Crystal structure of staphylococcal enterotoxin I (SEI) in complex with a human MHC class II molecule.

FERNÁNDEZ MM, GUAN R, SWAMINATHAN CP, MALCHIODI EL & MARIUZZA RA.

JOURNAL OF BIOLOGICAL CHEMISTRY

AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC

Año: 2006 vol. 281 p. 25356 - 25364

0021-9258

Superantigens (SAGs) are bacterial or viral proteins that elicit massive T cell activation through simultaneous binding to MHC class II molecules and T cell receptors (TCRs). This activation results in the uncontrolled release of inflammatory cytokines, causing toxic shock. A remarkable feature of bacterial SAGs, which distinguishes them from TCRs, is their ability to interact with multiple MHC class II alleles, independent of the MHC-bound peptide. Previous X-ray crystallographic studies have shown that staphylococcal and streptococcal SAGs belonging to the zinc family bind to a high-affinity site on the MHC class II b chain. However, the structural basis for promiscuous MHC recognition by zinc-dependent SAGs is not obvious, since the class II b chain is polymorphic and the MHC-bound peptide forms part of the binding interface. To better understand how zinc-dependent SAGs recognize MHC, we determined the crystal structure, at 2.0 Å resolution, of staphylococcal enterotoxin I (SEI) bound to the human class II molecule HLA-DR1 bearing a peptide from influenza virus hemagglutinin (HA). In the complex, interactions between SEI and the DR1 b chain are mediated by a zinc ion, and 22% of the buried surface of peptide/MHC is contributed by the HA peptide. Comparison of the SEI/HA/DR1 structure with ones determined previously reveals that zinc-dependent SAGs achieve promiscuous binding to MHC by targeting conserved, or conservatively substituted, residues of the polymorphic b chain. Furthermore, these SAGs circumvent peptide specificity by engaging MHC-bound peptides at their structurally conserved N-terminal regions, while minimizing sequence-specific interactions with peptide residues to enhance cross-reactivity.