IDEHU   05542
INSTITUTO DE ESTUDIOS DE LA INMUNIDAD HUMORAL PROF. RICARDO A. MARGNI
Unidad Ejecutora - UE
artículos
Título:
Superantigen Natural Affinity Maturation Revealed by the Crystal Structure of Staphylococcal Enterotoxin G and Its Binding to T-cell Receptor Vbeta8.2
Autor/es:
MM FERNÁNDEZ, S BHATTACHARYA, MC DE MARZI, PH BROWN, M KERZIC, P SCHUCK, RA MARIUZZA, EL MALCHIODI
Revista:
PROTEINS: STRUCTURE, FUNCTION AND GENETICS
Editorial:
Wiley-Liss
Referencias:
Lugar: United States; Año: 2006
ISSN:
0887-3585
Resumen:
The illnesses associated with bacterial superantigens (SAgs) such as food poisoning and toxic
shock syndrome, as well as the emerging threat of purpura fulminans and community-associated
methicillin-resistant S. aureus producer of SAgs, emphasize the importance of a better characterization
of SAg binding to their natural ligands, which would allow the development of drugs or biological
reagents able to neutralize their action. SAgs are toxins that bind major histocompatibility complex
class II molecules (MHC-II) and T-cell receptors (TCR), in a non-conventional manner, inducing Tcell
activation that leads to production of cytokines such as tumor necrosis factor and interleukin-2,
which may result in acute toxic shock. Previously, we cloned and expressed a new natural variant of
staphylococcal enterotoxin G (SEG) and evaluated its ability to stimulate in vivo murine T-cell
subpopulations. We found an early, strong and widespread stimulation of mouse Vb8.2 T-cells when
compared with other SAgs member of the SEB subfamily. In search for the reason of the strong
mitogenic potency, we determined the SEG crystal structure by X-ray crystallography to 2.2 A
resolution and analyzed SEG binding to mVb8.2 and MHC-II. Calorimetry and SPR analysis showed
that SEG has an affinity for mVb8.2 40 to 100-fold higher than that reported for other members of
SEB subfamily, and the highest reported for a wild type SAg-TCR couple. We also found that
mutations introduced in mVb8.2 to produce a high affinity mutant for other members of the SEB
subfamily do not greatly affect binding to SEG. Crystallographic analysis and docking into mVb8.2 in
complex with SEB, SEC3 and SPEA showed that the deletions and substitution of key amino acids
remodeled the putative surface of the mVb8.2 binding site without affecting the binding to MHC-II.
This results in a SAg with improved binding to its natural ligands, which may confer a possible
evolutionary advantage for bacterial strains expressing SEG.