Department of Pharmacology

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) and targeting receptors for internalization. Mammals express four arrestin subtypes, two specialized visual and two ubiquitous non-visual (systematic names arrestin-2 and -3). Free and receptor-bound non-visual arrestins are multi-functional signaling adapters, interacting with hundreds of different GPCR subtypes and >100 non-receptor signaling proteins each. Many arrestin partners play key role in “life-or-death” decisions in the cell. We are elucidating 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 and designed arrestins with increased specificity for particular GPCRs. We are identifying arrestin binding sites for other interaction partners. We will use this information to construct signaling-biased arrestins that link the receptor of interest to the signaling pathway of our choosing and to extract mono-functional peptides from multi-functional arrestin proteins. These tools will allow us to tell the cell what to do and when to do it in a way it cannot disobey. 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. We have derived a short 16-residue arrestin-3 peptide necessary and sufficient to facilitate the activation in cells of JNK family kinases with anti-proliferative, often pro-apoptotic action.    

The solution of the crystal structure of all four vertebrate arrestins, of arrestin-rhodopsin complex, 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 “enhanced” arrestins will prove useful for gene therapy of disorders associated with excessive signaling by various GPCRs (caused by defective phosphorylation or activating mutations) that range from night blindness and retinal degeneration to several forms of cancer. We found that transgenic expression of phosphorylation-independent visual arrestin prevents retinal degeneration. We are working on designing more efficient enhanced visual arrestin mutants. 

We believe that the combination of different approaches ranging from hard-core biochemical, biophysical, and structural methods to cell culture and transgenic animals is necessary to answer biologically relevant questions concerning various facets of arrestin function. Based on this information, innovative therapeutic tools can be designed. 

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Vanderbilt Brain Institute (VBI) 

Vanderbilt Institute of Chemical Biology (VICB)