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 - Funding Information:
We thank Drs B. Spiller, J. York, H. Hamm, C. Sanders, W. Hubbell, C. Goodman, and K. McCulloch for critical reading and insightful discussions, H.E. Xu for an advance on the rhodopsin-arrestin-1 coordinates, S. Prokop, I. Yamakawa, M. Schoenberger, K. McCulloch, X. Zhan. M. Tyska, H. McDonald, and K. Schultz for experimental assistance. This work was supported by NIH grants to VVG (GM077561, GM109955 (these two R01 grants were replaced by R35 GM122491), EY011500) and TMI (GM095633, GM120569), and TMI/VVG (DA043680), a Vanderbilt Discovery Grant (TMI/VVG), and a Vanderbilt Vision Research Center NEI Core Grant (EY008126). Q.C. was supported by the Vanderbilt International Scholars Program. N.A.P. was supported by T32 GM007628 and the American Heart Association (16PRE30180007). NCG was supported by the American Heart Association (13POST16910057). J.T. was supported by a DAAD RISE fellowship. The Vanderbilt crystallization facility is supported by S10 RR026915. A.U.C. is supported by the Vanderbilt Center for Structural Biology. The Advanced Photon Source, a User Facility operated for the U.S. DOE Office of Science, was supported under Contract DE-AC02-06CH11357. LS-CAT Sector 21 is supported by the Michigan Economic Development Corporation and the Michigan Technology Tri-Corridor (085P1000817). DEER instrumentation is supported by S10RR022422 and S10OD011937, use of the National Biomedical EPR Center is supported by P41EB001980.
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 -