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Functional Analysis of the TCR Binding Domain of Toxic Shock Syndrome Toxin-1 Predicts Further Diversity in MHC Class II/Superantigen/TCR Ternary Complexes ¹

John K. McCormick^2,*, Timothy J. Tripp^*, Andrea S. Llera^3,, Eric J. Sundberg, Martin M. Dinges^4,*, Roy A. Mariuzza and Patrick M. Schlievert^5,*

^* Department of Microbiology, University of Minnesota Medical School, Minneapolis, MN 55455; and Center for Advanced Research in Biotechnology, University of Maryland Biotechnology Institute, Rockville, MD 20850

Superantigens (SAGs) aberrantly alter immune system function through simultaneous interaction with lateral surfaces of MHC class II molecules on APCs and with particular variable regions of the TCR -chain (V). To further define the interface between the bacterial SAG toxic shock syndrome toxin-1 (TSST-1) and the TCR, we performed alanine scanning mutagenesis within the putative TCR binding region of TSST-1 along the central helix adjacent to the N-terminal helix and the 7-9 loop as well as with two universally conserved SAG residues (Leu¹³⁷ and Tyr¹⁴⁴ in TSST-1). Mutants were analyzed for multiple functional activities, and various residues appeared to play minor or insignificant roles in the TCR interaction. The locations of six residues (Gly¹⁶, Trp¹¹⁶, Glu¹³², His¹³⁵, Gln¹³⁶, and Gln¹³⁹), each individually critical for functional activity as well as direct interaction with the human TCR V2.1-chain, indicate that the interface occurs in a novel region of the SAG molecule. Based on these data, a model of the MHC/TSST-1/TCR ternary complex predicts similarities seen with other characterized SAGs, although the CDR3 loop of V2.1 is probably involved in direct SAG-TCR molecular interactions, possibly contributing to the TCR V specificity of TSST-1.

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