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

Research output: Contribution to journalArticle

33 Scopus citations


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.

Original languageEnglish (US)
Article number1427
JournalNature communications
Issue number1
StatePublished - Dec 1 2017

ASJC Scopus subject areas

  • Chemistry(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Physics and Astronomy(all)

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    Chen, Q., Perry, N. A., Vishnivetskiy, S. A., Berndt, S., Gilbert, N. C., Zhuo, Y., Singh, P. K., Tholen, J., Ohi, M. D., Gurevich, E. V., Brautigam, C. A., Klug, C. S., Gurevich, V. V., & Iverson, T. M. (2017). Structural basis of arrestin-3 activation and signaling. Nature communications, 8(1), [1427].