英国弗朗西斯·克里克研究所Edward W. Tate团队开发出一个棕榈酰转移酶化学遗传系统，用于绘制ZDHHC特异性S-酰基化图谱。2024年1月8日，《自然—生物技术》杂志在线发表了这项成果。

研究人员表示，23种含人类锌指Asp-His-His-Cys模体（ZDHHC）S-酰基转移酶催化半胱氨酸残基上的长链S-酰基化，它们广泛分布于数百种对正常生理起重要作用或在疾病中失调的蛋白质网络中。

研究人员介绍了一种在完整细胞中直接绘制特定ZDHHC蛋白底物全蛋白组水平图谱的技术。通过结构指导工程设计成对的ZDHHC“孔”突变体和“凸起的”化学标记脂肪酸探针，可以将探针转移到特定的蛋白质底物上，与野生型ZDHHC相比，具有极佳的选择性。

化学遗传系统为五种人类ZDHHC（3、7、11、15和20）提供了范例，并应用于生成新的ZDHHC底物图谱，在多个细胞系中为新的功能多样的蛋白质鉴定了超过300个底物和 S-酰基化位点。研究人员希望该平台能阐明多种模型和生物的S-酰基化生物学。

附：英文原文

Title: A palmitoyl transferase chemical–genetic system to map ZDHHC-specific S-acylation

Author: Ocasio, Cory A., Baggelaar, Marc P., Sipthorp, James, Losada de la Lastra, Ana, Tavares, Manuel, Volari, Jana, Soudy, Christelle, Storck, Elisabeth M., Houghton, Jack W., Palma-Duran, Susana A., MacRae, James I., Tomi, Goran, Carr, Lotte, Downward, Julian, Eggert, Ulrike S., Tate, Edward W.

Issue&Volume: 2024-01-08

Abstract: The 23 human zinc finger Asp-His-His-Cys motif-containing (ZDHHC) S-acyltransferases catalyze long-chain S-acylation at cysteine residues across an extensive network of hundreds of proteins important for normal physiology or dysregulated in disease. Here we present a technology to directly map the protein substrates of a specific ZDHHC at the whole-proteome level, in intact cells. Structure-guided engineering of paired ZDHHC ‘hole’ mutants and ‘bumped’ chemically tagged fatty acid probes enabled probe transfer to specific protein substrates with excellent selectivity over wild-type ZDHHCs. Chemical–genetic systems were exemplified for five human ZDHHCs (3, 7, 11, 15 and 20) and applied to generate de novo ZDHHC substrate profiles, identifying >300 substrates and S-acylation sites for new functionally diverse proteins across multiple cell lines. We expect that this platform will elucidate S-acylation biology for a wide range of models and organisms.

DOI: 10.1038/s41587-023-02030-0

Source: https://www.nature.com/articles/s41587-023-02030-0