ALTERED ORIENTATION OF STREPTOCOCCAL SUPERANTIGEN (SSA) ON HLA-DR1 ALLOWS UNCONVENTIONAL REGIONS TO CONTRIBUTE TO SSA V-BETA SPECIFICITY

Crystallographic studies reveal even distantly related bacterial super antigens (SAg) to adopt a common structural topology, Mutational analy ses confirm that this shared folding pattern often confers a conserved function to analogous residues in different SAg, albeit with specific ities for particular TCR or MHC class II molecules, It was thus surpri sing that the streptococcal SAg SSA differed from related SAg in the l ocation of its V beta-determining residues, Because it seemed unlikely that SSA would deviate significantly from an SAg-like topology, we hy pothesized that variations in SSA V beta-determining regions might res ult from differences in SSA-MHC class II interactions relative to othe r SAg during SSA presentation to the TCR, Comparison of the DR1-bindin g properties of SSA with its closest homologue SEE found different ami no acid positions within SAg primary sequences to contribute to SSA-DR 1 and SEB-DR1 interactions, and suggested that SSA bound DR1 with an a ltered orientation relative to SEE. The common involvement of DR1 alph a 39K, however, predicted that the two SAg bound overlapping sites on DR1, Nevertheless, SSA and SEE did not effectively cross-compete for D R1 binding and had opposite patterns of DR1-binding affinity in the pr esence of distinct DR1-expressing cell lines, The data thus suggest th at SSA and SEE bind not only with different orientations on DR1, but m ay bind preferentially to distinct DR1 subsets delineated by cell-spec ific factors, Differences in orientation of SSA on DR1 and/or interact ion of SSA with particular DR1 subsets may explain why unconventional regions influence SSA TCR V beta specificity.