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Nanobody-thioesterase chimeras to specifically target protein palmitoylation

Author

Listed:
  • Chien-Wen Kuo

    (University of Glasgow)

  • Caglar Gök

    (University of Glasgow
    University of Lincoln)

  • Hannah Fulton

    (University of Glasgow)

  • Eleanor Dickson-Murray

    (University of Glasgow)

  • Samuel Adu

    (University of Glasgow)

  • Emily K. Gallen

    (University of Glasgow
    Harvard Medical School)

  • Sheon Mary

    (University of Glasgow)

  • Alan D. Robertson

    (University of Glasgow)

  • Fiona Jordan

    (University of Glasgow)

  • Emma Dunning

    (University of Glasgow)

  • William Mullen

    (University of Glasgow)

  • Godfrey L. Smith

    (University of Glasgow)

  • William Fuller

    (University of Glasgow)

Abstract

The complexity of the cellular proteome is massively expanded by a repertoire of chemically distinct reversible post-translational modifications (PTMs) that control protein localisation, interactions, and function. The temporal and spatial control of these PTMs is central to organism physiology, and mis-regulation of PTMs is a hallmark of many diseases. Here we present an approach to manipulate PTMs on target proteins using nanobodies fused to enzymes that control these PTMs. Anti-GFP nanobodies fused to thioesterases (which depalmitoylate protein cysteines) depalmitoylate GFP tagged substrates. A chemogenetic approach to enhance nanobody affinity for its target enables temporal control of target depalmitoylation. Using a thioesterase fused to a nanobody directed against the Ca(v)1.2 beta subunit we reduce palmitoylation of the Ca(v)1.2 alpha subunit, modifying the channel’s voltage dependence and arrhythmia susceptibility in stem cell derived cardiac myocytes. We conclude that nanobody enzyme chimeras represent an approach to specifically manipulate PTMs, with applications in both the laboratory and the clinic.

Suggested Citation

  • Chien-Wen Kuo & Caglar Gök & Hannah Fulton & Eleanor Dickson-Murray & Samuel Adu & Emily K. Gallen & Sheon Mary & Alan D. Robertson & Fiona Jordan & Emma Dunning & William Mullen & Godfrey L. Smith & , 2025. "Nanobody-thioesterase chimeras to specifically target protein palmitoylation," Nature Communications, Nature, vol. 16(1), pages 1-13, December.
    • Handle: RePEc:nat:natcom:v:16:y:2025:i:1:d:10.1038_s41467-025-56716-x
    DOI: 10.1038/s41467-025-56716-x
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    References listed on IDEAS

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    1. Xiaofeng Sun & Chengjian Zhou & Simin Xia & Xi Chen, 2023. "Small molecule-nanobody conjugate induced proximity controls intracellular processes and modulates endogenous unligandable targets," Nature Communications, Nature, vol. 14(1), pages 1-16, December.
    2. Kimberly L. Dodge-Kafka & Joseph Soughayer & Genevieve C. Pare & Jennifer J. Carlisle Michel & Lorene K. Langeberg & Michael S. Kapiloff & John D. Scott, 2005. "The protein kinase A anchoring protein mAKAP coordinates two integrated cAMP effector pathways," Nature, Nature, vol. 437(7058), pages 574-578, September.
    3. Zifan Pei & Yucheng Xiao & Jingwei Meng & Andy Hudmon & Theodore R. Cummins, 2016. "Cardiac sodium channel palmitoylation regulates channel availability and myocyte excitability with implications for arrhythmia generation," Nature Communications, Nature, vol. 7(1), pages 1-13, November.
    4. Guoxia Liu & Arianne Papa & Alexander N. Katchman & Sergey I. Zakharov & Daniel Roybal & Jessica A. Hennessey & Jared Kushner & Lin Yang & Bi-Xing Chen & Alexander Kushnir & Katerina Dangas & Steven P, 2020. "Mechanism of adrenergic CaV1.2 stimulation revealed by proximity proteomics," Nature, Nature, vol. 577(7792), pages 695-700, January.
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