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: 18766-18775. doi:10.1074/jbc.M113.464560

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Author 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.
Cole, David K.
Title T-cell receptor specificity maintained by altered thermodynamics
Journal name Journal of Biological Chemistry   Check publisher's open access policy
ISSN 0021-9258
Publication date 2013-06
Year available 2013
Sub-type Article (original research)
DOI 10.1074/jbc.M113.464560
Open Access Status File (Publisher version)
Volume 288
Issue 26
Start page 18766
End page 18775
Total pages 10
Place of publication Bethesda, MD, United States
Publisher American Society for Biochemistry and Molecular Biology
Collection year 2014
Language eng
Abstract 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.
Q-Index Code C1
Q-Index Status Confirmed Code
Institutional Status UQ
Additional Notes Published online: 22 May 2013.

Document type: Journal Article
Sub-type: Article (original research)
Collections: Official 2014 Collection
School of Medicine Publications
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Citation counts: TR Web of Science Citation Count  Cited 13 times in Thomson Reuters Web of Science Article | Citations
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