Protein-based bandpass filters for controlling cellular signaling with chemical inputs

Abstract

Biological signal processing is vital for cellular function. Similar to electronic circuits, cells process signals via integrated mechanisms. In electronics, bandpass filters transmit frequencies with defined ranges, but protein-based counterparts for controlled responses are lacking in engineered biological systems. Here, we rationally design protein-based, chemically responsive bandpass filters (CBPs) showing OFF-ON-OFF patterns that respond to chemical concentrations within a specific range and reject concentrations outside that range. Employing structure-based strategies, we designed a heterodimeric construct that dimerizes in response to low concentrations of a small molecule (ON), and dissociates at high concentrations of the same molecule (OFF). The CBPs have a multidomain architecture in which we used known drug receptors, a computationally designed protein binder and small-molecule inhibitors. This modular system allows fine-tuning for optimal performance in terms of bandwidth, response, cutoff and fold changes. The CBPs were used to regulate cell surface receptor signaling pathways to control cellular activities in engineered cells.

Targeting protein-ligand neosurfaces using a generalizable deep learning approach

“…Chemically controllable components have important applications in synthetic biology and have been shown to be useful in modulating the activity of emerging cell-based therapies ( 10 , 11 , 47 ). To test whether our computationally designed CIDs would assemble in a more complex cellular context, we engineered reporter proximity-based systems that were expressed in cell-free system or mammalian cells and that in the presence of the small molecule could activate a signaling pathway or lead to the reconstitution of a reporter protein.…”