Vsevolod V. Gurevich
Vanderbilt University, United States
Title: Engineering signaling-biased arrestins for targeted regulation of cell behavior
Biography
Biography: Vsevolod V. Gurevich
Abstract
Arrestins specifically bind active phopshorylated GPCRs, blocking further G protein activation and orchestrating G protein-independent signaling. Based on the elucidation of arrestin structure and key functional elements we constructed special arrestins to channel cell signaling in desired direction. We designed enhanced phosphorylation-independent arrestin-1 mutants and showed that they can compensate for the defects of rhodopsin phosphorylation in vivo. We identified the residues on the receptor-binding surface of non-visual arrestins that determine their preference for particular GPCRs. Based on this information we created arrestin-3 mutants with high receptor specificity by a few substitutions. We designed arrestin-3 mutant that suppresses JNK activation in the cell. We found that caspase-cleaved arrestin-2 facilitates apoptotic cell death, whereas its caspase-resistant mutant protects the cells. We also identified a small element of arrestin-3 that acts as a mini-scaffold, promoting JNK activation in vitro, in cells, and in the brain in vivo. Arrestins play a role in numerous signaling pathways and physiological processes. Therefore, targeted mutagenesis can yield arrestin-based molecular tools to tell the cell what to do in a language it cannot disobey.