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binding side was also reported.
83,131
Both polar core and the three-element
interaction clearly support the basal conformation in all arrestin
structures,
18-20,22
so their destabilization by the phosphates was consistent
with the idea that global rearrangement is necessary for receptor binding.
Partial destabilization of the interface between the two domains enhanced
arrestin binding to inactive receptor,
132
again suggesting that arrestin confor-
mation must change upon receptor binding.
Arrestin interaction with nonreceptor partners also appears to be consis-
tent with the idea that the conformations of free and receptor-bound
arrestins must be different.
31
C-Raf1 and especially ERK1/2 preferentially
interact with receptor-associated arrestins.
133
In contrast, the ubiquitin
ligases Mdm2 and parkin
134,135
strongly prefer arrestins in a conformation
induced by hinge deletions that impairs receptor binding.
35,105,136
JNK3 also
appears to prefer this conformation, although the difference in binding is less
dramatic.
134,136
Thus, it appeared almost certain that the conformation of receptor-
bound arrestin is significantly different from the basal one observed in crystal
structures, but direct evidence was missing. A recent study employing site-
directed spin-labeling and long-range distance measurements using pulse
EPR technique double electron-electron resonance (DEER) yielded the
first experimental data on conformational rearrangements in arrestin-1
beyond the release of the C-tail.
72
More than 25 distances between different
residues in free and rhodopsin-associated arrestin-1 were measured. Signif-
icant changes in multiple distances combined with molecular modeling rev-
ealed binding-induced movements of several arrestin-1 elements. Some of
the findings supported earlier predictions, whereas others were rather unex-
pected. Flexible “finger loop” (residues 67-79)
73
(
Fig. 3.1
) in the central
crest of arrestins exist in fully extended or bent conformation in different
protomers in crystal oligomers.
18,19
Multiple residues in this loop were
shown to be immobilized upon receptor binding in both arrestin-1
73
and
-2.
71
Previous studies using fluorescent labels
131
and NMR
83
suggested that
this loop extends and forms an
a
-helix upon receptor binding. Indeed, this
loop was found to move in the direction of the receptor, although not as
much as previously proposed,
131
and the data were consistent with its helical
conformation in receptor-associated arrestin-1.
72
However, hypothetical
movement of the two arrestin domains relative to each other, which was
proposed to improve the fit between arrestins and GPCRs,
30
turned out
to be very small, clearly insufficient to significantly reduce the size of the
receptor-binding arrestin surface.
72
Two other plastic loops containing
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