Structural Determinants of Arrestin Functions - Progress in Molecular Biology and Translational Science - page 59

We also do not know the structure of the active receptor-bound arrestin so
that the notion that the receptor and arrestin do not fit will be purely the-
oretical until the first structure of the arrestin-receptor complex is solved.
Nonetheless, the idea that arrestins and the cytoplasmic tips of GPCRs
do not fit has certain merits and remains quite popular. So far two elegant
models have been proposed as possible solutions for this problem.
3.2. The stoichiometry of the complex
One model is based on the high Arrhenius activation energy of the
arrestin-rhodopsin interaction 104 and subsequent finding that elements of
arrestin-1 that do not interact either with light-activated (Rh*) or inactive
phosphorylated rhodopsin (P-Rh) become engaged by the active phosphor-
ylated form (P-Rh*). 25,27 Collectively, these data suggested that a substantial
conformational change in arrestin, which brings additional parts into contact
with the receptor, is necessary for high-affinity binding to P-Rh*. 25 The
evidence that shortening of the inter-domain hinge impedes the binding
of all arrestins to their cognate receptors, 35,105 suggested that this conforma-
tional change could be a clam-like movement of the two arrestin domains. 30
This type of movement could solve the problem of the misfit between the
large receptor-binding surface of arrestin and the expected size of the
arrestin-binding cytoplasmic side of GPCRs. Although this idea could still
be considered plausible simply because it was not unambiguously refuted,
there is no direct evidence for the large movement of the two domains rel-
ative to each other. Existing evidence suggests that while domain movement
actually accompanies receptor binding, it is rather small, 72,106 certainly
not big enough to significantly reduce the receptor-binding “face” of
arrestin. However, detected movement of the loops on both distal tips of
arrestin-1 toward the center of the receptor-binding side of the molecule
likely contributes to the reduction of the surface of arrestin-1 that binds rho-
dopsin, 72 improving the fit in a different way ( Fig. 3.2 ).
An alternative model attacks the problem even more radically, proposing
that a single arrestin binds two GPCRs in a dimer. 107 Indeed, one can simul-
taneously fit two cytoplasmic tips of smaller GPCRs, such as rhodopsin, into
the cavities of the two arrestin domains. 107 Unfortunately, to achieve this,
one needs to disregard the receptor C-terminus, which is not visible in crys-
tals, even though it is certainly involved in arrestin binding, 26,28,90,108 and
ignore the fact that inactive rhodopsin does not bind arrestin with high affin-
ity. 25,80,109 However, this model was proposed without mentioning these
obvious caveats and has gained certain popularity, despite complete lack