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Custom-designed proteins as novel therapeutic tools? The case of arrestins

Published online by Cambridge University Press:  23 April 2010

Vsevolod V. Gurevich  and
Eugenia V. Gurevich
Vsevolod V. Gurevich*
Affiliation:
Vanderbilt University, Nashville, TN 37232, USA.
Eugenia V. Gurevich
Affiliation:
Vanderbilt University, Nashville, TN 37232, USA.
*
*Corresponding author: Vsevolod V. Gurevich, Department of Pharmacology, Vanderbilt University, Nashville, TN 37232, USA. E-mail: vsevolod.gurevich@vanderbilt.edu
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Abstract

Multiple genetic disorders can be associated with excessive signalling by mutant G-protein-coupled receptors (GPCRs) that are either constitutively active or have lost sites where phosphorylation by GPCR kinases is necessary for desensitisation by cognate arrestins. Phosphorylation-independent arrestin1 can compensate for defects in phosphorylation of the GPCR rhodopsin in retinal rod cells, facilitating recovery, improving light responsiveness, and promoting photoreceptor survival. These proof-of-principle experiments show that, based on mechanistic understanding of the inner workings of a protein, one can modify its functional characteristics to generate custom-designed mutants that improve the balance of signalling in congenital and acquired disorders. Manipulations of arrestin elements responsible for scaffolding mitogen-activated protein kinase cascades and binding other signalling proteins involved in life-or-death decisions in the cell are likely to yield mutants that affect cell survival and proliferation in the desired direction. Although this approach is still in its infancy, targeted redesign of individual functions of many proteins offers a promise of a completely new therapeutic toolbox with huge potential.

Type
Review Article
Information
Expert Reviews in Molecular Medicine , Volume 12 , January 2010 , e13
Copyright
Copyright © Cambridge University Press 2010

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References

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