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Nat Commun. 2018 Nov 29;9(1):5057. doi: 10.1038/s41467-018-07610-2.

A scalable peptide-GPCR language for engineering multicellular communication.

Author information

1
Department of Chemistry, Columbia University, New York, New York, 10027, USA.
2
Institute for Systems Genetics and Department of Biochemistry and Molecular Pharmacology, NYU Langone Health, 430 East 29th Street, New York, 10016, USA.
3
The Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, Massachusetts, 02139, USA.
4
Department of Chemistry, Columbia University, New York, New York, 10027, USA. vc114@columbia.edu.
5
Department of Systems Biology, Columbia University, New York, New York, 10032, USA. vc114@columbia.edu.

Abstract

Engineering multicellularity is one of the next breakthroughs for Synthetic Biology. A key bottleneck to building multicellular systems is the lack of a scalable signaling language with a large number of interfaces that can be used simultaneously. Here, we present a modular, scalable, intercellular signaling language in yeast based on fungal mating peptide/G-protein-coupled receptor (GPCR) pairs harnessed from nature. First, through genome-mining, we assemble 32 functional peptide-GPCR signaling interfaces with a range of dose-response characteristics. Next, we demonstrate that these interfaces can be combined into two-cell communication links, which serve as assembly units for higher-order communication topologies. Finally, we show 56 functional, two-cell links, which we use to assemble three- to six-member communication topologies and a three-member interdependent community. Importantly, our peptide-GPCR language is scalable and tunable by genetic encoding, requires minimal component engineering, and should be massively scalable by further application of our genome mining pipeline or directed evolution.

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