Engineering extrinsic disorder to control protein activity in living cells

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Science  16 Dec 2016:
Vol. 354, Issue 6318, pp. 1441-1444
DOI: 10.1126/science.aah3404

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Engineering control of cellular proteins

The ability to switch proteins between active and inactive conformations can give insight into their function. Dagliyan et al. present a method to insert domains that control protein activity. They computationally identified protein loops that are coupled to the active site. Sensory domains inserted into these loops could modulate protein activity when their conformation was changed by light or ligand binding. The authors engineered domains into three different classes of proteins involved in cell signaling and found that switching the proteins between active and inactive states could control the shape and movement of living cells.

Science, this issue p. 1441


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.

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