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binding between blades 4 and 5. 152 The AP2 binding site was localized
downstream of the N-domain contact in the distal C-tail, by extensive
mutagenesis 147,153 and cocrystallization of an arrestin peptide with the
AP2 beta-appendage. 154
No other partners have so far been cocrystallized with arrestins or even
their elements. Only the binding sites of microtubules, 35 calmodulin, 146 and
cAMP phosphodiesterase PDE4D5 155 were mapped with any degree of pre-
cision. Particular residues in arrestin-2 were implicated in binding of
MEK1 156 and c-Raf1, 157 and several residues in arrestin-3 were found to
be critical for its ability to promote JNK3 activation. 158 Thus, the structural
basis of arrestin interactions with the great majority of putative partners still
remains to be elucidated.
4.2. The shape of the arrestin - MAPK signaling complex
The first reports of arrestin-mediated activation of MAP kinases suggested
that in each MAPKKK-MAPKK-MAPK cascade only MAPKKKs
(ASK1 and c-Raf1) and MAPKs (JNK3 and ERK1/2) directly bind
arrestins, whereas MAPKKs (MKK4 and MEK1) are recruited via interac-
tions with corresponding MAPKKKs and/or MAPKs. 148,149 This model
further suggested that MAPKKKs bind to the N-domain of arrestins,
whereas MAPKs interact with the C-domain. 159 Subsequently, two
MAPKKs, MEK1 156 and MKK4, 160 were shown to bind arrestins directly
in the absence of MAPKKKs or MAPKs. Moreover, separately expressed
arrestin N- and C-domains were shown to interact with all three kinases
in c-Raf1-MEK1-ERK1/2 and ASK1-MKK4-JNK3 cascades. 161,162 This
led to an alternative model of the arrestin complex with MAP kinases, where
MAPKKK, MAPKK, and MAPK have bipartite binding sites, each inter-
acting with both arrestin domains, 162 so that the three kinases are arranged
on arrestin-like three hotdogs on a single bun. 141 Considering that receptor
binding induces a conformational change in arrestins, the dependence of
arrestin scaffolding function on GPCR activation can be easily explained
by this arrangement.
4.3. Conformational preferences determine outcomes
The first reports of arrestin binding to nonreceptor partners focused on
GPCR-associated arrestins, 145,147-149 creating an impression that these
interactions are contingent on arrestin binding to receptors. This implied
that only “active” receptor-bound arrestin can engage other proteins, which
turned out not to be the case. In fact, accumulating evidence suggests that
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