Within integrin subfamilies, a common beta subunit can combine with different alpha subunits to form receptors with distinct ligand recognition specificities. We have determined that the ligand recognition specificity of beta3 integrins is regulated by the amino terminal one-third of the a subunit. These data demonstrate further indicate that the ligand binding pocket is a folded structure assembled from elements of both the alpha and beta subunits. The identification of a number of potential ligand contact points implies that multiple sites are involved in ligand-receptor interaction. Effective ligand binding may require the sequential engagement of different sites.
Studies are ongoing to identify discrete residues that contribute to ligand binding and specificity.
Identification of specific ligand contact points may provide valuable insight into the development of agents to selectively modulate the function of the beta3 integrins and additional insights into wound healing and vascular proliferation. Current methods, such as gene knockouts, to study integrin function in differentiated cells are not practical approaches since they have proven to be prohibitive of normal development. The identification of structural elements in integrins that abolish or enhance ligand binding function provides a unique, alternative means to alter the adhesive properties of cells in an integrin class specific and tissue specific manner. To explore this potential, we are examining the effects of expression of integrin mutants, which exhibit either loss of function or gain of function, in vascular cells in vitro and in transgenic mice. Loss of function integrin mutants are modeled on the beta3 mutants exhibiting a complete loss of ligand binding function.