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At a molecular level, these effects are dependent upon conformation-
specific interaction of USP33 and b -arrestin2. The b 2 AR-induced confor-
mation of “active” b -arrestin2 enhances its binding with USP33, whereas
the V 2 R-induced “active” b -arrestin2 conformation reduces it ( Fig. 7.4 ).
These conformation-specific interactions are supported by observations
from two sets of assays conducted in vitro: (1) interaction of purified
b -arrestin2 and USP33 is augmented by addition of a synthetic peptide
mimicking the phosphorylated carboxyl tail of the b 2 AR, but not that of
the V 2 R or nonphosphorylated forms of either tail peptide and (2) differen-
tial trypsin-digestion profiles of purified b -arrestin2 in the presence of phos-
phorylated peptides representing the carboxyl tails of b 2 AR and the V 2 R.
Accordingly, b -arrestin-receptor interaction is regulated by the phosphor-
ylation motifs on the carboxyl tail of 7TMRs, which is followed by
ubiquitination of specific residues by E3 ubiquitin ligase(s), and recruitment
and conformation-specific interaction with deubiquitinating enzymes.
Therefore, two types of unique codes dictate b -arrestin-dependent cellular
effects: a “phosphorylation code” at the receptors generated by specific
GRK-mediated phosphorylation, followed by “ubiquitination code” on
b -arrestin conferred by E3 ubiquitin ligase(s). Although receptor interaction
causes a conformational change in b -arrestin, further addition of ubiquitin
moieties would result in a second phase of conformational modification
ensuing binding or dissociation of specific cellular proteins.
4. ARRESTINS ACT AS ADAPTORS FOR UBIQUITINATION
The E3 ubiquitin ligases or DUBs recognize their substrates via spe-
cific protein interaction domains or conformational cues appended to the
substrate by another posttranslation modification (e.g., phosphorylation/
dephosphorylation). 33 Nonetheless, a majority of substrates are predicted
to bind these enzymes via adaptor molecules, which function as accessory
proteins in escorting the E3 ubiquitin ligases or scaffolding both E2 and
E3 enzymes. 22,33,62 These adaptor proteins provide an added layer of regu-
lation, increase specificity as well as efficiency, and define timing and local-
ization of substrate ubiquitination.
Both b -arrestin isoforms act as indispensable E3 ligase adaptors for 7TMRs
and non-7TMRs to mediate ubiquitination, and they can play an equally
important role in escorting DUBs. 22 As adaptors, b -arrestins can potentially
determine the dynamics of ubiquitination/deubiquitination of endocytic pro-
teins that are important for proper steering of internalizing cargo across various
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