Repeat Module‐Based Rational Design of a Photoswitchable Protein for Light‐Driven Control of Biological Processes

Light‐driven control of biological processes using photoswitchable proteins allows high spatiotemporal interrogation or manipulation of such processes, assisting in understanding their functions. Despite considerable advances, however, the wide spread use of optical control has been hampered by a limited repertoire of photoswitchable proteins and a lack of generalized design strategy. Herein, we present a repeat module‐based rational design of a photoswitchable protein composed of LRR (Leucine‐rich repeat) modules using azobenzene as a photochromic ligand. Our design approach involves the rational selection of a Cβ pair between two nearby modules within a convex region and subsequent cross‐linking with a photochromic ligand. We demonstrate the general utility and potential of our strategy by showing the design of three target‐specific photoswitchable proteins and a light‐driven modulation of the cell signaling. With an abundance of LRR proteins in nature, our approach can expand the repertoire of photoswitchable proteins for light‐driven control of biological processes. Light‐driven cell signaling: A repeat module‐based rational design of a photoswitchable protein composed of LRR (Leucine‐rich repeat) modules is presented using azobenzene as a photochromic ligand. The utility and potential of the strategy are shown by designing three photoswitchable proteins and the light‐driven modulation of the cell signaling.