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Science. 2016 Dec 16;354(6318):1441-1444.

Engineering extrinsic disorder to control protein activity in living cells.

Author information

1
Program in Molecular and Cellular Biophysics, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
2
Department of Biochemistry and Biophysics, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
3
Department of Pharmacology and Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
4
Department of Biomolecular Mechanisms, Max Planck Institute for Medical Research, Jahnstrasse 29, 69120 Heidelberg, Germany.
5
Program in Molecular and Cellular Biophysics, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA. khahn@med.unc.edu dokh@email.unc.edu.
6
Department of Pharmacology and Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA. khahn@med.unc.edu dokh@email.unc.edu.

Abstract

Optogenetic and chemogenetic control of proteins has revealed otherwise inaccessible facets of signaling dynamics. Here, we use light- or ligand-sensitive domains to modulate the structural disorder of diverse proteins, thereby generating robust allosteric switches. Sensory domains were inserted into nonconserved, surface-exposed loops that were tight and identified computationally as allosterically coupled to active sites. Allosteric switches introduced into motility signaling proteins (kinases, guanosine triphosphatases, and guanine exchange factors) controlled conversion between conformations closely resembling natural active and inactive states, as well as modulated the morphodynamics of living cells. Our results illustrate a broadly applicable approach to design physiological protein switches.

PMID:
27980211
PMCID:
PMC5362825
DOI:
10.1126/science.aah3404
[Indexed for MEDLINE]
Free PMC Article

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