Faculty Collaboration Database

The Two Non-Visual Arrestins Engage ERK2 Differently. J Mol Biol 2022 Apr 15;434(7):167465

Date

01/26/2022

Pubmed ID

35077767

Pubmed Central ID

PMC8977243

DOI

10.1016/j.jmb.2022.167465

Scopus ID

2-s2.0-85124130291 (requires institutional sign-in at Scopus site)   14 Citations

Abstract

Arrestin binding to active phosphorylated G protein-coupled receptors terminates G protein coupling and initiates another wave of signaling. Among the effectors that bind directly to receptor-associated arrestins are extracellular signal-regulated kinases 1/2 (ERK1/2), which promote cellular proliferation and survival. Arrestins may also engage ERK1/2 in isolation in a pre- or post-signaling complex that is likely in equilibrium with the full signal initiation complex. Molecular details of these binary complexes remain unknown. Here, we investigate the molecular mechanisms whereby arrestin-2 and arrestin-3 (a.k.a. β-arrestin1 and β-arrestin2, respectively) engage ERK1/2 in pairwise interactions. We find that purified arrestin-3 binds ERK2 more avidly than arrestin-2. A combination of biophysical techniques and peptide array analysis demonstrates that the molecular basis in this difference of binding strength is that the two non-visual arrestins bind ERK2 via different parts of the molecule. We propose a structural model of the ERK2-arrestin-3 complex in solution using size-exclusion chromatography coupled to small angle X-ray scattering (SEC-SAXS). This binary complex exhibits conformational heterogeneity. We speculate that this drives the equilibrium either toward the full signaling complex with receptor-bound arrestin at the membrane or toward full dissociation in the cytoplasm. As ERK1/2 regulates cell migration, proliferation, and survival, understanding complexes that relate to its activation could be exploited to control cell fate.

Author List

Perry-Hauser NA, Hopkins JB, Zhuo Y, Zheng C, Perez I, Schultz KM, Vishnivetskiy SA, Kaya AI, Sharma P, Dalby KN, Chung KY, Klug CS, Gurevich VV, Iverson TM

Authors

Candice S. Klug PhD Professor in the Biophysics department at Medical College of Wisconsin
Kathryn M. Schultz Research Scientist I in the Biophysics department at Medical College of Wisconsin

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

Mitogen-Activated Protein Kinase 1
Protein Binding
Scattering, Small Angle
X-Ray Diffraction
beta-Arrestin 1
beta-Arrestin 2