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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.

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


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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