Computational design of a modular protein sense-response system

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Science  22 Nov 2019:
Vol. 366, Issue 6468, pp. 1024-1028
DOI: 10.1126/science.aax8780

Sense and respond

Many signaling pathways start with cellular proteins sensing and responding to small molecules. Despite advances in protein design, creating a protein-based sense-and-respond system remains challenging. Glasgow et al. designed binding sites at the interface of protein heterodimers (see the Perspective by Chica). By fusing each monomer to one half of a split reporter, they linked ligand-driven dimerization to the reporter output. The computational design strategy provides a generalizable approach to create synthetic sensing systems with different outputs.

Science, this issue p. 1024; see also p. 952


Sensing and responding to signals is a fundamental ability of living systems, but despite substantial progress in the computational design of new protein structures, there is no general approach for engineering arbitrary new protein sensors. Here, we describe a generalizable computational strategy for designing sensor-actuator proteins by building binding sites de novo into heterodimeric protein-protein interfaces and coupling ligand sensing to modular actuation through split reporters. Using this approach, we designed protein sensors that respond to farnesyl pyrophosphate, a metabolic intermediate in the production of valuable compounds. The sensors are functional in vitro and in cells, and the crystal structure of the engineered binding site closely matches the design model. Our computational design strategy opens broad avenues to link biological outputs to new signals.

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