GO:0016018 cyclosporin A binding: Mechanism, Genes and Research Methods
Research-grade guide for scientists and biopharma professionals
Key Takeaways
• GO:0016018 cyclosporin A binding describes the molecular function of binding to cyclosporin A, a cyclic undecapeptide immunosuppressant.
• The primary proteins annotated with this function are cyclophilins, a family of peptidyl-prolyl cis-trans isomerases (PPIases).
• Cyclosporin A binding to mitochondrial cyclophilin (PPIF) inhibits the permeability transition pore (PTP), protecting hearts from ischaemia/reperfusion injury.
• Cyclophilin A (PPIA) binding to cyclosporin A is a key determinant of HIV-1 restriction and integration.
• Cyclosporin A binding to ABCA3 acts as a molecular corrector, offering therapeutic potential for ABCA3-related lung disease.
• Structural and thermodynamic studies reveal that cyclosporin A binding to cyclophilin A is driven by specific residues and conformational changes.
Description
Cyclosporin A binding (GO:0016018) is a molecular function defined as the binding to cyclosporin A, a cyclic undecapeptide that contains several N-methylated and unusual amino acids. This function is primarily mediated by cyclophilins, a family of proteins with peptidyl-prolyl cis-trans isomerase (PPIase) activity. Cyclosporin A is a widely used immunosuppressant, and its binding to cyclophilins is central to its biological effects, including inhibition of the mitochondrial permeability transition pore (PTP) and modulation of immune responses. Researchers study cyclosporin A binding to understand immunosuppression, mitochondrial biology, and viral pathogenesis. The interaction between cyclosporin A and cyclophilin A (PPIA) has been characterized structurally and thermodynamically, revealing key binding determinants. Additionally, cyclosporin A binds to plasma proteins, which affects its pharmacokinetics and distribution. In recent years, cyclosporin A binding has been implicated in diverse processes, such as HIV-1 integration and ABCA3-mediated lung surfactant metabolism. This article provides a comprehensive overview of the ontology, mechanisms, genes, and research methods associated with GO:0016018.
cyclosporin A binding At A Glance
| GO ID | GO:0016018 |
|---|---|
| GO term | cyclosporin A binding |
| Ontology | molecular_function |
| Synonym | cyclophilin |
| Definition | Binding to cyclosporin A, a cyclic undecapeptide that contains several N-methylated and unusual amino acids. |
| Major function | Mediates immunosuppression, mitochondrial PTP inhibition, and viral restriction |
| Key proteins | Cyclophilins (PPIA, PPIB, PPIF, etc.) |
| Related diseases | Ischaemia/reperfusion injury, HIV-1 infection, ABCA3 deficiency |
What Is GO:0016018?
Cyclosporin A binding (GO:0016018) is the molecular function of selectively interacting with cyclosporin A, a cyclic undecapeptide immunosuppressant. This binding typically occurs through hydrophobic and aromatic residues in a defined binding pocket, as seen in cyclophilins.
Why Is cyclosporin A binding Important in Cell Biology?
Cyclosporin A binding is critically important because it underlies the pharmacological action of cyclosporin A, a cornerstone immunosuppressant used in organ transplantation and autoimmune diseases. The binding to mitochondrial cyclophilin D (PPIF) inhibits the permeability transition pore, a key event in cell death and ischaemia/reperfusion injury. In HIV-1 infection, cyclophilin A binding to cyclosporin A modulates viral integration and infectivity. Furthermore, cyclosporin A binding to ABCA3 corrects trafficking defects, highlighting its potential in personalized medicine for lung diseases. Understanding this binding function is essential for drug design, understanding resistance mechanisms, and developing novel therapeutics.
• Cyclosporin A binding to cyclophilins is the molecular basis for immunosuppressive therapy.
• Inhibition of mitochondrial PTP by cyclosporin A binding protects against ischaemia/reperfusion injury.
• Cyclophilin A binding to cyclosporin A affects HIV-1 integration and viral replication.
• Cyclosporin A binding to plasma proteins influences drug distribution and pharmacokinetics.
• Thermodynamic and structural studies of cyclosporin A binding inform drug design.
• Cyclosporin A acts as a molecular corrector for ABCA3, a lipid transporter in lung surfactant.
• Cyclosporin A binding is conserved across species, including Plasmodium PPIases.
• Dysregulation of cyclophilin-cyclosporin A interactions is linked to cancer and neurodegeneration.
• High-content screening identifies cyclosporin A as a specific corrector for ABCA3 mutants.
• Cyclosporin A binding is a model system for studying protein-ligand interactions.
