RT Journal Article
SR Electronic
T1 Computational design of a modular protein sense/response system
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 648485
DO 10.1101/648485
A1 Anum A. Glasgow
A1 Yao-Ming Huang
A1 Daniel J. Mandell
A1 Michael Thompson
A1 Ryan Ritterson
A1 Amanda L. Loshbaugh
A1 Jenna Pellegrino
A1 Cody Krivacic
A1 Roland A. Pache
A1 Kyle A. Barlow
A1 Noah Ollikainen
A1 Deborah Jeon
A1 Mark J. S. Kelly
A1 James S. Fraser
A1 Tanja Kortemme
YR 2019
UL http://biorxiv.org/content/early/2019/05/24/648485.abstract
AB Sensing and responding to signals is a fundamental ability of living systems, but despite remarkable progress in 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 via 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 matches the design model with atomic accuracy. Our computational design strategy opens broad avenues to link biological outputs to new signals.One Sentence Summary An engineering strategy to design modular synthetic signaling systems that respond to new small molecule inputs.