Ion channels are among the most important proteins in biology, regulating the activity of excitable cells and changing in diseases. Ideally it would be possible to actuate endogenous ion channels, in a temporally precise and reversible manner, and without requiring chemical cofactors. Here we present a modular protein architecture for fully genetically encoded, light-modulated control of ligands that modulate ion channels of a targeted cell. Our reagent, which we call a lumitoxin, combines a photoswitch and an ion channel-blocking peptide toxin. Illumination causes the photoswitch to unfold, lowering the toxin's local concentration near the cell surface, and enabling the ion channel to function. We explore lumitoxin modularity by showing operation with peptide toxins that target different voltage-dependent K + channels. The lumitoxin architecture may represent a new kind of modular protein-engineering strategy for designing light-activated proteins, and thus may enable development of novel tools for modulating cellular physiology.
Bibliographical noteFunding Information:
This work was supported by NIH Grants NIH 1DP2OD002002, NIH 1R01DA029639, NIH 1R01NS075421, NIH 1RC1MH088182, the NSF CAREER Award CBET 1053233, DARPA Living Foundries Contract HR0011-12-C-0068 and the New York Stem Cell Foundation-Robertson Investigator Award. D.S. was supported by the Damon Runyon Cancer Research Foundation (DRG 2095-11). P.W.T was supported by the Fannie and John Hertz Foundation. F.C. was supported by the National Science Foundation Graduate Research Fellowship under grant no. 1122374 and the Synthetic Intelligence Project.