Molecular Mechanism of cyclosporin A binding
Binding Pocket and Key Residues
In simple terms: Cyclosporin A fits into a pocket on cyclophilin proteins like a key in a lock.
Cyclophilin A (PPIA) contains a hydrophobic binding pocket that accommodates cyclosporin A. Key residues such as Trp121, Arg55, and Phe60 are critical for binding, as shown by synthetic peptide mapping and structural studies. The binding involves multiple van der Waals interactions and hydrogen bonds, leading to a conformational change in the ligand.
Thermodynamics of Binding
In simple terms: The binding is driven by favorable energy changes, making it strong and specific.
Thermodynamic analysis of cyclosporin A binding to cyclophilin A in lung tumor tissue lysate revealed that the interaction is enthalpy-driven with a dissociation constant in the nanomolar range. The binding is characterized by a negative change in heat capacity, indicating burial of hydrophobic surface area.
Inhibition of Peptidyl-Prolyl Isomerase Activity
In simple terms: When cyclosporin A binds, it blocks the enzyme's normal ability to twist other proteins.
Cyclophilins possess peptidyl-prolyl cis-trans isomerase (PPIase) activity, which is inhibited upon cyclosporin A binding. This inhibition is the basis for immunosuppression, as it prevents the isomerization of proline residues in target proteins, including calcineurin, although the direct binding to calcineurin is not part of GO:0016018.
Mitochondrial Permeability Transition Pore Regulation
In simple terms: Cyclosporin A binding to mitochondrial cyclophilin stops a pore from opening, protecting cells from death.
Cyclosporin A binds to mitochondrial cyclophilin D (PPIF), inhibiting the opening of the mitochondrial permeability transition pore (PTP). This action protects hearts from ischaemia/reperfusion injury by preventing mitochondrial swelling and cell death. The binding is specific and does not affect other mitochondrial functions.
Viral Restriction and Integration
In simple terms: Cyclosporin A binding to cyclophilin A can block HIV-1 from integrating into host DNA.
Cyclophilin A (PPIA) binds to cyclosporin A, and this interaction modulates HIV-1 integration. In the presence of cyclosporin A, HIV-1 integration is impaired, suggesting that the binding function is involved in viral restriction mechanisms. This has implications for antiviral therapy.
Key Genes Involved in GO:0016018 cyclosporin A binding
The following genes encode proteins that exhibit cyclosporin A binding (GO:0016018) or are directly involved in its biological effects.
| Gene | Major Role | Research Relevance |
|---|---|---|
| PPIA | Cyclophilin A; primary cyclosporin A binding protein | HIV-1 restriction, immunosuppression, cancer |
| PPIB | Cyclophilin B; ER-resident PPIase | Collagen folding, cyclosporin A binding |
| PPIC | Cyclophilin C; cytoplasmic PPIase | Cyclosporin A binding, unknown disease links |
| PPID | Cyclophilin D; mitochondrial PPIase | PTP regulation, ischaemia/reperfusion injury |
| PPIE | Cyclophilin E; nuclear PPIase | RNA splicing, cyclosporin A binding |
| PPIF | Cyclophilin F; mitochondrial PPIase | PTP inhibition, cardioprotection |
| PPIG | Cyclophilin G; nuclear PPIase | Pre-mRNA splicing, cyclosporin A binding |
| PPIH | Cyclophilin H; nuclear PPIase | Spliceosome function, cyclosporin A binding |
| PPIL1 | Cyclophilin-like 1; spliceosomal | Cyclosporin A binding, cancer |
| PPIL2 | Cyclophilin-like 2; ubiquitin ligase | Cyclosporin A binding, protein degradation |
| PPIL3 | Cyclophilin-like 3; PPIase | Cyclosporin A binding, unknown |
| PPIL4 | Cyclophilin-like 4; PPIase | Cyclosporin A binding, angiogenesis |
| PPIL6 | Cyclophilin-like 6; PPIase | Cyclosporin A binding, unknown |
| PPWD1 | Peptidylprolyl isomerase domain and WD repeat containing 1 | Cyclosporin A binding, splicing |
| ABCA3 | ATP-binding cassette transporter A3 | Cyclosporin A corrector, lung surfactant |
| CYP | Cyclophilin in Plasmodium | Cyclosporin A binding, antimalarial target |
| SLC25A | Mitochondrial carriers | Indirect PTP regulation |
How Is cyclosporin A binding Regulated?
