A rational blueprint for the design of chemically-controlled protein switches

Sailan Shui, Pablo Gainza, Leo Scheller, Che Yang, Yoichi Kurumida, Stéphane Rosset, Sandrine Georgeon, Raphaël B. Roberto, Rocío Castellanos-Rueda, Sai T. Reddy and Bruno E. Correia ()
Additional contact information
Sailan Shui: Laboratory of Protein Design and Immunoengineering (LPDI) - STI - EPFL
Pablo Gainza: Laboratory of Protein Design and Immunoengineering (LPDI) - STI - EPFL
Leo Scheller: Laboratory of Protein Design and Immunoengineering (LPDI) - STI - EPFL
Che Yang: Laboratory of Protein Design and Immunoengineering (LPDI) - STI - EPFL
Yoichi Kurumida: Tokyo Institute of Technology, Meguro-ku
Stéphane Rosset: Laboratory of Protein Design and Immunoengineering (LPDI) - STI - EPFL
Sandrine Georgeon: Laboratory of Protein Design and Immunoengineering (LPDI) - STI - EPFL
Raphaël B. Roberto: ETH Zürich
Rocío Castellanos-Rueda: ETH Zürich
Sai T. Reddy: ETH Zürich
Bruno E. Correia: Laboratory of Protein Design and Immunoengineering (LPDI) - STI - EPFL

Nature Communications, 2021, vol. 12, issue 1, 1-12

Abstract: Abstract Small-molecule responsive protein switches are crucial components to control synthetic cellular activities. However, the repertoire of small-molecule protein switches is insufficient for many applications, including those in the translational spaces, where properties such as safety, immunogenicity, drug half-life, and drug side-effects are critical. Here, we present a computational protein design strategy to repurpose drug-inhibited protein-protein interactions as OFF- and ON-switches. The designed binders and drug-receptors form chemically-disruptable heterodimers (CDH) which dissociate in the presence of small molecules. To design ON-switches, we converted the CDHs into a multi-domain architecture which we refer to as activation by inhibitor release switches (AIR) that incorporate a rationally designed drug-insensitive receptor protein. CDHs and AIRs showed excellent performance as drug responsive switches to control combinations of synthetic circuits in mammalian cells. This approach effectively expands the chemical space and logic responses in living cells and provides a blueprint to develop new ON- and OFF-switches.

Date: 2021
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DOI: 10.1038/s41467-021-25735-9

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