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PMID: 29127291 Published · epublish English Journal Article Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't Research Support, U.S. Gov't, Non-P.H.S.

Structural basis of arrestin-3 activation and signaling.

Nature communications ·Vol. 8 ·No. 1 ·2017-00-10 ·Pages 1427

Chen Q, Perry NA, Vishnivetskiy SA, Berndt S, Gilbert NC, Zhuo Y, Singh PK, Tholen J, Ohi MD, Gurevich EV, Brautigam CA, Klug CS, Gurevich VV, Iverson TM

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.

MeSH Terms
Amino Acid Sequence Animals Arrestins/chemistry,genetics,metabolism Binding Sites Cattle Crystallography, X-Ray Humans Mitogen-Activated Protein Kinase 10/metabolism Models, Molecular Phytic Acid/metabolism Protein Conformation Protein Structure, Quaternary Recombinant Proteins/chemistry,genetics,metabolism Signal Transduction
Chemicals
Arrestins Recombinant Proteins arrestin3 Phytic Acid Mitogen-Activated Protein Kinase 10
Authors & Affiliations
14 authors, click to expand affiliations / ORCID
Chen Qiuyan
Department of Pharmacology, Vanderbilt University, Nashville, TN, 37232, USA.
Perry Nicole A
Department of Pharmacology, Vanderbilt University, Nashville, TN, 37232, USA.
Vishnivetskiy Sergey A
Department of Pharmacology, Vanderbilt University, Nashville, TN, 37232, USA.
Berndt Sandra
Department of Pharmacology, Vanderbilt University, Nashville, TN, 37232, USA.
Gilbert Nathaniel C
Department of Pharmacology, Vanderbilt University, Nashville, TN, 37232, USA. | Louisiana State University, Baton Rouge, LA, 70803, USA.
Zhuo Ya
Department of Biophysics, Medical College of Wisconsin, Milwaukee, WI, 53226, USA.
Singh Prashant K
Department of Cell and Developmental Biology, Vanderbilt University, Nashville, TN, 37232, USA.
Tholen Jonas
University of Applied Sciences Emden/Leer, Emden, 26723, Germany.
Ohi Melanie D
Department of Cell and Developmental Biology, Vanderbilt University, Nashville, TN, 37232, USA. | Department of Biochemistry, Vanderbilt University, Nashville, TN, 37232, USA. | Center for Structural Biology, Vanderbilt University, Nashville, TN, 37232, USA.
Gurevich Eugenia V
Department of Pharmacology, Vanderbilt University, Nashville, TN, 37232, USA.
Brautigam Chad A
Departments of Biophysics and Microbiology, The University of Texas Southwestern Medical Center, Dallas, TX, 75390, USA.
Klug Candice S
Department of Biophysics, Medical College of Wisconsin, Milwaukee, WI, 53226, USA.
Gurevich Vsevolod V ORCID
Department of Pharmacology, Vanderbilt University, Nashville, TN, 37232, USA. vsevolod.gurevich@vanderbilt.edu.
Iverson T M ORCID
Department of Pharmacology, Vanderbilt University, Nashville, TN, 37232, USA. tina.iverson@vanderbilt.edu. | Department of Biochemistry, Vanderbilt University, Nashville, TN, 37232, USA. tina.iverson@vanderbilt.edu. | Center for Structural Biology, Vanderbilt University, Nashville, TN, 37232, USA. tina.iverson@vanderbilt.edu. | Vanderbilt Institute of Chemical Biology, Vanderbilt University, Nashville, TN, 37232, USA. tina.iverson@vanderbilt.edu.
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Article Info
Journal
Nature communications
Abbr.
Nat Commun
ISSN
2041-1723
DOI
10.1038/s41467-017-01218-8
Email
vsevolod.gurevich@vanderbilt.edu
tina.iverson@vanderbilt.edu
Published
2017-00-10
Epub
2017-00-10
Pages
1427
Language
English
Region
England
NLM ID
101528555
PMCID
PMC5681653
Subset
IM
Grants
NIGMS NIH HHS · R01 GM120569 · United States
NIH HHS · S10 OD011937 · United States
NIGMS NIH HHS · R01 GM077561 · United States
NEI NIH HHS · P30 EY008126 · United States
NCRR NIH HHS · S10 RR022422 · United States
NIBIB NIH HHS · P41 EB001980 · United States
NEI NIH HHS · R01 EY011500 · United States
NIH HHS · S10 OD021483 · United States
NIGMS NIH HHS · T32 GM007628 · United States
NIDA NIH HHS · R21 DA043680 · United States
NIGMS NIH HHS · R01 GM109955 · United States
NIGMS NIH HHS · R01 GM095633 · United States
NCRR NIH HHS · S10 RR026915 · United States
NIGMS NIH HHS · R35 GM122491 · United States
External Links
PubMed source DOI: 10.1038/s41467-017-01218-8 PMC Full Text View journal details
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