True Arrestins and Arrestin-Fold Proteins: A Structure-Based Appraisal - Progress in Molecular Biology and Translational Science - page 19

sort (VPS)26). 11,12 Surprisingly, their tertiary structure is strongly reminis-
cent of that of arrestins. Altogether, they now constitute the arrestin clan
(CL0135).
We review here the structure and the functional and mechanistic deter-
minants of the diverse members of the arrestin clan, from the data published
in the literature and obtained by modeling. We conclude that they share
indeed a stable convergent conformation and generally act as scaffolds.
However, the family is heterogeneous in terms of functional properties.
ARTs and ARRDCs share some important functional characteristics of
arrestins, whereas VPS26 functions in a different type of trafficking, with
a different mode of recognition and different partners. The nature of the
arrestin-fold protein (arrestins vs. ARRDCs) recruited by some GPCRs also
determines their fate toward recycling or lysosomal degradation pathways.
2. TRUE ARRESTINS: A STRUCTURE ADAPTED TO
MULTIPLE SCAFFOLDING
2.1. Function of arrestins
The search for proteins involved in the desensitization of the GPCRs rho-
dopsin or b -adrenergic receptor led to the discovery of visual- and
b -arrestins, here referred to as true arrestins. 13-17
In response to agonist binding, GPCRs experience a conformational
change and interact with heterotrimeric G proteins, on which they act as
a guanylate nucleotide exchange factor (GEF). GTP-loaded G a dissociates
from G b / g and both entities transduce the receptor-dependent signal to
downstream second-messenger producing effectors. Activation of GPCRs
immediately activates a negative feedback loop to dampen persistent activa-
tion of the triggered signaling pathways. This loop involves the phosphor-
ylation of the cytoplasmic tail of the GPCRs by G-protein-coupled receptor
kinases (GRKs), the recruitment of cytoplasmic arrestins to the activated,
phosphorylated receptors, and the steric uncoupling of the GPCRs from
the G proteins. 18-23
Arrestins further interfere with receptor-dependent signaling by pro-
moting internalization of activated receptors. The binding of arrestins to
the phosphorylated receptors destabilizes their polar core and releases cryptic
binding sites for proteins of the endocytic machinery, adaptins, and clathrin.
The fate of internalized receptors, either recycling or routing to degradation
in lysosomes, depends on their ubiquitination promoted by the scaffolding
of HECT-type ubiquitin ligases by arrestins. 24,25 The chemokine receptor