T-cell receptor specificity maintained by altered thermodynamics

Madura, Florian, Rizkallah, Pierre J., Miles, Kim M., Holland, Christopher J., Bulek, Anna M., Fuller, Anna, Schauenburg, Andrea J.A., Miles, John J., Liddy, Nathaniel, Sami, Malkit, Li, Yi, Hossain, Moushumi, Baker, Brian M., Jakobsen, Bent K., Sewell, Andrew K., and Cole, David K. (2013) T-cell receptor specificity maintained by altered thermodynamics. Journal of Biological Chemistry, 288 (26). pp. 18766-18775.

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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 (K(D) = 100 nM to 270 μM). We used phage-display to produce a melanoma-specific TCR (α24β17) with a 30,000-fold enhanced binding affinity (K(D) = 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.

Item ID: 45065
Item Type: Article (Research - C1)
ISSN: 1083-351X
Keywords: crystal structure; high affinity T cell receptor (TCR); melanoma; peptide-major histocompatibility complex (pMHC); surface plasmon resonance (SPR); T-cell; T-cell receptor
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© 2013 by The American Society for Biochemistry and Molecular Biology, Inc.

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Funders: UK Biotechnology and Biological Science Research Council (BBSRC), Tenovus Foundation (TF), National Institute of General Medical Sciences (NIGMS), National Institutes of Health (NIH), Research Councils UK (RCUK), Australian National Health and Medical Research Council (NHMRC), Wellcome Trust (WT)
Projects and Grants: BBSRC BB/H001085/1, NIGMS GM067079, WT 095767
Date Deposited: 11 Aug 2016 01:45
FoR Codes: 11 MEDICAL AND HEALTH SCIENCES > 1107 Immunology > 110702 Applied Immunology (incl Antibody Engineering, Xenotransplantation and T-cell Therapies) @ 100%
SEO Codes: 92 HEALTH > 9201 Clinical Health (Organs, Diseases and Abnormal Conditions) > 920108 Immune System and Allergy @ 100%
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