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Computational design of chemogenetic and optogenetic split proteins

Author

Listed:
  • Onur Dagliyan

    (University of North Carolina at Chapel Hill
    University of North Carolina at Chapel Hill
    University of North Carolina at Chapel Hill
    Harvard Medical School)

  • Andrey Krokhotin

    (University of North Carolina at Chapel Hill
    Stanford University School of Medicine)

  • Irem Ozkan-Dagliyan

    (University of North Carolina at Chapel Hill
    University of North Carolina at Chapel Hill)

  • Alexander Deiters

    (University of Pittsburgh)

  • Channing J. Der

    (University of North Carolina at Chapel Hill
    University of North Carolina at Chapel Hill)

  • Klaus M. Hahn

    (University of North Carolina at Chapel Hill
    University of North Carolina at Chapel Hill)

  • Nikolay V. Dokholyan

    (University of North Carolina at Chapel Hill
    University of North Carolina at Chapel Hill
    Penn State College of Medicine)

Abstract

Controlling protein activity with chemogenetics and optogenetics has proven to be powerful for testing hypotheses regarding protein function in rapid biological processes. Controlling proteins by splitting them and then rescuing their activity through inducible reassembly offers great potential to control diverse protein activities. Building split proteins has been difficult due to spontaneous assembly, difficulty in identifying appropriate split sites, and inefficient induction of effective reassembly. Here we present an automated approach to design effective split proteins regulated by a ligand or by light (SPELL). We develop a scoring function together with an engineered domain to enable reassembly of protein halves with high efficiency and with reduced spontaneous assembly. We demonstrate SPELL by applying it to proteins of various shapes and sizes in living cells. The SPELL server (spell.dokhlab.org) offers an automated prediction of split sites.

Suggested Citation

  • Onur Dagliyan & Andrey Krokhotin & Irem Ozkan-Dagliyan & Alexander Deiters & Channing J. Der & Klaus M. Hahn & Nikolay V. Dokholyan, 2018. "Computational design of chemogenetic and optogenetic split proteins," Nature Communications, Nature, vol. 9(1), pages 1-8, December.
    • Handle: RePEc:nat:natcom:v:9:y:2018:i:1:d:10.1038_s41467-018-06531-4
    DOI: 10.1038/s41467-018-06531-4
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    Cited by:

    1. Yashavantha L. Vishweshwaraiah & Jiaxing Chen & Venkat R. Chirasani & Erdem D. Tabdanov & Nikolay V. Dokholyan, 2021. "Two-input protein logic gate for computation in living cells," Nature Communications, Nature, vol. 12(1), pages 1-12, December.
    2. Zhong Guo & Rinky D. Parakra & Ying Xiong & Wayne A. Johnston & Patricia Walden & Selvakumar Edwardraja & Shayli Varasteh Moradi & Jacobus P. J. Ungerer & Hui-wang Ai & Jonathan J. Phillips & Kirill A, 2022. "Engineering and exploiting synthetic allostery of NanoLuc luciferase," Nature Communications, Nature, vol. 13(1), pages 1-12, December.
    3. Lauren Gambill & August Staubus & Kim Wai Mo & Andrea Ameruoso & James Chappell, 2023. "A split ribozyme that links detection of a native RNA to orthogonal protein outputs," Nature Communications, Nature, vol. 14(1), pages 1-12, December.

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