A superantigen such as<unk> -1 stimulates human T cells that express VB 2, which may represent 5-30% of all host T cells. PTSAgs induce the VB-specific expansion of both CD4 and CD8- subsets of T-lymphocytes.<unk> -1 forms homodimers in most of its known crystal forms. The SAGs show remarkably conserved architecture and are divided into the N- and C- terminal domains. Mutational analysis has mapped the putative TCR binding region of<unk> -1 to a site located on the back-side groove. If the TCR occupies this site, the amino terminal alpha helix forms a large wedge between the TCR and MHC class II molecules. The wedge would physically separate the TCR from the MHC class II molecules. A novel domain may exist in the SAGs that is separate from the TCR and class II MHC-binding domains. The domain consists of residues 150 to 161 in SEB, and similar regions exist in all the other SAGs as well. In this study a synthetic peptide containing this sequence was able to prevent SAG-induced lethality in D-galactosamine-sensitized mice with staphylococcal<unk> -1, as well as some other SAGs. Significant differences exist in the sequences of MHC Class II alleles and TCR Vbeta elements expressed by different species, and these differences have important effects on the interaction of PTSAgs and with MCH class II and TCR molecules. Binding site<unk> -1 binds primarily to the alpha-chain of class II MHC exclusively through a low-affinity (or generic) binding site on the SAG N-terminal domain. This is opposed to other super antigens (SAGs) such as DEA and SEE, that bind to class II MHC through the low-affinity site, and to the beta-chain through a high-affinity site. This high-affinity site is a zinc-dependent site on the SAG C-terminal domain. When this site is bound, it extends over part of the binding groove, makes contacts with the bound peptide, and then binds regions of both the alpha and beta chains. MHC-binding by<unk> -1 is partially peptide-dependent. Mutagenesis studies with SEA have indicated that both binding sites are required for optimal T-cell activation. These studies containing<unk> -1 indicate that the TCR binding domain lies at the top of the back side of this<unk> , though the complete interaction remains to be determined. There have also been indications that the TCR binding site of<unk> -1 is mapped to the major groove of the central alpha helix or the short amino terminal alpha helix. Residues in the beta claw motif of<unk> -1 are known<unk> teract primarily with the invariant region of the Alpha chain of this MHC class II molecule. Residues forming minor contacts with<unk> -1 were also identified in the HLA-DR1 β-chain, as well as the antigenic peptide, located in the interchain groove. The arrangement of<unk> -1 with respect to the MHC class II molecule imposes steric restriction on the three component complex composed of<unk> -1, MHC class II, and the TCR. Mutational analysis Initial studies of mutants revealed that residues on the back side of the central alpha helix were required for super antigenic activity. Changing the histidine at position 135 to alanine caused<unk> -1 to be neither lethal or superantigenic. Changes in residues that were in close proximity to H135A, also had the effect of diminishing the lethality and superantigenic quality of these mutants. Although most of these mutants did not result in loss of antigenicity of<unk> -1. Tests done using mutagenic<unk> -1<unk> s indicated that the lethal and superantigenic properties are separable. When Lys-132 in<unk> -O was changed to a Glu, the resulting mutant became completely lethal but non superantigenic. The same results, lethal but not superantigenic, were found for<unk> -1 Gly16Val. Residues Gly16, Glu132, and Gln 136, located on the back of the back-side groove of the putative TCR binding region of<unk> -1, it has been proposed that they are also a part of a second functionally lethal site in the<unk> -1.
Toxic shock syndrome toxin
Chlorotoxin
BeKm-1 toxin
Vanillotoxin
Grammotoxin
Psalmotoxin
Neurotoxin
Dinotoxin