Staphylococcal enterotoxin A has two cooperative binding sites on major histocompatibility complex class II.

Abstract

The superantigen staphylococcal enterotoxin A (SEA) binds to major histocompatibility complex (MHC) class II molecules at two sites on either side of the peptide groove. Two separate but cooperative interactions to the human class II molecule HLA-DR1 were detected. The first high affinity interaction to the DR1 beta chain is mediated by a zinc atom coordinated by H187, H225, and D227 in SEA and H81 in the polymorphic DR1 beta chain. The second low affinity site is to the DR1 alpha chain analogous to SEB binding and is mediated by residue F47 in SEA. Binding of one SEA to the DR1 beta chain enhances the binding of a second SEA molecule to the DR1 alpha chain. The zinc site is on the opposite side of the SEA molecule from residue F47 so that one SEA molecule can readily bind two class II molecules. Both binding sites on SEA are required for maximal activity. Thus, unlike, SEB, SEA requires two separate binding sites for optimal activity, which may allow it to stabilize SEA interaction with T cell receptors, as well as to activate the antigen-presenting cell by cross-linking MHC class II.

Mutagenesis, biochemical, and biophysical characterization of Mycoplasma arthritidis-derived mitogen

“…It is well established that metal ions, Zn 2+ in particular, play an important role in the biological function of certain SAgs (Etongue-Mayer et al, 2002;Hudson et al, 1995;Kozono et al, 1995;Langlois et al, 2003;Li et al, 1999Li et al, , 2001. Zinc may regulate the SAg activity in several ways.…”

“…First, the metal ion may be directly involved in the interactions between SAgs and their host receptors (Li et al, 1999(Li et al, , 2001Petersson et al, 2001). Such interactions result in a so-called "high-affinity" SAg-binding site, via a zinc bridge, on the MHC class II molecules (Hudson et al, 1995;Kozono et al, 1995;Li et al, 2001;Petersson et al, 2001). Second, some SAgs can form zinc-dependent homodimers, which could in turn cause dimerization of the MHC class II molecules on the APC surface (Al-Daccak et al, 1998;Baker et al, 2004a,b;Li et al, 1997;Papageorgiou et al, 1995Papageorgiou et al, , 2004Roussel et al, 1997;Sundstrom et al, 1996).…”

Therapy of human non-small-cell lung carcinoma using antibody targeting of a modified superantigen

“…The structure and function properties of SEA have been well characterized (Abrahmsén et al, 1995;Hudson et al, 1995;Schad et al, 1995). To reduce the systemic toxicity, a major drawback in the use of wild-type SEA (Alphaug et al, 1998), a substitution of Asp 227 has been made.…”

TCR recognition of peptide/MHC class II complexes and superantigens

“…Group III SAGs contain only staphylococcal SAGs (such as SEA), and these toxins are able to crosslink MHC molecules [43,44] through a low-affinity site similar to that used by Group II [45], as well as a high-affinity, zinc-dependent MHC binding interface located within the β-grasp domain of the SAG [46]. There is currently little available information regarding how Group III SAGs engage the TCR.…”