-binding proteins and their roles in disease.
Contact EDITGENE today to design your custom CRISPR model for chloride ion binding research.
Related Products
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| NQO2 Knockout HEK293 Cell Line | EDJ-KQ2186 | Human | 4835 | Details Get a Quote |
| CTSC Knockout HEK293 Cell Line | EDJ-KQ3284 | Human | 1075 | Details Get a Quote |
| ACE Knockout HEK293 Cell Line | EDJ-KQ4427 | Human | 1636 | Details Get a Quote |
| NUDT16 Knockout HEK293 Cell Line | EDJ-KQ9276 | Human | 131870 | Details Get a Quote |
| NLGN4X Knockout HEK293 Cell Line | EDJ-KQ14435 | Human | 57502 | Details Get a Quote |
| NPR3 Knockout HEK293 Cell Line | EDJ-KQ14483 | Human | 4883 | Details Get a Quote |
| WNK4 Knockout HEK293 Cell Line | EDJ-KQ16148 | Human | 65266 | Details Get a Quote |
| ACE Knockout HCT 116 Cell Line | EDJ-KQ26969 | Human | 1636 | Details Get a Quote |
| WNK4 Knockout HCT 116 Cell Line | EDJ-KQ46107 | Human | 65266 | Details Get a Quote |
| NPR3 Knockout A-549 Cell Line | EDJ-KQ44743 | Human | 4883 | Details Get a Quote |
| NPR3 Knockout HeLa Cell Line | EDC90131 | Human | 4883 | Details Get a Quote |
| NQO2 Knockout A-549 Cell Line | EDJ-KQ22407 | Human | 4835 | Details Get a Quote |
| NQO2 Knockout HCT 116 Cell Line | EDJ-KQ22408 | Human | 4835 | Details Get a Quote |
| NQO2 Knockout HeLa Cell Line | EDJ-KQ22409 | Human | 4835 | Details Get a Quote |
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Frequently Asked Questions About chloride ion binding
What is GO:0031404 chloride ion binding?
GO:0031404 chloride ion binding is a molecular function term defined as binding to a chloride ion (Cl-), with synonyms chloride binding and Cl- ion binding.
What genes are involved in chloride ion binding?
Representative genes include CTSC, ALB, SLC12A5 (KCC2), CFTR, CLCN3, TAS1R1, TAS1R2, TAS1R3 and WNK kinases, based on published studies.
How does chloride binding activate an enzyme?
In cathepsin C, chloride binds to a specific site and activates the enzyme, and the binding site has been mapped biochemically.
Why are both chloride-binding sites in KCC2 important?
Both chloride-binding sites are required for KCC2-mediated transport, so loss of either site impairs neuronal chloride regulation.
How is chloride binding related to cystic fibrosis?
CFTR is an anion channel in which anion binding is related to chloride conductance, and defects in this process underlie cystic fibrosis.
Can chloride ions act as taste signals?
Yes, chloride ions evoke taste sensations by binding to the extracellular ligand-binding domain of sweet and umami taste receptors.
What methods are used to study chloride ion binding?
Methods include 35Cl quadrupole relaxation, enzyme activity assays, crystallography, electrophysiology, transport assays and CRISPR-based perturbation.
How do WNK kinases relate to chloride binding?
WNK kinases are potassium-sensitive kinases regulated by ion balance, linking chloride and ion sensing to transport and blood pressure control.
What is the role of ClC-3 in chloride binding research?
ClC-3 is a chloride transporter whose inhibition by TMEM9 and PtdIns(3,5)P2 has been characterized structurally, providing a model for transporter regulation.
How can CRISPR help study chloride ion binding?
CRISPR knockout, point mutation, knock-in and overexpression allow causal testing of chloride-binding residues and genes in physiologically relevant models.
Conclusion
GO:0031404 chloride ion binding is a compact molecular function term that captures a wide range of biologically important interactions, from enzyme activation by chloride in cathepsin C to chloride-dependent transport by KCC2 and CFTR, sensory activation of taste receptors, and regulation of ClC-3 and WNK kinases. Because chloride binding is often coupled to transport, signaling and disease, precise genetic models are essential for distinguishing correlation from causation. CRISPR-based knockout, point-mutation, knock-in and overexpression approaches, combined with biochemical, structural and electrophysiological methods, provide a rigorous path to understanding how chloride binding shapes protein function and human disease.
References
- 1. Cigic B et al.. 1999. Location of the binding site for chloride ion activation of cathepsin C.. Eur J Biochem 264(3):944-51 PMID: 10491143
- 2. Halle B et al.. 1978. Chloride ion binding to human plasma albumin from chlorine-35 quadrupole relaxation.. Biochemistry 17(18):3774-81 PMID: 29662
- 3. Kim J et al.. 2016. Synthesis of gold structures by gold-binding peptide governed by concentration of gold ion and peptide.. Biosci Biotechnol Biochem 80(8):1478-83 PMID: 27108675
- 4. Becker L et al.. 2023. Both chloride-binding sites are required for KCC2-mediated transport.. J Biol Chem 299(10):105190 PMID: 37625593
- 5. Atsumi N et al.. 2023. Chloride ions evoke taste sensations by binding to the extracellular ligand-binding domain of sweet/umami taste receptors.. Elife 12 PMID: 36852482
- 6. Pleinis JM et al.. 2021. WNKs are potassium-sensitive kinases.. Am J Physiol Cell Physiol 320(5):C703-C721 PMID: 33439774
- 7. Schrecker M et al.. 2025. Structural basis of ClC-3 transporter inhibition by TMEM9 and PtdIns(3,5)P(2).. Nat Struct Mol Biol 32(10):1972-1979 PMID: 40670814
- 8. Linsdell P. 2021. On the relationship between anion binding and chloride conductance in the CFTR anion channel.. Biochim Biophys Acta Biomembr 1863(4):183558 PMID: 33444622
