Faculty Collaboration Database

Structural basis of arrestin-3 activation and signaling. Nat Commun 2017 Nov 10;8(1):1427

Date

11/12/2017

Pubmed ID

29127291

Pubmed Central ID

PMC5681653

DOI

10.1038/s41467-017-01218-8

Scopus ID

2-s2.0-85033606940 (requires institutional sign-in at Scopus site)   79 Citations

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.

Author List

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

Author

Candice S. Klug PhD Professor in the Biophysics department at Medical College of Wisconsin

MESH terms used to index this publication - Major topics in bold

Amino Acid Sequence
Animals
Arrestins
Binding Sites
Cattle
Crystallography, X-Ray
Humans
Mitogen-Activated Protein Kinase 10
Models, Molecular
Phytic Acid
Protein Conformation
Protein Structure, Quaternary
Recombinant Proteins
Signal Transduction