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domains. In addition, the loops at the tips of both arrestin-1 domains move
toward the receptor,
72
possibly far enough to achieve direct contact with it,
as suggested by reduced mobility of several residues in these loops in the
complex.
71,73
As far as the receptor is concerned, the comparison of the
structures of the same active
b
2AR in complex with an agonist,
42
nanobody
mimicking G protein,
65
and cognate heterotrimeric G protein
66
shows that,
with activation, the receptor helices on the cytoplasmic side progressively
move further apart. Thus, it is entirely possible that in complex with arrestin
the helices move out even more, thereby increasing the size of the cytoplas-
mic tip of the receptor to better accommodate arrestin. Naturally, these are
no more than plausible speculations and should be viewed as such. Ulti-
mately, the issue of the arrestin-receptor fit can only be definitively resolved
by the elucidation of the structure of the complex.
3.3. Phosphate-binding residues and the phosphate sensor
The fact that arrestins preferentially bind phosphorylated forms of their
cognate receptors was established early on, but the first model explaining
how arrestin “selects” active phosphorylated receptors from among at
least four coexisting forms (active and inactive, both of which can be
unphosphorylated or phosphorylated) was proposed in 1993.
25
Specific bind-
ing to inactive phosphorylated (P-Rh) and light-activated unphosphorylated
rhodopsin (Rh*) showed that arrestin-1 has interaction sites that recognize
rhodopsin-attached phosphates and the active state of rhodopsin inde-
pendently of each other.
25
However, the binding to light-activated pho-
sphorhodopsin (P-Rh*) was many times greater than either to P-Rh or
Rh*,
24,25
which cannot be explained by a simple cooperative two-site inter-
action. This led to the idea that primary binding sites engaged by Rh* and
inactive P-Rh also serve as sensors. Only P-Rh* can engage both at the same
time, suggesting that arrestin-1 acts as a molecular coincidence detector,
where simultaneous activation of these two sensors triggers a global confor-
mational change, which brings additional arrestin-1 elements in contact with
rhodopsin, greatly increasing the energy of the interaction and therefore
observed binding (reviewed in Ref.
30
). This model predicts that among
phosphate-binding residues in arrestin-1 and other family members, there
must be at least one that not only contributes to the interaction but also serves
as a sensor. The elimination of positive charges that simply bind phosphates
was expected to reduce arrestin binding to P-Rh*, and even to a greater
extent
to inactive P-Rh, where the phosphates must be driving the
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