Crystal structure of staphylococcal enterotoxin I (SEI) in complex with a human major histocompatibility complex class II molecule.
Superantigens are bacterial or viral proteins that elicit massive T cell activation through simultaneous binding to major histocompatibility complex (MHC) class II and T cell receptors. This activation results in uncontrolled release of inflammatory cytokines, causing toxic shock. A remarkable property of superantigens, which distinguishes them from T cell receptors, is their ability to interact with multiple MHC class II alleles independently of MHC-bound peptide. Previous crystallographic studies have shown that staphylococcal and streptococcal superantigens belonging to the zinc family bind to a high affinity site on the class II beta-chain. However, the basis for promiscuous MHC recognition by zinc-dependent superantigens is not obvious, because the beta-chain is polymorphic and the MHC-bound peptide forms part of the binding interface. To understand how zinc-dependent superantigens recognize MHC, we determined the crystal structure, at 2.0 A resolution, of staphylococcal enterotoxin I bound to the human class II molecule HLA-DR1 bearing a peptide from influenza hemagglutinin. Interactions between the superantigen and DR1 beta-chain are mediated by a zinc ion, and 22% of the buried surface of peptide.MHC is contributed by the peptide. Comparison of the staphylococcal enterotoxin I.peptide.DR1 structure with ones determined previously revealed that zinc-dependent superantigens achieve promiscuous binding to MHC by targeting conservatively substituted residues of the polymorphic beta-chain. Additionally, these superantigens circumvent peptide specificity by engaging MHC-bound peptides at their conformationally conserved N-terminal regions while minimizing sequence-specific interactions with peptide residues to enhance cross-reactivity.
Fernández
Marisa M
MM
Instituto de Estudios de la Inmunidad Humoral, Laboratorio de Inmunología Estructural, Consejo Nacional de Investigaciones Científicas y Técnicas, Facultad de Farmacia y Bioquímica, Universidad de Buenos Aires, Buenos Aires, Argentina.
Guan
Rongjin
R
Swaminathan
Chittoor P
CP
Malchiodi
Emilio L
EL
Mariuzza
Roy A
RA
D000595:Amino Acid Sequence; D001665:Binding Sites; D018360:Crystallography, X-Ray; D004768:Enterotoxins / Q000737:chemistry*; D015798:HLA-DR1 Antigen / Q000737:chemistry*; D006388:Hemagglutinins / Q000737:chemistry; D006801:Humans; D007249:Inflammation; D007477:Ions; D008285:Major Histocompatibility Complex; D008958:Models, Molecular; D008969:Molecular Sequence Data; D010455:Peptides / Q000737:chemistry; D011485:Protein Binding; D011487:Protein Conformation; D017386:Sequence Homology, Amino Acid; D018089:Superantigens / Q000737:chemistry*; D015032:Zinc
D004768:Enterotoxins; D015798:HLA-DR1 Antigen; D006388:Hemagglutinins; D007477:Ions; D010455:Peptides; D018089:Superantigens; C419398:enterotoxin I, staphylococcal; D015032:Zinc