Crystal Structure of the Streptococcal Superantigen SpeI and Functional Role of a Novel Loop Domain in T Cell Activation by Group V Superantigens

Authors

Jean-Nicholas P. Brouillard, University of Western Ontario
Sebastian Günther, Boston Biomedical Research Institute
Ashok K. Varma, Boston Biomedical Research Institute
Irene Gryski, University of Western Ontario
Christine A. Herfst, University of Western Ontario
A. K. M. Nur-ur Rahman, University of Western OntarioFollow
Donald Y. M. Leung, University of Colorado
Patrick M. Schlievert, University of Minnesota
Joaquin Madrenas, University of Western OntarioFollow
Eric J. Sundberg, Boston Biomedical Research Institute
John K. McCormick, University of Western OntarioFollow

Document Type

Article

Publication Date

4-6-2007

Journal

Journal of Molecular Biology

Volume

367

Issue

4

First Page

925

Last Page

934

Abstract

Superantigens (SAgs) are potent microbial toxins that bind simultaneously to T cell receptors (TCRs) and class II major histocompatibility complex molecules, resulting in the activation and expansion of large T cell subsets and the onset of numerous human diseases. Within the bacterial SAg family, streptococcal pyrogenic exotoxin I (SpeI) has been classified as belonging to the group V SAg subclass, which are characterized by a unique, relatively conserved approximately 15 amino acid extension (amino acid residues 154 to 170 in SpeI; herein referred to as the alpha3-beta8 loop), absent in SAg groups I through IV. Here, we report the crystal structure of SpeI at 1.56 A resolution. Although the alpha3-beta8 loop in SpeI is several residues shorter than that of another group V SAg, staphylococcal enterotoxin serotype I, the C-terminal portions of these loops, which are located adjacent to the putative TCR binding site, are structurally similar. Mutagenesis and subsequent functional analysis of SpeI indicates that TCR beta-chains are likely engaged in a similar general orientation as other characterized SAgs. We show, however, that the alpha3-beta8 loop length, and the presence of key glycine residues, are necessary for optimal activation of T cells. Based on Vbeta-skewing analysis of human T cells activated with SpeI and structural models, we propose that the alpha3-beta8 loop is positioned to form productive intermolecular contacts with the TCR beta-chain, likely in framework region 3, and that these contacts are required for optimal TCR recognition by SpeI, and likely all other group V SAgs.

Notes

Published in: Journal of Molecular Biology, Volume 367, Issue 4, 6 April 2007, Pages 925-934. doi: 10.1016/j.jmb.2007.01.024