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De novo design of bioactive protein switches

Author

Listed:
  • Robert A. Langan

    (University of Washington
    University of Washington
    University of Washington)

  • Scott E. Boyken

    (University of Washington
    University of Washington)

  • Andrew H. Ng

    (University of California, San Francisco
    University of California, Berkeley
    The UC Berkeley–UCSF Graduate Program in Bioengineering, UCSF
    The UC Berkeley–UCSF Graduate Program in Bioengineering, UC Berkeley)

  • Jennifer A. Samson

    (University of California, Berkeley)

  • Galen Dods

    (University of California, San Francisco)

  • Alexandra M. Westbrook

    (University of California, San Francisco)

  • Taylor H. Nguyen

    (University of California, San Francisco)

  • Marc J. Lajoie

    (University of Washington
    University of Washington)

  • Zibo Chen

    (University of Washington
    University of Washington
    University of Washington)

  • Stephanie Berger

    (University of Washington
    University of Washington)

  • Vikram Khipple Mulligan

    (University of Washington
    University of Washington)

  • John E. Dueber

    (University of California, Berkeley)

  • Walter R. P. Novak

    (Wabash College)

  • Hana El-Samad

    (University of California, San Francisco
    Chan-Zuckerberg Biohub)

  • David Baker

    (University of Washington
    University of Washington
    University of Washington)

Abstract

Allosteric regulation of protein function is widespread in biology, but is challenging for de novo protein design as it requires the explicit design of multiple states with comparable free energies. Here we explore the possibility of designing switchable protein systems de novo, through the modulation of competing inter- and intramolecular interactions. We design a static, five-helix ‘cage’ with a single interface that can interact either intramolecularly with a terminal ‘latch’ helix or intermolecularly with a peptide ‘key’. Encoded on the latch are functional motifs for binding, degradation or nuclear export that function only when the key displaces the latch from the cage. We describe orthogonal cage–key systems that function in vitro, in yeast and in mammalian cells with up to 40-fold activation of function by key. The ability to design switchable protein functions that are controlled by induced conformational change is a milestone for de novo protein design, and opens up new avenues for synthetic biology and cell engineering.

Suggested Citation

  • Robert A. Langan & Scott E. Boyken & Andrew H. Ng & Jennifer A. Samson & Galen Dods & Alexandra M. Westbrook & Taylor H. Nguyen & Marc J. Lajoie & Zibo Chen & Stephanie Berger & Vikram Khipple Mulliga, 2019. "De novo design of bioactive protein switches," Nature, Nature, vol. 572(7768), pages 205-210, August.
  • Handle: RePEc:nat:nature:v:572:y:2019:i:7768:d:10.1038_s41586-019-1432-8
    DOI: 10.1038/s41586-019-1432-8
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    Cited by:

    1. Akter, Shahriar & Dwivedi, Yogesh K. & Sajib, Shahriar & Biswas, Kumar & Bandara, Ruwan J. & Michael, Katina, 2022. "Algorithmic bias in machine learning-based marketing models," Journal of Business Research, Elsevier, vol. 144(C), pages 201-216.
    2. Zhihong Xiao & Jinyin Zha & Xu Yang & Tingting Huang & Shuxin Huang & Qi Liu & Xiaozheng Wang & Jie Zhong & Jianting Zheng & Rubing Liang & Zixin Deng & Jian Zhang & Shuangjun Lin & Shaobo Dai, 2024. "A three-level regulatory mechanism of the aldo-keto reductase subfamily AKR12D," Nature Communications, Nature, vol. 15(1), pages 1-15, December.
    3. Migchelbrink, Koen & Raymaekers, Pieter, 2023. "Nudging people to pay their parking fines on time. Evidence from a cluster-randomized field experiment," Journal of Behavioral and Experimental Economics (formerly The Journal of Socio-Economics), Elsevier, vol. 105(C).
    4. Yasmine S. Zubi & Kosuke Seki & Ying Li & Andrew C. Hunt & Bingqing Liu & Benoît Roux & Michael C. Jewett & Jared C. Lewis, 2022. "Metal-responsive regulation of enzyme catalysis using genetically encoded chemical switches," Nature Communications, Nature, vol. 13(1), pages 1-10, December.
    5. Willow Coyote-Maestas & David Nedrud & Antonio Suma & Yungui He & Kenneth A. Matreyek & Douglas M. Fowler & Vincenzo Carnevale & Chad L. Myers & Daniel Schmidt, 2021. "Probing ion channel functional architecture and domain recombination compatibility by massively parallel domain insertion profiling," Nature Communications, Nature, vol. 12(1), pages 1-16, December.
    6. Shodai Komatsu & Hirohisa Ohno & Hirohide Saito, 2023. "Target-dependent RNA polymerase as universal platform for gene expression control in response to intracellular molecules," Nature Communications, Nature, vol. 14(1), pages 1-11, December.
    7. 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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