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J. Biol. Chem., Vol. 279, Issue 28, 29175-29184, July 9, 2004
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¶

||**
From the
Department of Chemistry and Biochemistry and the ||Walther Cancer Research Center, University of Notre Dame, Notre Dame, Indiana 46556 and the
Molecular Immunology Section, Neuroimmunology Branch, NINDS, National Institutes of Health, Bethesda, Maryland 20892
Mutational studies of T cell receptor (TCR) contact residues on the surface of the human class I major histocompatibility complex (MHC) molecule HLA-A2 have identified a "functional hot spot" that comprises Arg65 and Lys66 and is involved in recognition by most peptide-specific HLA-A2-restricted TCRs. Although there is a significant amount of functional data on the effects of mutations at these positions, there is comparatively little biochemical information that could illuminate their mode of action. Here, we have used a combination of fluorescence anisotropy, functional assays, and Biacore binding experiments to examine the effects of mutations at these positions on the peptide-MHC interaction and TCR recognition. The results indicate that mutations at both position 65 and position 66 influence peptide binding by HLA-A2 to various extents. In particular, mutations at position 66 result in significantly increased peptide dissociation rates. However, these effects are independent of their effects on TCR recognition, and the Arg65-Lys66 region thus represents a true "hot spot" for TCR recognition. We also made the observation that in vitro T cell reactivity does not scale with the half-life of the peptide-MHC complex, as is often assumed. Finally, position 66 is implicated in the "dual recognition" of both peptide and TCR, emphasizing the multiple roles of the class I MHC peptide-binding domain.
Received for publication, March 26, 2004 , and in revised form, April 30, 2004.
* This work was supported in part by NIGMS, National Institutes of Health Grant GM067079
¶ Supported by a fellowship from the German Academic Exchange Service.
** To whom correspondence should be addressed. Tel.: 574-631-9810; Fax: 574-631-6652; E-mail: bbaker2{at}nd.edu.
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M. A. Cuendet and O. Michielin
Protein-Protein Interaction Investigated by Steered Molecular Dynamics: The TCR-pMHC Complex
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O. Y. Borbulevych, T. K. Baxter, Z. Yu, N. P. Restifo, and B. M. Baker
Increased Immunogenicity of an Anchor-Modified Tumor-Associated Antigen Is Due to the Enhanced Stability of the Peptide/MHC Complex: Implications for Vaccine Design
J. Immunol.,
April 15, 2005;
174(8):
4812 - 4820.
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