Multi-input chemical control of protein dimerization for programming graded cellular responses

Abstract

Chemical and optogenetic methods for post-translationally controlling protein function have enabled new discoveries and the engineering of synthetic cellular functions. However, most of these methods only confer single-input, single-output control. To increase the diversity of posttranslational behaviors that can be programmed we built a system based on a single protein receiver that can integrate multiple drug inputs, including approved therapeutics. Our system translates drug inputs into diverse outputs with engineered reader proteins that provide variable dimerization states of the receiver protein. We show that our single receiver protein architecture can be used to program diverse cellular responses, including graded and proportional dual-output control of transcription and mammalian cell signaling. We apply our tools to titrate the competing activities of the Rac and Rho GTPases to control cell morphology. Our receiver protein and suite Users may view, print, copy, and download text and data-mine the content in such documents, for the purposes of academic research, subject always to the full Conditions of use:

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