Arrestin mutations: Some cause diseases, others promise cure

Abstract

Arrestins play a key role in homologous desensitization of G protein-coupled receptors (GPCRs) and regulate several other vital signaling pathways in cells. Considering the critical roles of these proteins in cellular signaling, surprisingly few disease-causing mutations in human arrestins were described. Most of these are loss-of-function mutations of visual arrestin-1 that cause excessive rhodopsin signaling and hence night blindness. Only one dominant arrestin-1 mutation was discovered so far. It reduces the thermal stability of the protein, which likely results in photoreceptor death via unfolded protein response. In case of the two nonvisual arrestins, only polymorphisms were described, some of which appear to be associated with neurological disorders and altered response to certain treatments. Structure-function studies revealed several ways of enhancing arrestins’ ability to quench GPCR signaling. These enhanced arrestins have potential as tools for gene therapy of disorders associated with excessive signaling of mutant GPCRs.

β−Arrestins: Structure, Function, Physiology, and Pharmacological Perspectives

“…Following activation by agonist ligands, phosphorylated GPCRs are able to bind β-arrestins with high affinity via destabilization of two key interactions that keep β-arrestins in their basal state: the polar core and the three-element interaction between β-strand I, β-strand XX of the Cterminus, and α-helix I (Gurevich and Gurevich, 2019a;Karnam et al, 2021) (Fig. 1).…”

“…1). These intramolecular interactions in βarr1 and βarr2 can be destabilized by mutations, yielding mutant β-arrestins that bind active phosphorylated and even unphosphorylated GPCRs more readily than WT β-arrestins (Gurevich and Gurevich, 2019a;Karnam et al, 2021). Gain-of-function mutations that can occur in numerous GPCRs are known to cause various human disorders (Arang and Gutkind, 2020;Schöneberg et al, 2004;Stoy and Gurevich, 2015).…”

Endocytic Adaptor Proteins in Health and Disease: Lessons from Model Organisms and Human Mutations

“…Constitutive KO: altered µ-opioid receptor signaling causing enhanced morphine analgesia [297]; DKO with β-arrestin2: embryonic lethality due to developmental defects [298] Polymorphisms of unclear significance linked to neurological diseases [289]; somatic mutations in breast cancer [370] β-Arres-tin2 = Arrestin3 (ARRB2) pSer/ pThr in GPCR-NT Constitutive KO: altered cardiac β-adrenergic receptor signaling causing increased cardiac contractility [296] CALM (PICALM) SNARE motif-ANTH APP [129], Aβ-bound LRP1 [128], Nicastrin [131], TfR [113,124], VAMP2/3/4/7/8 [110,112,122] AP-2, Clathrin, PI(4,5)P 2…”

“…There are two so-called visual Arrestins (Arrestin1 and 4) and two Arrestins operating outside the visual transduction cascade commonly known as β-Arrestin1 and β-Arrestin2 (alternative nomenclature: Arrestin2 and 3) which appear to bind to hundreds of different GPCRs [289]. One mechanism underlying GPCR desensitization is their Arrestin-triggered endocytosis [290].…”

“…For the visual Arrestin4 no disease causing mutations are known. For the β-Arrestins there are likewise no disease-causing mutations identified yet, however some polymorphisms were reported which might be associated with neurological diseases [289]. Overall, it remains a challenge to understand how the small number of Arrestins can regulate the signaling of hundreds of GPCRs and even fulfill additional non-GPCR connected functions as signaling scaffolds.…”