Structural basis of arrestin-3 activation and signaling

Nat Commun. 2017 Nov 10;8(1):1427. doi: 10.1038/s41467-017-01218-8.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Amino Acid Sequence
  • Animals
  • Arrestins / chemistry*
  • Arrestins / genetics
  • Arrestins / 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
  • Recombinant Proteins / genetics
  • Recombinant Proteins / metabolism
  • Signal Transduction

Substances

  • Arrestins
  • Recombinant Proteins
  • arrestin3
  • Phytic Acid
  • Mitogen-Activated Protein Kinase 10