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

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Strategic Mutations in the Class I Major Histocompatibility Complex HLA-A2 Independently Affect Both Peptide Binding and T Cell Receptor Recognition^*

Tiffany K. Baxter, Susan J. Gagnon, Rebecca L. Davis-Harrison, John C. Beck, Anne-Kathrin Binz¶, Richard V. Turner, William E. Biddison, and Brian M. Baker||**

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 (to B. M. B.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

^¶ 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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