Modular Thermal Control of Protein Dimerization
Protein–protein interactions and protein localization are essential mechanisms of cellular signal transduction. The ability to externally control such interactions using chemical and optogenetic methods has facilitated biological research and provided components for the engineering of cell-based therapies and materials. However, chemical and optical methods are limited in their ability to provide spatiotemporal specificity in light-scattering tissues. To overcome these limitations, we present "thermomers", modular protein dimerization domains controlled with temperature—a form of energy that can be delivered to cells both globally and locally in a wide variety of in vitro and in vivo contexts. Thermomers are based on a sharply thermolabile coiled-coil protein, which we engineered to heterodimerize at a tunable transition temperature within the biocompatible range of 37–42 °C. When fused to other proteins, thermomers can reversibly control their association, as demonstrated via membrane localization in mammalian cells. This technology enables remote control of intracellular protein–protein interactions with a form of energy that can be delivered with spatiotemporal precision in a wide range of biological, therapeutic, and living material scenarios.
© 2019 American Chemical Society. Received: July 2, 2019; Published: September 6, 2019. The authors thank Mohamad Abedi and Andres Collazo for helpful discussions. Microscopy was performed at the Biological Imaging Facility of the Beckman Institute at Caltech. This research was supported by the Defense Advanced Research Projects Agency (D14AP0050), the Sontag Foundation and the Army Institute for Collaborative Biotechnologies (W911NF-19-D-0001). D.I.P. was supported by the NIH fellowship for Predoctoral Training in Biology and Chemistry (T32GM007616). Author Contributions: D.I.P. and M.G.S. conceived the study. D.I.P. designed the experiments and analyzed the data. D.I.P. and Y.W. performed the experiments. D.I.P. and M.G.S. wrote the manuscript. The authors declare no competing financial interest.
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