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At the membrane, the stability of the association of
b
-arrestin 2 with
GPCRs is dependent on its ubiquitination of K
11
and K
12
by the ubiquitin
E3 ligase Mdm2.
68
A stable receptor-arrestin complex on the endosome is
essential for the arrestin-dependent signaling, for example, ERK phosphor-
ylation and sequestering in the cytoplasm.
69
As discussed earlier, these two
lysines serve as phosphate-sensors when
b
-arrestins bind activated and phos-
phorylated GPCRs. Use of the same residues to recognize the receptor and
to stabilize the interaction by ubiquitination may provide a sequential switch
to temporally order interaction events. The deubiquitinating protease
USP33 binds to N- and C-domains of
b
-arrestin 2 and promotes its
deubiquitination. The reciprocal activities of Mdm2 and USP33 exerted
on
b
-arrestins are essential for the regulation of GPCR trafficking and
downstream signaling.
68
Bovine
b
-arrestin 1 and 2 are also modified by SUMO-1 upon activation
of the
b
2
-adrenergic receptor. The main SUMOylation site in
b
-arrestin 2 is
K
400
close to the C-terminus and this modification regulates GPCR inter-
nalization.
70
This lysine is not conserved in a multiprotein alignment of
b
-arrestins from different species. Interestingly, a second lysine (K
295
) can
be modified by SUMO-1.
70
This lysine resides in a consensus motif [L,I]
KxE found as such in all but one arrestin of the metazoan clade
(
Fig. 2.2
), suggesting that both visual and
b
-arrestins could potentially be
SUMOylated. This point awaits experimental verification.
2.5. Binding sites for inositol phosphates
Soluble phosphoinositols and membrane-inserted phosphoinositides are
major regulators of the inactive/active states of visual and nonvisual arrestins.
Arrestins bind InsP
6
(also known as inositol hexakisphosphate or phytic acid)
on patches of positive residues in their N- and C-domains. A first InsP
6
binding site (high-affinity site) is located on the concave surface of the
C-domain (K
232
,R
236
,K
250
,K
324
,K
326
in bovine
b
-arrestin 1). A low-
affinity site, also formed from positively charged residues (K
157
,K
160
,
R
161
), is present in the N-domain.
4,5
InsP
6
and another polyanionic
compound, heparin, act as mimics of the phosphorylated tail of GPCRs.
Upon binding to the N-domain of rod arrestin, they are able to release
its C-terminal tail.
74
InsP
6
promotes the homo-oligomerization of
b
-arrestin 1 and its hetero-oligomerization with
b
-arrestin 2.
4
Given the
high cytosolic concentration of InsP
6,
75
cytosolic basal-state arrestins are
mostly stored in an oligomeric InsP
6
-bound form. The binding of arrestins
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