Signaling

Vsevolod Gurevich, Ph.D.

Professor of Pharmacology

Cornelius Vanderbilt Chair in Pharmacology

417D PRB 2200 Pierce Avenue, Nashville, TN, 37232-6600
(615) 322-7070 (office)

Research Description

We are interested in structure, function, and biology of arrestin proteins. Arrestins bind activated phosphorylated G protein-coupled receptors (GPCRs), thereby shutting down their signaling via G proteins (desensitization), targeting receptors for internalization. Free and receptor-bound arrestins are multi-functional signaling adapters, interacting with hundreds of different GPCRs and more than non-receptor 100 signaling proteins, many of which play key role in "life-or-death" decisions in the cell. We want to understand the molecular mechanisms that arrestins use to "decide" when to bind particular interaction partners and when to dissociate. We have mapped receptor-arrestin interaction interface fairly well and we want to elucidate arrestin binding sites for its other interaction partners with the same precision. We intend to use this information to construct "custom-designed" arrestins that link the receptor of interest to the signaling pathway of our choosing. These tools will allow us to tell the cell what to do and when to do it. For example, "biased" arrestins can enhance pro-survival signaling, preventing cell death characteristic for neurodegenerative diseases (such as Alzheimer's, Parkinson's, or retinal degeneration), or tip the balance toward cell death, which would be useful to prevent uncontrolled proliferation characteristic for cancer.
The solution of the crystal structure of all four vertebrate arrestins and the elucidation of the mechanism of arrestin phosphate sensor action allowed us to construct arrestin mutants that bind the active form of their cognate GPCRs regardless of receptor phosphorylation. These "super-arrestins" may prove useful for gene therapy of disorders associated with excessive signaling by various GPCRs that range from night blindness and retinal degeneration to several forms of cancer. We are testing whether transgenic expression of phosphorylation-independent mutants of visual arrestin prevents retinal degeneration in several mouse models.
We believe that the combination of different approaches ranging from hard-core biochemical and biophysical methods and X-ray crystallography to cell culture and transgenic animals is necessary to answer biologically relevant questions concerning various facets of arrestin function and to create novel therapeutic tools based on this information.

Selected Publications