Crystal structure of a Staphylococcus aureus protein A domain complexed with the Fab fragment of a human IgM antibody: Structural basis for recognition of B-cell receptors and superantigen activity

Staphylococcus aureus produces a virulence factor, protein A (SpA), that co ntains five homologous Ig-binding domains. The interactions of SpA with the Fab region of membrane-anchored Igs can stimulate a large fraction of a ce lls, contributing to lymphocyte clonal selection. To understand the molecul ar basis for this activity, we have solved the crystal structure of the com plex between domain D of SpA and the Fab fragment of a human IgM antibody t o 2.7-Angstrom resolution. In the complex, helices II and III of domain D i nteract with the variable region of the Fab heavy chain (V-H) through frame work residues, without the involvement of the hypervariable regions implica ted in antigen recognition. The contact residues are highly conserved in hu man V(H)3 antibodies but not in other families. The contact residues from d omain D also are conserved among all SpA 19-binding domains, suggesting tha t each could bind in a similar manner. Features of this interaction paralle l those reported for staphylococcal enterotoxins that are superantigens for many T cells. The structural homology between Ig V-H regions and the T-cel l receptor V-beta regions facilitates their comparison, and both types of i nteractions involve lymphocyte receptor surface remote from the antigen bin ding site. However, T-cell superantigens reportedly interact through hydrog en bonds with T-cell receptor V-beta backbone atoms in a primary sequence-i ndependent manner, whereas SpA relies on a sequence-restricted conformation al binding with residue side chains, suggesting that this common bacterial pathogen has adopted distinct molecular recognition strategies for affectin g large sets of B and T lymphocytes.