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leading from the endosomes to the TGN; VPS26 within the retromer com-
plex in the retrieval of Golgi proteins in endosome-derived vesicles, and
RGP1 more downstream when these vesicles fuse with the TGN.
5. ARE ARRESTINS AND ARRESTIN-FOLD PROTEINS
RELATED BY A SHARED MECHANISM
FOR THEIR FUNCTION?
Recent findings have pinpointed several protein subfamilies with an
arrestin fold. True arrestins, ARTs, ARRDCs, VPS26, and DSCR3 are
now clustered in the arrestin clan.
The crucial question raised by the similar structure of arrestin-fold pro-
teins only distantly related to arrestins in terms of sequence conservation is
whether they are functionally related. Such a question seems all the more
pertinent as we know that evolution has produced preserved basic folds
in proteins with little conservation in their amino acid sequences or their
biological functions.
128,129
Although proteins with a similar tertiary struc-
ture in the absence of sequence conservation may have evolved by processes
of convergent evolution, it is in fact highly probable that they adopt one
among a small number of thermodynamically preferred conformations,
because of either the facility of the folding process or the stability of the
obtained structure.
128
The first discovered function of arrestins, and the origin of their name, is
the arrest of the G-protein signaling triggered by the activation of 7TM-
receptors. This desensitizing function was extended by their ability, once
bound to an activated GPCR, to recruit components of the endocytosis
machinery and to promote internalization of the GPCR. The interaction
of arrestins with the phosphorylated tail of activated GPCRs exploits a subtle
mechanism involving a polar core and the unfolding of their C-terminal tail,
unmasking adaptin and clathrin-binding sites. More recently, arrestins were
described as G-protein independent signaling platforms recruited to acti-
vated GPCRs.
We have examined the functions of the arrestin-fold proteins in the light
of the above functions of arrestins to determine the extent to which they
conform to this paradigm. We followed Alvarez's suggestion to divide
arrestin fold proteins in two classes:
a
-arrestins (ARTs, ARRDCs) and
b
-arrestins that include visual arrestins.
130
VPS26 and DSCR3 proteins form
a third subfamily. Similarities and differences between the functional mech-
anisms of diverse arrestin-fold proteins are summarized in
Table 2.I
.
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