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6. CONCLUSIONS: WHERE DO WE GO FROM HERE?
It might appear that as proteins go, arrestins are fairly well studied
structurally and functionally. It is clear that members of this small protein
family, which apparently emerged relatively late in evolution, 12 likely after
GPCR kinases, 176 serve as multifunctional signaling organizers in the cell.
However, while known phenomenology is rich and pretty well
described, 177 the structural basis of most arrestin functions remains obscure.
The molecular mechanisms underlying arrestin interactions with most part-
ners, as well as expected inter-dependence of these interactions, must be elu-
cidated. This will greatly improve our understanding of cell signaling,
particularly the integration of different inputs into coherent cell behavior,
which is arguably the greatest challenge in modern cell biology. 142 As an
added bonus, elucidation of the molecular mechanisms underlying individ-
ual arrestin functions and identification of the residues involved will pave the
way to intelligent design of mutant arrestins with desired signaling bias. The
mutants of this type are not just valuable research tools but also hold promise
of enormous therapeutic potential.
ACKNOWLEDGMENTS
The authors are grateful to our collaborators, whose expertise and efforts made many of the
studies discussed here possible. Supported by NIH Grants EY011500, GM077561,
GM081756 (VVG), NS065868, and DA030103 (EVG).
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