title: Prediction of the multimeric assembly of staphylococcal enterotoxin A with cell-surface protein receptors.
abstract: Staphylococcal enterotoxin A (SEA) cross-links two class II major histocompatibility complex (MHC) molecules and forms a multimeric assembly with T-cell receptors (TcRs). The X-ray crystal structure of SEA has been solved, yet details describing molecular recognition and association remain unclear. We present a structural model for the interactions of SEA with cell-surface proteins. Molecular docking calculations predicting SEA association with the class II MHC molecule HLA-DR1 were performed by using a rigid-body docking method. Docked orientations were evaluated by a Poisson-Boltzmann model for the electrostatic free energy of binding and the hydrophobic effect calculated from molecular surface areas. We found that the best-scoring SEA conformers for the DR1alpha interface display a binding mode similar to that determined crystallographically for staphylococcal enterotoxin B bound to HLA-DR1. For the zinc-binding site of SEA, docking DR1beta yielded several orientations exhibiting tetrahedral-like coordination geometries. Combining the two interfaces, tetramers were modeled by docking an alphabeta TcR with trimolecular complexes DR1beta-SEA-DR1alpha and SEA-betaDR1alpha-SEA. Our results indicate that the complex DR1beta-SEA-DR1alpha provides a more favorable assembly for the engagement of TcRs, forming SEA molecular contacts that are in accord with reported mutagenesis studies. In contrast, the cooperative association of two SEA molecules on a single DR1 molecule sterically inhibits interactions with TcRs. We suggest that signal transduction stimulated by SEA through large-scale assembly is limited to four or five TcR-(DR1beta-SEA-DR1alpha) tetramers and requires the dimerization of class II MHC molecules, while TcR dimerization is unlikely.
authors.affiliation: Department of Cell Biology and Biochemistry, USAMRIID, 1425 Porter Street, Frederick, MD 21702, USA.
authors.forename: Lilee
authors.initials: L
authors.lastname: Cuff
authors.forename: Robert G
authors.initials: RG
authors.lastname: Ulrich
authors.forename: Mark A
authors.initials: MA
authors.lastname: Olson
mesh_terms: D004768:Enterotoxins / Q000378:metabolism*; D008958:Models, Molecular; D017434:Protein Structure, Tertiary; D011956:Receptors, Cell Surface / Q000378:metabolism*; D013816:Thermodynamics
chemical_list: D004768:Enterotoxins; D011956:Receptors, Cell Surface; C026066:enterotoxin A, Staphylococcal