TY - JOUR
T1 - Structural basis of arrestin-3 activation and signaling
AU - Chen, Qiuyan
AU - Perry, Nicole A.
AU - Vishnivetskiy, Sergey A.
AU - Berndt, Sandra
AU - Gilbert, Nathaniel C.
AU - Zhuo, Ya
AU - Singh, Prashant K.
AU - Tholen, Jonas
AU - Ohi, Melanie D.
AU - Gurevich, Eugenia V.
AU - Brautigam, Chad A
AU - Klug, Candice S.
AU - Gurevich, Vsevolod V.
AU - Iverson, T. M.
N1 - Publisher Copyright:
© 2017 The Author(s).
PY - 2017/12/1
Y1 - 2017/12/1
N2 - 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.
AB - 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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U2 - 10.1038/s41467-017-01218-8
DO - 10.1038/s41467-017-01218-8
M3 - Article
C2 - 29127291
AN - SCOPUS:85033606940
SN - 2041-1723
VL - 8
JO - Nature communications
JF - Nature communications
IS - 1
M1 - 1427
ER -