Arrestins specifically bind active phopshorylated GPCRs, precluding further G protein activation and channeling the signaling to G protein-independent pathways. 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 mutants and showed that enhanced arrestin-1 can compensate for the defects of rhodopsin phosphorylation in vivo. We identified the elements of non-visual arrestins that determine their receptor preference and showed that we can create arrestin-3 with high receptor specificity by a few mutations. We designed arrestin-3 mutant that acts as a silent scaffold, suppressing JNK activation in the cell.  We also identified a small element of arrestin-3 that acts as a mini-scaffold, promoting JNK activation in vitro and in cells. Since arrestins play a role in numerous signaling pathways, targeted mutagenesis can yield arrestin-based molecular tools to tell the cell what to do in a language it cannot disobey.

Engineering enhanced, receptor-specific, and signaling-biased arrestins<br />

249th National Meeting (2015)

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