Structural Determinants of Arrestin Functions - Progress in Molecular Biology and Translational Science - page 65

residues 157 and 344, localized at the tips of the N- and C-domain, respec-
tively, that had different conformations in crystal strcutures, 18 were found to
move “inward,” in the direction of the cavities of their respective domains.
These movements also slightly reduce the long axis of the receptor-binding
surface, but only by a few angstroms. The most unexpected finding was a
dramatic movement of the loop with residue 139 at its tip, which is adjacent
to the finger loop in the basal state. This element shifts by more than 10 ˚ ,
moving in the direction of the N-domain and to the side of the molecule. 72
This movement would take it out of the way of incoming receptor. Con-
sistent with this model, spin label in position 139 was immobilized by inac-
tive P-Rh, but in high-affinity complex with P-Rh*, its mobility increased
to the level observed in free arrestin. 73 Moreover, deletions in this loop,
taking it out of the way without movement, increased arrestin-1 binding
to rhodopsin, most dramatically to the nonpreferred forms Rh* and inactive
P-Rh. 72 Interestingly, the same deletions reduced the thermal stability of
arrestin-1. 72 Thus, it appears that the 139-loop structurally stabilizes the
basal arrestin conformation and serves as a “brake”, precluding its binding
to any form of rhodopsin except its preferred target, P-Rh*.
While this study clearly revealed multiple receptor-binding-induced
rearrangements in arrestin-1, which are likely similar to those in nonvisual
arrestins, biophysical methods cannot yield detailed atomic resolution struc-
ture of the receptor-bound arrestin. Crystal structure of the
arrestin-receptor complex is necessary to obtain this information and clearly
reveal the changes in arrestin molecule that underlie conformational prefer-
ences of nonreceptor binding partners.

3.5. Key determinants of receptor preference
As a general rule, arrestins preferentially bind active phosphorylated forms of
their cognate receptors. Obviously, receptor-attached phosphates that acti-
vate the phosphate sensor are the common theme, so arrestin elements that
bind other nonphosphorylated parts of the receptor in response to
activation-induced conformational change must be responsible for receptor
specificity of arrestin proteins. Two out of four arrestin subtypes in mammals
are specialized and expressed primarily in photoreceptors. Interestingly, the
specificity of cone arrestin-4 for cone opsins appears to be largely ensured by
its selective expression in cone photoreceptors. 137 In vitro , it is quite promis-
cuous, binding other GPCRs almost as well as nonvisual arrestins, 22 both of
which readily interact with dozens, if not hundreds, of different