Faculty Collaboration Database

An Eight Amino Acid Segment Controls Oligomerization and Preferred Conformation of the two Non-visual Arrestins. J Mol Biol 2021 Feb 19;433(4):166790

Date

01/03/2021

Pubmed ID

33387531

Pubmed Central ID

PMC7870585

DOI

10.1016/j.jmb.2020.166790

Scopus ID

2-s2.0-85100159529 (requires institutional sign-in at Scopus site)   12 Citations

Abstract

G protein coupled receptors signal through G proteins or arrestins. A long-standing mystery in the field is why vertebrates have two non-visual arrestins, arrestin-2 and arrestin-3. These isoforms are ~75% identical and 85% similar; each binds numerous receptors, and appear to have many redundant functions, as demonstrated by studies of knockout mice. We previously showed that arrestin-3 can be activated by inositol-hexakisphosphate (IP₆). IP₆ interacts with the receptor-binding surface of arrestin-3, induces arrestin-3 oligomerization, and this oligomer stabilizes the active conformation of arrestin-3. Here, we compared the impact of IP₆ on oligomerization and conformational equilibrium of the highly homologous arrestin-2 and arrestin-3 and found that these two isoforms are regulated differently. In the presence of IP₆, arrestin-2 forms "infinite" chains, where each promoter remains in the basal conformation. In contrast, full length and truncated arrestin-3 form trimers and higher-order oligomers in the presence of IP₆; we showed previously that trimeric state induces arrestin-3 activation (Chen et al., 2017). Thus, in response to IP₆, the two non-visual arrestins oligomerize in different ways in distinct conformations. We identified an insertion of eight residues that is conserved across arrestin-2 homologs, but absent in arrestin-3 that likely accounts for the differences in the IP₆ effect. Because IP₆ is ubiquitously present in cells, this suggests physiological consequences, including differences in arrestin-2/3 trafficking and JNK3 activation. The functional differences between two non-visual arrestins are in part determined by distinct modes of their oligomerization. The mode of oligomerization might regulate the function of other signaling proteins.

Author List

Chen Q, Zhuo Y, Sharma P, Perez I, Francis DJ, Chakravarthy S, Vishnivetskiy SA, Berndt S, Hanson SM, Zhan X, Brooks EK, Altenbach C, Hubbell WL, Klug CS, Iverson TM, Gurevich VV

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 Acids
Arrestins
Binding Sites
Humans
Models, Molecular
Phytic Acid
Protein Binding
Protein Conformation
Protein Isoforms
Protein Multimerization
Solutions
Spectrum Analysis