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Title: Structural basis of arrestin-3 activation and signaling

Abstract

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.

Authors:
; ; ; ; ; ; ; ; ; ; ; ; ORCiD logo; ORCiD logo
Publication Date:
Research Org.:
Argonne National Lab. (ANL), Argonne, IL (United States). Advanced Photon Source (APS)
Sponsoring Org.:
UNIVERSITYNIH
OSTI Identifier:
1410119
Resource Type:
Journal Article
Resource Relation:
Journal Name: Nature Communications; Journal Volume: 8; Journal Issue: 1
Country of Publication:
United States
Language:
ENGLISH
Subject:
59 BASIC BIOLOGICAL SCIENCES; 60 APPLIED LIFE SCIENCES

Citation Formats

Chen, Qiuyan, Perry, Nicole A., Vishnivetskiy, Sergey A., Berndt, Sandra, Gilbert, Nathaniel C., Zhuo, Ya, Singh, Prashant K., Tholen, Jonas, Ohi, Melanie D., Gurevich, Eugenia V., Brautigam, Chad A., Klug, Candice S., Gurevich, Vsevolod V., and Iverson, T. M.. Structural basis of arrestin-3 activation and signaling. United States: N. p., 2017. Web. doi:10.1038/s41467-017-01218-8.
Chen, Qiuyan, Perry, Nicole A., Vishnivetskiy, Sergey A., Berndt, Sandra, Gilbert, Nathaniel C., Zhuo, Ya, Singh, Prashant K., Tholen, Jonas, Ohi, Melanie D., Gurevich, Eugenia V., Brautigam, Chad A., Klug, Candice S., Gurevich, Vsevolod V., & Iverson, T. M.. Structural basis of arrestin-3 activation and signaling. United States. doi:10.1038/s41467-017-01218-8.
Chen, Qiuyan, Perry, Nicole A., Vishnivetskiy, Sergey A., Berndt, Sandra, Gilbert, Nathaniel C., Zhuo, Ya, Singh, Prashant K., Tholen, Jonas, Ohi, Melanie D., Gurevich, Eugenia V., Brautigam, Chad A., Klug, Candice S., Gurevich, Vsevolod V., and Iverson, T. M.. Fri . "Structural basis of arrestin-3 activation and signaling". United States. doi:10.1038/s41467-017-01218-8.
@article{osti_1410119,
title = {Structural basis of arrestin-3 activation and signaling},
author = {Chen, Qiuyan and Perry, Nicole A. and Vishnivetskiy, Sergey A. and Berndt, Sandra and Gilbert, Nathaniel C. and Zhuo, Ya and Singh, Prashant K. and Tholen, Jonas and Ohi, Melanie D. and Gurevich, Eugenia V. and Brautigam, Chad A. and Klug, Candice S. and Gurevich, Vsevolod V. and Iverson, T. M.},
abstractNote = {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.},
doi = {10.1038/s41467-017-01218-8},
journal = {Nature Communications},
number = 1,
volume = 8,
place = {United States},
year = {Fri Nov 10 00:00:00 EST 2017},
month = {Fri Nov 10 00:00:00 EST 2017}
}