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Design of protein switches based on an ensemble model of allostery

Author

Listed:
  • Jay H. Choi

    (Johns Hopkins University)

  • Abigail H. Laurent

    (Johns Hopkins University)

  • Vincent J. Hilser

    (Johns Hopkins University)

  • Marc Ostermeier

    (Johns Hopkins University)

Abstract

Switchable proteins that can be regulated through exogenous or endogenous inputs have a broad range of biotechnological and biomedical applications. Here we describe the design of switchable enzymes based on an ensemble allosteric model. First, we insert an enzyme domain into an effector-binding domain such that both domains remain functionally intact. Second, we induce the fusion to behave as a switch through the introduction of conditional conformational flexibility designed to increase the conformational entropy of the enzyme domain in a temperature- or pH-dependent fashion. We confirm the switching behaviour in vitro and in vivo. Structural and thermodynamic studies support the hypothesis that switching result from an increase in conformational entropy of the enzyme domain in the absence of effector. These results support the ensemble model of allostery and embody a strategy for the design of protein switches.

Suggested Citation

  • Jay H. Choi & Abigail H. Laurent & Vincent J. Hilser & Marc Ostermeier, 2015. "Design of protein switches based on an ensemble model of allostery," Nature Communications, Nature, vol. 6(1), pages 1-9, November.
    • Handle: RePEc:nat:natcom:v:6:y:2015:i:1:d:10.1038_ncomms7968
    DOI: 10.1038/ncomms7968
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    Cited by:

    1. 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.
    2. Luhao Zhang & Maodong Li & Zhirong Liu, 2018. "A comprehensive ensemble model for comparing the allosteric effect of ordered and disordered proteins," PLOS Computational Biology, Public Library of Science, vol. 14(12), pages 1-22, December.
    3. Heonjoon Lee & Tian Xie & Byunghwa Kang & Xinjie Yu & Samuel W. Schaffter & Rebecca Schulman, 2024. "Plug-and-play protein biosensors using aptamer-regulated in vitro transcription," Nature Communications, Nature, vol. 15(1), pages 1-11, December.

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