Structural basis of arrestin-3 activation and signaling


Qiuyan Chen, Nicole A. Perry, Sergey A. Vishnivetskiy, Sandra Berndt, Nathaniel C. Gilbert, Ya Zhuo, Prashant K. Singh, Jonas Tholen, Melanie D. Ohi, Eugenia V. Gurevich, Chad A. Brautigam, Candice S. Klug, Vsevolod V. Gurevich & T. M. Iverson

Nature Communications
2017 vol: 8 article number: 1427 doi: 10.1038/s41467-017-01218-8

A unique aspect of arrestin-3 is its ability to support both receptor-dependent and receptor-independent signaling. Here, we show that inositol hexakisphosphate (IP6) is a non-receptor activator of arrestin-3 and report the structure of IP6-activated arrestin-3 at 2.4-Å resolution. IP6-activated arrestin-3 exhibits an inter-domain twist and a displaced C-tail, hallmarks of active arrestin. IP6 binds to the arrestin phosphate sensor, and is stabilized by trimerization. Analysis of the trimerization surface, which is also the receptor-binding surface, suggests a feature called the finger loop as a key region of the activation sensor. We show that finger loop helicity and flexibility may underlie coupling to hundreds of diverse receptors and also promote arrestin-3 activation by IP6. Importantly, we show that effector-binding sites on arrestins have distinct conformations in the basal and activated states, acting as switch regions. These switch regions may work with the inter-domain twist to initiate and direct arrestin-mediated signaling.

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Topics: Cell signalling, G protein-coupled receptors, X-ray crystallography, Monolith – MicroScale Thermophoresis, MST, Proteins, Publications



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