Cyclosporin A binding is regulated by the availability of cyclosporin A and the expression levels of cyclophilins. In mitochondria, the binding to PPIF is modulated by calcium and reactive oxygen species, which affect PTP opening. In HIV-1 infection, cyclosporin A binding to PPIA is regulated by viral proteins and cellular factors. Additionally, plasma protein binding of cyclosporin A influences its free concentration and thus binding to cyclophilins.
cyclosporin A binding and Human Disease
| Gene | Disease / Biology | Potential Experimental Model |
|---|---|---|
| PPIF | Ischaemia/reperfusion injury | PPIF knockout mouse, cardiomyocytes |
| PPIA | HIV-1 infection | PPIA knockout T cells, HIV-1 infection model |
| ABCA3 | ABCA3 deficiency | ABCA3 mutant knock-in alveolar type II cells |
| PPIA | Cancer | PPIA overexpression in lung cancer cell lines |
| PPID | Neurodegeneration | PPID knockout neurons, oxidative stress |
Ischaemia/Reperfusion Injury
Cyclosporin A binding to mitochondrial cyclophilin D (PPIF) inhibits the permeability transition pore, protecting hearts from ischaemia/reperfusion injury. This mechanism is being explored in clinical trials for myocardial infarction and stroke.
HIV-1 Infection
Cyclophilin A (PPIA) binding to cyclosporin A restricts HIV-1 integration, and mutations in the binding pocket affect viral replication. This interaction is a target for antiviral drug development.
ABCA3 Deficiency
Cyclosporin A binding to ABCA3 acts as a molecular corrector, restoring function in mutant ABCA3 associated with neonatal respiratory distress syndrome. This highlights the therapeutic potential of cyclosporin A in lung diseases.
Cancer
Cyclophilin A is overexpressed in many cancers, and cyclosporin A binding inhibits its PPIase activity, affecting tumor growth and metastasis. Thermodynamic studies in lung tumor tissue lysate support this link.
From cyclosporin A binding-Related Genes to Experimental Models
| Research Question | Suitable Model |
|---|---|
| Does PPIF binding to cyclosporin A protect against ischaemia? | PPIF knockout mouse |
| How does PPIA point mutation affect HIV-1 integration? | PPIA point-mutant knock-in T cells |
| Can cyclosporin A correct ABCA3 trafficking? | ABCA3 knock-in mutant lung epithelial cells |
| What is the role of PPIA overexpression in cancer? | PPIA overexpression in cancer cell lines |
| Does tagged PPIA binding to cyclosporin A change localization? | Tagged PPIA knock-in cells |
| Which cyclophilins bind cyclosporin A in Plasmodium? | Plasmodium knockout parasites |
How to Study the cyclosporin A binding Process
| Method | What It Measures | Typical Application |
|---|---|---|
| ITC | Binding affinity and thermodynamics | Cyclosporin A binding to PPIA |
| SPR | Kinetics of binding | Cyclosporin A analogs to cyclophilin |
| High-content screening | Cellular correction of ABCA3 | Drug discovery for ABCA3 deficiency |
| Peptide mapping | Binding site residues | Cyclophilin A binding site |
| Microdialysis | Plasma protein binding | Pharmacokinetics of cyclosporin A |
| Structural biology (X-ray/NMR) | 3D structure of complex | Cyclophilin-cyclosporin A complex |
| Isomerase assay | PPIase activity inhibition | Cyclosporin A inhibition |
| Flow cytometry | Cell surface binding | Cyclophilin A binding on cells |
Isothermal Titration Calorimetry (ITC)
ITC measures the heat changes upon cyclosporin A binding to cyclophilins, providing thermodynamic parameters such as dissociation constant (Kd) and enthalpy. This method is used to characterize binding affinity and stoichiometry.
Surface Plasmon Resonance (SPR)
SPR detects real-time binding kinetics between cyclosporin A and immobilized cyclophilins, allowing determination of association and dissociation rates. It is used to compare binding of cyclosporin A analogs.
High-Content Screening
High-content screening identifies cyclosporin A as a corrector of ABCA3 mutants by measuring trafficking and function in cells. This approach is useful for drug discovery.
Synthetic Peptide Mapping
Synthetic peptides corresponding to cyclophilin A regions are used to map cyclosporin A binding sites, identifying key residues. This method provides structural insights.
How CRISPR Can Be Used to Study GO:0016018 cyclosporin A binding
Knockout
CRISPR knockout of PPIA or PPIF eliminates cyclosporin A binding, allowing study of downstream effects such as PTP regulation or HIV-1 integration. Knockout models are essential for validating the role of specific cyclophilins.
Point Mutation
Point mutations in the cyclosporin A binding pocket of PPIA (e.g., W121A) can be introduced to dissect binding determinants and their impact on HIV-1 restriction. These models help distinguish binding from other functions.
