How does arrestin respond to the phosphorylated state of rhodopsin?

Visual arrestin quenches light-induced signaling by binding to light-activa ted, phosphorylated rhodopsin (P-Rh*). Here are present structure-function data, which in conjunction with the refined crystal structure of arrestin ( Hirsch, J. A., Schubert, C., Gurevich, V. V., and Sigler, P.B. (1999) Cell, in press), support a model for the conversion of a basal or "inactive" con formation of free arrestin to one that can bind to and inhibit the light ac tivated receptor. The trigger for this transition is an interaction of the phosphorylated COOH-terminal segment of the receptor with arrestin that dis rupts intramolecular interactions, including a hydrogen-bonded network of b uried, charged side chains, referred to as the "polar core." This disruptio n permits structural adjustments that allow arrestin to bind to the recepto r. Our mutational survey identifies residues in arrestin (Arg(175), Asp(30) , Asp(296), ASp(303), Arg(382)), which when altered bypass the need for the interaction with the receptor's phosphopeptide, enabling arrestin to bind to activated, nonphosphorylated rhodopsin (Rh*), These mutational changes d isrupt interactions and substructures which the crystallographic model and previous biochemical studies have shown are responsible for maintaining the inactive state, The molecular basis for these disruptions was confirmed by successfully introducing structure-based second site substitutions that re stored the critical interactions. The nearly absolute conservation of the m utagenically sensitive residues throughout the arrestin family suggests tha t this mechanism is likely to be applicable to arrestin-mediated desensitiz ation of most G-protein-coupled receptors.