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Phosphoregulated orthogonal signal transduction in mammalian cells

Author

Listed:
  • Leo Scheller

    (ETH Zurich
    École Polytechnique Fédérale de Lausanne)

  • Marc Schmollack

    (ETH Zurich
    Technical University of Munich)

  • Adrian Bertschi

    (ETH Zurich)

  • Maysam Mansouri

    (ETH Zurich)

  • Pratik Saxena

    (ETH Zurich)

  • Martin Fussenegger

    (ETH Zurich
    Faculty of Science)

Abstract

Orthogonal tools for controlling protein function by post-translational modifications open up new possibilities for protein circuit engineering in synthetic biology. Phosphoregulation is a key mechanism of signal processing in all kingdoms of life, but tools to control the involved processes are very limited. Here, we repurpose components of bacterial two-component systems (TCSs) for chemically induced phosphotransfer in mammalian cells. TCSs are the most abundant multi-component signal-processing units in bacteria, but are not found in the animal kingdom. The presented phosphoregulated orthogonal signal transduction (POST) system uses induced nanobody dimerization to regulate the trans-autophosphorylation activity of engineered histidine kinases. Engineered response regulators use the phosphohistidine residue as a substrate to autophosphorylate an aspartate residue, inducing their own homodimerization. We verify this approach by demonstrating control of gene expression with engineered, dimerization-dependent transcription factors and propose a phosphoregulated relay system of protein dimerization as a basic building block for next-generation protein circuits.

Suggested Citation

  • Leo Scheller & Marc Schmollack & Adrian Bertschi & Maysam Mansouri & Pratik Saxena & Martin Fussenegger, 2020. "Phosphoregulated orthogonal signal transduction in mammalian cells," Nature Communications, Nature, vol. 11(1), pages 1-10, December.
  • Handle: RePEc:nat:natcom:v:11:y:2020:i:1:d:10.1038_s41467-020-16895-1
    DOI: 10.1038/s41467-020-16895-1
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    Cited by:

    1. Yuan Liang & Yunkai Qie & Jing Yang & Ranfeng Wu & Shuang Cui & Yuliang Zhao & Greg J. Anderson & Guangjun Nie & Suping Li & Cheng Zhang, 2023. "Programming conformational cooperativity to regulate allosteric protein-oligonucleotide signal transduction," Nature Communications, Nature, vol. 14(1), pages 1-13, December.
    2. Ross D. Jones & Yili Qian & Katherine Ilia & Benjamin Wang & Michael T. Laub & Domitilla Del Vecchio & Ron Weiss, 2022. "Robust and tunable signal processing in mammalian cells via engineered covalent modification cycles," Nature Communications, Nature, vol. 13(1), pages 1-17, December.
    3. Yuanli Gao & Lei Wang & Baojun Wang, 2023. "Customizing cellular signal processing by synthetic multi-level regulatory circuits," Nature Communications, Nature, vol. 14(1), pages 1-14, December.

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