title: Conservation and variation in superantigen structure and activity highlighted by the three-dimensional structures of two new superantigens from Streptococcus pyogenes.
abstract: Bacterial superantigens (SAgs) are a structurally related group of protein toxins secreted by Staphylococcus aureus and Streptococcus pyogenes. They are implicated in a range of human pathologies associated with bacterial infection whose symptoms result from SAg-mediated stimulation of a large number (2-20%) of T-cells. At the molecular level, bacterial SAgs bind to major histocompatability class II (MHC-II) molecules and disrupt the normal interaction between MHC-II and T-cell receptors (TCRs). We have determined high-resolution crystal structures of two newly identified streptococcal superantigens, SPE-H and SMEZ-2. Both structures conform to the generic bacterial superantigen folding pattern, comprising an OB-fold N-terminal domain and a beta-grasp C-terminal domain. SPE-H and SMEZ-2 also display very similar zinc-binding sites on the outer concave surfaces of their C-terminal domains. Structural comparisons with other SAgs identify two structural sub-families. Sub-families are related by conserved core residues and demarcated by variable binding surfaces for MHC-II and TCR. SMEZ-2 is most closely related to the streptococcal SAg SPE-C, and together they constitute one structural sub-family. In contrast, SPE-H appears to be a hybrid whose N-terminal domain is most closely related to the SEB sub-family and whose C-terminal domain is most closely related to the SPE-C/SMEZ-2 sub-family. MHC-II binding for both SPE-H and SMEZ-2 is mediated by the zinc ion at their C-terminal face, whereas the generic N-terminal domain MHC-II binding site found on many SAgs appears not to be present. Structural comparisons provide evidence for variations in TCR binding between SPE-H, SMEZ-2 and other members of the SAg family; the extreme potency of SMEZ-2 (active at 10(-15) g ml-1 levels) is likely to be related to its TCR binding properties. The smez gene shows allelic variation that maps onto a considerable proportion of the protein surface. This allelic variation, coupled with the varied binding modes of SAgs to MHC-II and TCR, highlights the pressure on SAgs to avoid host immune defences.
authors.affiliation: School of Biological Sciences, University of Auckland, New Zealand.
authors.forename: V L
authors.initials: VL
authors.lastname: Arcus
authors.forename: T
authors.initials: T
authors.lastname: Proft
authors.forename: J A
authors.initials: JA
authors.lastname: Sigrell
authors.forename: H M
authors.initials: HM
authors.lastname: Baker
authors.forename: J D
authors.initials: JD
authors.lastname: Fraser
authors.forename: E N
authors.initials: EN
authors.lastname: Baker
mesh_terms: D000483:Alleles; D000595:Amino Acid Sequence; D001665:Binding Sites; D017124:Conserved Sequence / Q000235:genetics; D018360:Crystallography, X-Ray; D004220:Disulfides / Q000378:metabolism; D019143:Evolution, Molecular; D005798:Genes, Bacterial; D014644:Genetic Variation / Q000235:genetics; D000949:Histocompatibility Antigens Class II / Q000276:immunology / Q000378:metabolism; D008958:Models, Molecular; D008969:Molecular Sequence Data; D010802:Phylogeny; D011485:Protein Binding; D017510:Protein Folding; D017433:Protein Structure, Secondary; D017434:Protein Structure, Tertiary; D011948:Receptors, Antigen, T-Cell / Q000276:immunology / Q000378:metabolism; D016415:Sequence Alignment; D013297:Streptococcus pyogenes / Q000737:chemistry* / Q000145:classification / Q000235:genetics / Q000276:immunology*; D018089:Superantigens / Q000737:chemistry* / Q000145:classification / Q000276:immunology / Q000378:metabolism*; D015032:Zinc / Q000378:metabolism
chemical_list: D004220:Disulfides; D000949:Histocompatibility Antigens Class II; D011948:Receptors, Antigen, T-Cell; D018089:Superantigens; D015032:Zinc