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arrestins, which lack the classical clathrin box (L
F
x
F
[D/E]), harbor this
alternate binding site. This site in the looser form
FF
Gx
F
is also present
in other species and may contribute to the recruitment of clathrin and the
endocytosis of rhodopsin that have been described in flies.
56-58
2.4. Sites of posttranslational modifications
Nonvisual arrestins are regulated by multiple posttranslational modifications
such as phosphorylation, nitrosylation, ubiquitination, and SUMOylation.
34
The exact temporal sequence and functional cross talk of these posttransla-
tional modification events are not yet clearly established.
In the cytosol, both
b
-arrestins 1 and 2 are phosphorylated on sites
located on their C-terminal tail in proximity of the binding sites for clathrin
and adaptin;
b
-arrestin 1 is phosphorylated on S
412
by ERK; and
b
-arrestin 2
is phosphorylated on S
361
and T
383
by casein kinase II. The recruitment of
b
-arrestins 1 and 2 by activated receptors at the PM leads to their rapid
dephosphorylation by an as yet unknown phosphatase. This dephosphory-
lation does not affect the desensitization of the receptor but is essential for the
scaffolding of clathrin and internalization of the receptor. Once on an
endocytic vesicle,
b
-arrestins 1 and 2 are rapidly rephosphorylated.
59-62
Analogously, visual arrestin is phosphorylated at a similar position (S
366
)
by a calcium/calmodulin-dependent protein kinase upon light activation,
63
and dephosphorylation is required for the arrestin-clathrin interaction to
proceed.
64
Following activation of some G protein-independent receptors,
b
-arrestin 1 can also be phosphorylated on S
412
by GRK5.
65
Besides the Ser/Thr phosphorylation, the interaction between
b
-arrestin
1 and the
m
-subunit of AP-2 is negatively regulated by phosphorylation of
Y
54
by Src. Introducing a Y
54
F mutation into
b
-arrestin 1 results in
improved arrestin-adaptin interaction and enhanced
b
2
-adrenergic receptor
internalization.
66
Bovine
b
-arrestin 2 is nitrosylated at the level of its C-terminal cysteine.
Following
b
-adrenergic receptor activation, S-nitrosylation of
b
-arrestin 2
promotes its binding to the clathrin/adaptin endocytic machinery and accel-
erates receptor internalization.
67
This residue is conserved in
b
-arrestin 2
paralogues from
Xenopus laevis
and
Danio rerio
to mammals, within a
[D,E][D,E]x
C
C consensus sequence, where
C
is a hydrophobic residue
and C is the C-terminal nitrosylated cysteine residue. Whether this type
of modification is general to all arrestins is not clear, as visual arrestins and
b
-arrestin 1 have no cysteine at their C-terminus and S-nitrosylation at other
predicted sites has not yet been documented.
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