T-cell Receptor Specificity Maintained by Altered Thermodynamics*
| Autor: | Kim M. Miles, Bent K. Jakobsen, Anna Marta Bulek, Yi Li, Moushumi Hossain, Andrew K. Sewell, Malkit Sami, Brian M. Baker, Anna Fuller, Pierre J. Rizkallah, Nathaniel Liddy, Andrea J. A. Schauenburg, Christopher J. Holland, John J. Miles, David K. Cole, Florian Madura |
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| Jazyk: | angličtina |
| Rok vydání: | 2013 |
| Předmět: |
Peptide-major Histocompatibility Complex (pMHC)
Molecular Conformation Peptide T-Cell Antigen Receptor Specificity Crystallography X-Ray Biochemistry Major Histocompatibility Complex 0302 clinical medicine T-cell Receptor Melanoma chemistry.chemical_classification 0303 health sciences Alanine T-cell Receptor hemic and immune systems 3. Good health Gene Expression Regulation Neoplastic Biotinylation Crystal Structure Thermodynamics Protein Binding Immunology Receptors Antigen T-Cell chemical and pharmacologic phenomena Biology Major histocompatibility complex High Affinity T Cell Receptor (TCR) 03 medical and health sciences Peptide Library Humans Surface Plasmon Resonance (SPR) Peptide library Molecular Biology 030304 developmental biology T-cell receptor Water Hydrogen Bonding Cell Biology MHC restriction Surface Plasmon Resonance chemistry Mutation biology.protein Biophysics Solvents Peptides 030215 immunology |
| Zdroj: | The Journal of Biological Chemistry |
| ISSN: | 1083-351X 0021-9258 |
| Popis: | Background: The molecular principles governing T-cell specificity are poorly understood. Results: High affinity binding of a melanoma-specific T-cell receptor (TCR) is mediated through new MHC contacts and distinct thermodynamics. Conclusion: A novel thermodynamic mechanism upholds TCR-peptide specificity. Significance: TCRs can maintain peptide specificity using a mechanism that may enable widespread, safe enhancement of TCR binding affinity in therapeutic applications. The T-cell receptor (TCR) recognizes peptides bound to major histocompatibility molecules (MHC) and allows T-cells to interrogate the cellular proteome for internal anomalies from the cell surface. The TCR contacts both MHC and peptide in an interaction characterized by weak affinity (KD = 100 nm to 270 μm). We used phage-display to produce a melanoma-specific TCR (α24β17) with a 30,000-fold enhanced binding affinity (KD = 0.6 nm) to aid our exploration of the molecular mechanisms utilized to maintain peptide specificity. Remarkably, although the enhanced affinity was mediated primarily through new TCR-MHC contacts, α24β17 remained acutely sensitive to modifications at every position along the peptide backbone, mimicking the specificity of the wild type TCR. Thermodynamic analyses revealed an important role for solvation in directing peptide specificity. These findings advance our understanding of the molecular mechanisms that can govern the exquisite peptide specificity characteristic of TCR recognition. |
| Databáze: | OpenAIRE |
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