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

J Mol Biol. 2007 Apr 6;367(4):925-34. doi: 10.1016/j.jmb.2007.01.024. Epub 2007 Jan 12.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Sequence
  • Antigens, Bacterial / chemistry
  • Bacterial Proteins / chemistry*
  • Bacterial Proteins / genetics
  • Bacterial Proteins / immunology
  • Bacterial Proteins / physiology
  • Crystallography, X-Ray*
  • Epitopes, T-Lymphocyte / chemistry
  • Epitopes, T-Lymphocyte / immunology
  • Evolution, Molecular
  • Exotoxins / chemistry*
  • Exotoxins / genetics
  • Exotoxins / immunology
  • Exotoxins / physiology
  • Humans
  • Lymphocyte Activation / immunology*
  • Models, Molecular
  • Molecular Sequence Data
  • Phylogeny
  • Protein Structure, Tertiary / genetics
  • Protein Structure, Tertiary / physiology
  • Pyrogens / chemistry
  • Pyrogens / classification
  • Sequence Homology, Amino Acid
  • Superantigens / chemistry*
  • Superantigens / genetics
  • Superantigens / physiology

Substances

  • Antigens, Bacterial
  • Bacterial Proteins
  • Epitopes, T-Lymphocyte
  • Exotoxins
  • Pyrogens
  • Superantigens
  • erythrogenic toxin

Associated data

  • PDB/2ICI