Nanobody-thioesterase chimeras to specifically target protein palmitoylation

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 and William Fuller ()
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Chien-Wen Kuo: University of Glasgow
Caglar Gök: University of Glasgow
Hannah Fulton: University of Glasgow
Eleanor Dickson-Murray: University of Glasgow
Samuel Adu: University of Glasgow
Emily K. Gallen: University of Glasgow
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

Nature Communications, 2025, vol. 16, issue 1, 1-13

Abstract: 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.

Date: 2025
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DOI: 10.1038/s41467-025-56716-x

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