MODELING THE ALPHA(IIB)BETA(3) INTEGRIN SOLUTION CONFORMATION

The alpha11bbeta3 platelet integrin is the prototypical member of a wi dely distributed class of transmembrane receptors formed by the noncov alent association of alpha and beta subunits. Electron microscopic (EM ) images of the alpha11bbeta3 complex show an asymmetric particle with a globular domain from which two extended regions protrude to contact the lipid bilayer. Distance constraints provided by disulfide bond pa tterns, epitope mapping, and ligand mimetic cross-linking studies rath er suggest a somewhat more compact conformation for the alpha11bbeta3 complex. We have studied the shape of detergent-solubilized alpha11bbe ta3 by employing a low-resolution modeling procedure in which each pol ypeptide has been represented as an array of interconnected, nonoverla pping spheres (beads) of various sizes. The number, size, and three-di mensional relationships among the beads were defined either solely by dimensions obtained from published EM images of integrin receptors (EM models, 21 beads), or solely by interdomain constraints derived from published biochemical data (biochemical model, 37 beads). Interestingl y, although no EM data were employed in its construction, the resultin g overall shape of the biochemical model was still compatible with the EM data. Both kinds of models were then evaluated for their calculate d solution properties. The more elongated EM models have diffusion and sedimentation coefficients that differ, at best, by +2% and -18% from the experimental values, determined, respectively, in octyl glucoside and Triton X-100. On the other hand, the parameters calculated for th e more compact biochemical model showed a more consistent agreement wi th experimental values, differing by -7% (octyl glucoside) to -6% (Tri ton X-100). Thus, it appears that using the biochemical constraints as a starting point has resulted in not only a more detailed model of th e detergent-solubilized alpha11bbeta3 complex, where the relative spat ial location of specific domains the size of 5-10 kDa can be tentative ly mapped, but in a model that can also reconcile the electron microsc opy with the biochemical and the solution data.