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A Genetically Encodable and Chemically Disruptable System for Synthetic Post-Translational Modification Dependent Signaling

Jeffrey B. McMahan, View ORCID ProfileJohn T. Ngo
doi: https://doi.org/10.1101/2022.05.29.493928
Jeffrey B. McMahan
1Department of Biomedical Engineering and Biological Design Center, Boston University, Boston, MA 02215, USA
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John T. Ngo
1Department of Biomedical Engineering and Biological Design Center, Boston University, Boston, MA 02215, USA
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  • ORCID record for John T. Ngo
  • For correspondence: jtngo@bu.edu
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ABSTRACT

We describe an engineered “writer/reader” framework for programming post-translational control into synthetic mammalian signaling proteins. In this approach, a bacterially-derived biotin protein ligase (BirA) was used as a “writer” element for the modification of artificial receptors and transcription factors containing a biotin acceptor peptide (AP) fusion tag. To enable modification events to transmit biochemical information, we designed encodable “reader” modules using sequences from a biotinamide-binding antibody. Proteins fused to reader domains were able to interact with AP-tagged polypeptides in a biotinylation-dependent manner, and control over the timing and extent of these interactions could be modulated through both genetic and chemically-based strategies. Genetic and cell-specific control over AP-reader module interactions was achieved via regulated BirA expression, and the interaction states of both intra-and inter-cellular complexes could be modulated with biotinamide-based and bioorthogonally-functionalized compounds. The utility of this approach was demonstrated by installing post-translational and chemogenetic control into synthetic Notch (“SynNotch”)-based systems.

Competing Interest Statement

JTN is an inventor on a patent related to the work described herein.

Copyright 
The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. All rights reserved. No reuse allowed without permission.
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Posted May 30, 2022.
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A Genetically Encodable and Chemically Disruptable System for Synthetic Post-Translational Modification Dependent Signaling
Jeffrey B. McMahan, John T. Ngo
bioRxiv 2022.05.29.493928; doi: https://doi.org/10.1101/2022.05.29.493928
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A Genetically Encodable and Chemically Disruptable System for Synthetic Post-Translational Modification Dependent Signaling
Jeffrey B. McMahan, John T. Ngo
bioRxiv 2022.05.29.493928; doi: https://doi.org/10.1101/2022.05.29.493928

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