Apr 18, 2020

Elucidation and refinement of synthetic receptor mechanisms

BioRxiv : the Preprint Server for Biology
H. I. EdelsteinJoshua Nathaniel Leonard

Abstract

Synthetic receptors are powerful tools for engineering mammalian cell-based devices. These biosensors confer unique capabilities for detecting environmental ligands and transducing signals to control downstream gene expression events such as therapeutic protein production. For many applications, it would be useful to understand how receptor design choices impart desirable performance metrics and trade-offs. Towards this goal, we employed the existing modular extracellular sensor architecture (MESA) and systematically characterized biosensors with previously unexamined protein domain choices. A key finding that might extend to other receptor systems is that choice of transmembrane domain (TMD) is highly consequential. To provide mechanistic insights, we adopted and employed a FRET-based assay to elucidate how TMDs affect receptor complex formation and connected these observations to functional performance. To build further insight into these phenomena, we developed a library of new MESA receptors that sense an expanded set of ligands. Based upon these explorations, we conclude that TMDs affect signaling primarily by modulating intracellular domain geometry, and we apply this understanding to rationally tune receptors. Finally, t...Continue Reading

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Mentioned in this Paper

In Vivo
Virus
Genome
Virus Replication
Cell Culture Techniques
Site
Deep Sequencing
Structure
Whole Genome Sequencing
Regulatory Sequences, Nucleic Acid

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