The process of vision begins with the absorption of light by the visual pigment, rhodopsin. In a carefully choreographed process, rhodopsin transmits this information in the form of a conformational change to the G-protein transducin. However, in order for the eye to achieve reproducibility and rapid response, the action of rhodopsin is antagonized by arrestin which selectively binds light-activated rhodopsin that has been phosphorylated, and thus sterically occludes further activation of transducin. This selective binding of rhodopsin by arrestin is at the core of the entire visual process. Despite arrestin's discovery nearly thirty years ago, we know relatively little about the mechanism by which arrestin regulates its selectivity for rhodopsin, binding rhodopsin only after it has been both light activated and phosphorylated. In this application, we seek to understand the regulation of the binding interaction between photoactivated, phosphorylated rhodopsin and arrestin, both in terms of the molecular dynamics of the arrestin structure and in terms of the arrestin/rhodopsin complex. Understanding the regulation of this interaction between arrestin and rhodopsin is central not only to vision, but also to other G protein-coupled receptor systems that are regulated by a similar arrestin-like mechanism. We will specifically address the following questions: 1) For arrestin to bind rhodopsin, what structural changes need to occur? 2) What are the effects of the phosphorylated C-terminus of rhodopsin on the molecular dynamics of arrestin? 3) What is the supramolecular nature of the arrestin/rhodopsin complex? The answers to these questions will provide an important advance in our understanding of the visual process and will provide important information on which to build therapies in diseases caused by deficiencies in the inactivation of the visual pigment. PUBLIC HEATH
The arrestin protein is at the core of vision, serving to quench the visual pigment after it has absorbed light. Diseases such as congenital stationary night blindness and retinitis pigmentosa (a form of retinal degeneration) result from mutations in arrestin that interfere with the function of this protein. Understanding how these mutations affect the function of the protein will help direct the development of therapeutic interventions for diseases that result from arrestin defects.