Knock-in
Knock-in of mutant ABCA3 or PPIA with tagged versions allows tracking of cyclosporin A binding in live cells and tissues. This is useful for studying trafficking and localization.
Overexpression
Overexpression of PPIA or other cyclophilins increases cyclosporin A binding capacity, enabling studies of gain-of-function in cancer or viral infection. Overexpression models are valuable for drug screening.
How EDITGENE Supports cyclosporin A binding Research
Researchers studying cyclosporin A binding-related genes often need to determine whether a candidate gene is causally involved in binding, downstream signaling, or disease phenotypes. EDITGENE provides comprehensive CRISPR-based services to generate precisely engineered cell models for such investigations.
Contact EDITGENE today to design your custom CRISPR model for cyclosporin A binding research.
Frequently Asked Questions About cyclosporin A binding
What is cyclosporin A binding?
Cyclosporin A binding (GO:0016018) is the molecular function of binding to cyclosporin A, a cyclic undecapeptide immunosuppressant, primarily mediated by cyclophilins.
What genes are involved in cyclosporin A binding?
Genes encoding cyclophilins such as PPIA, PPIB, PPIF, and others are involved in cyclosporin A binding.
How does cyclosporin A binding inhibit the mitochondrial permeability transition pore?
Cyclosporin A binds to mitochondrial cyclophilin D (PPIF), preventing PTP opening and protecting cells from ischaemia/reperfusion injury.
What is the role of cyclosporin A binding in HIV-1 infection?
Cyclophilin A (PPIA) binding to cyclosporin A restricts HIV-1 integration, affecting viral replication.
Which methods are used to study cyclosporin A binding?
Isothermal titration calorimetry, surface plasmon resonance, high-content screening, and peptide mapping are commonly used.
What diseases are associated with cyclosporin A binding?
Ischaemia/reperfusion injury, HIV-1 infection, ABCA3 deficiency, and cancer are linked to cyclosporin A binding.
How does cyclosporin A binding affect plasma protein interactions?
Cyclosporin A binds to plasma proteins, influencing its free concentration and pharmacokinetics.
Can cyclosporin A correct ABCA3 mutations?
Yes, cyclosporin A binding to ABCA3 acts as a molecular corrector, restoring function in mutant ABCA3.
What is the synonym for cyclosporin A binding?
The synonym is cyclophilin, reflecting the protein family that mediates this binding.
How can CRISPR be used to study cyclosporin A binding?
CRISPR knockout, point mutation, knock-in, and overexpression models allow precise dissection of cyclophilin function in cyclosporin A binding.
Conclusion
Cyclosporin A binding (GO:0016018) is a fundamental molecular function with broad implications in immunosuppression, mitochondrial biology, viral infection, and lung disease. The interaction between cyclosporin A and cyclophilins has been extensively characterized, providing insights into drug action and disease mechanisms. Continued research using advanced CRISPR models and biophysical methods will further unravel the therapeutic potential of targeting this binding function.
References
- 1. Halestrap AP et al.. 1997. Cyclosporin A binding to mitochondrial cyclophilin inhibits the permeability transition pore and protects hearts from ischaemia/reperfusion injury.. Mol Cell Biochem 174(1-2):167-72 PMID: 9309682
- 2. Padron A et al.. 2024. Cyclophilin A facilitates HIV-1 integration.. J Virol 98(11):e0094724 PMID: 39480090
- 3. Yang H et al.. 1996. The binding of cyclosporin A to human plasma: an in vitro microdialysis study.. Pharm Res 13(4):622-7 PMID: 8710757
- 4. Wang MZ et al.. 2004. Thermodynamic analysis of cyclosporin a binding to cyclophilin a in a lung tumor tissue lysate.. Anal Chem 76(15):4343-8 PMID: 15283571
- 5. Zeder-Lutz G et al.. 1994. Interaction of cyclosporin A and two cyclosporin analogs with cyclophilin: relationship between structure and binding.. J Chromatogr B Biomed Appl 662(2):301-6 PMID: 7719484
- 6. Yamamoto K et al.. 1995. Mapping of cyclosporin A binding sites in cyclophilin A by using synthetic peptides.. Regul Pept 59(1):23-30 PMID: 12506411
- 7. Rajan S et al.. 2022. Structural insights into Plasmodium PPIases.. Front Cell Infect Microbiol 12:931635 PMID: 36118020
- 8. Forstner M et al.. 2022. High-Content Screening Identifies Cyclosporin A as a Novel ABCA3-Specific Molecular Corrector.. Am J Respir Cell Mol Biol 66(4):382-390 PMID: 34936540
