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Interestingly, even very limited and imprecise identification of structural requirements
for the interaction with very few other proteins has enabled the development
of signaling-biased arrestin mutants. More comprehensive understanding of the struc-
tural underpinning of different arrestin functions will pave the way for the construc-
tion of arrestins that can link the receptor we want to the signaling pathway of our
choosing.
1. INTRODUCTION
As far as size is concerned, arrestins are quite average, 44-48 kDa sol-
uble proteins. Functionally, however, arrestins are far from being average in
many ways, demonstrating that evolution can pack incredible versatility into
400 amino acids.
The discovery of the first member of the arrestin family (modern system-
atic name arrestin-1 a ) was rather unremarkable, except that it was discovered
twice: first as S-antigen, the target of auto-antibodies in uveitis, 1 then as a
48-kDa protein that binds light-activated rhodopsin, 2 preferring the phos-
phorylated form. 3 Eventually it became clear that both are the same protein,
which prevents G protein activation by light-activated phosphorylated rho-
dopsin, 4 thereby blocking (arresting) further signaling.
All this happened before the seminal discovery of striking similarity in
sequence and topology between the b 2-adrenergic receptor ( b 2AR) and
rhodopsin, 5 which led to the concept that there is a large family of
G-protein-coupled receptors (GPCRs; also known as seven transmembrane
domain receptors or 7TMRs) and fruitful ideas regarding the similarity of
signaling and regulatory mechanisms in this family. The first nonvisual
arrestin, termed b -arrestin because of its preference for the b 2AR over rho-
dopsin, was cloned soon thereafter, 6 followed by another nonvisual subtype
(termed b -arrestin2, 7 arrestin-3, 8 and hTHY-ARRX, 9 respectively) and
cone-specific arrestin. 10,11 Considering that different vertebrate species
express from 800 to > 3400 distinct GPCRs (SEVENS database; http://
sevens.cbrc.jp/ ) , the fact that we only have four arrestin subtypes 12 is rather
remarkable. Moreover, arrestin-1 and -4 are largely restricted to photore-
ceptors, 13 whereas the two nonvisual subtypes are ubiquitously expressed
a
We use systematic names of arrestin proteins: arrestin-1 (historic names S-antigen, 48-kDa protein,
visual or rod arrestin); arrestin-2 ( b -arrestin or b -arrestin1); arrestin-3 ( b -arrestin2 or hTHY-ARRX);
and arrestin-4 (cone or X-arrestin; for unclear reasons, its gene is called arrestin 3 in the HUGO
database).
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