Two-input protein logic gate for computation in living cells

Yashavantha L. Vishweshwaraiah, Jiaxing Chen, Venkat R. Chirasani, Erdem D. Tabdanov and Nikolay V. Dokholyan ()
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Yashavantha L. Vishweshwaraiah: Penn State College of Medicine
Jiaxing Chen: Penn State College of Medicine
Venkat R. Chirasani: Penn State College of Medicine
Erdem D. Tabdanov: Penn State College of Medicine
Nikolay V. Dokholyan: Penn State College of Medicine

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

Abstract: Abstract Advances in protein design have brought us within reach of developing a nanoscale programming language, in which molecules serve as operands and their conformational states function as logic gates with precise input and output behaviors. Combining these nanoscale computing agents into larger molecules and molecular complexes will allow us to write and execute “code”. Here, in an important step toward this goal, we report an engineered, single protein design that is allosterically regulated to function as a ‘two-input logic OR gate’. Our system is based on chemo- and optogenetic regulation of focal adhesion kinase. In the engineered FAK, all of FAK domain architecture is retained and key intramolecular interactions between the kinase and the FERM domains are externally controlled through a rapamycin-inducible uniRapR module in the kinase domain and a light-inducible LOV2 module in the FERM domain. Orthogonal regulation of protein function was possible using the chemo- and optogenetic switches. We demonstrate that dynamic FAK activation profoundly increased cell multiaxial complexity in the fibrous extracellular matrix microenvironment and decreased cell motility. This work provides proof-of-principle for fine multimodal control of protein function and paves the way for construction of complex nanoscale computing agents.

Date: 2021
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DOI: 10.1038/s41467-021-26937-x

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