Structure-Function Analysis of Beta-Arrestin

Science Center, Bent Corridor

Beta-arrestins are proteins with a wide range of effects on cell signaling, which are highly conserved throughout different model systems. Primarily, beta-arrestins have been studied for their inhibitory effect on GPCR function, but interactions with other signaling pathways are being explored. The AMP-Activated Kinase (AMPK) cascade, which is important for cell growth and development, has not yet been studied in this regard. Our research aimed to analyze the functional consequences of mutating specific amino acids on beta-arrestin, using both in silico and in vivo methods. Based on survival-rate assays of Drosophila mutants combined with the results of 3D modeling analysis, we were able to come up with hypothesized roles for several of the sequences. Here we specifically focused on interactions with AMPK. Using RNAi knockdowns and mutant strains, we were able to show a potentially critical role of beta-arrestins in the modulation of AMPK phosphorylation. This work has implications for understanding GPCR-related beta-arrestin functions, as well as a possible novel regulatory role of beta-arrestin in controlling AMPK activity. Furthermore, this research offers an opportunity for future development of new, targeted therapies for GPCRand arrestin-related diseases.