Evolution of cullin E3 ubiquitin ligases and function in trypanosomes
Evolution of cullin E3 ubiquitin ligases and function in trypanosomes
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DOI：
10.1101/2023.07.24.550360
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发表时间：
2023-07
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影响因子：
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通讯作者：
R. C. del Pino;M. Zoltner;Kayo Yamada;Erin R Butterfield;Mark C. Field
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作者：
R. C. del Pino;M. Zoltner;Kayo Yamada;Erin R Butterfield;Mark C. Field
翻译后修饰（PTM）调节蛋白质功能，其中泛素化是蛋白质周转中的主要作用的突出例子。泛素化利用连接酶级联将泛素缀合至客户蛋白，并且cullin-RING连接酶是已知最复杂的。我们重建进化的cullin-RING E3泛素连接酶在真核生物和实验特征的两个cullin复合体锥虫，高度分化的动物和真菌的分类。我们发现相当大的多样性内cullin，特别是锥虫与其他谱系只有少数cullin。此外，我们确定了cullin客户端适配器蛋白家族的扩展，新的客户端适配器，并证明了客户端特异性。最后，我们表明，鸟氨酸脱羧酶（TbODC），药物锥虫依氟鸟氨酸的一个重要目标，是TbCul-A的底物，并推翻了依氟鸟氨酸特异性的早期模型。这些研究强调了cullin E3的谱系特异性作用及其对真核生物复杂性的贡献。
Post-translational modifications (PTMs) modulate protein function, with ubiquitylation a pre-eminent example with major roles in protein turnover. Ubiquitylation utilises a ligase enzyme cascade for conjugation of ubiquitin to client proteins and cullin-RING ligases are amongst the most complex known. We reconstructed evolution of cullin-RING E3 ubiquitin ligases across eukaryotes and experimentally characterised two cullin complexes in trypanosomatids, a taxon highly divergent from animals and fungi. We find considerable diversity within cullins and, in particular, trypanosomatids share only a minority of cullins with other lineages. Furthermore, we identify expansions in cullin client adaptor protein families, novel client adaptors and demonstrate client specificity. Finally we show that ornithine decarboxylase (TbODC), an important target of the drug trypanosome eflornithine, is a substrate for TbCul-A and overturn earlier models for eflornithine specificity. These studies highlight lineage-specific roles for cullin E3s and their contributions towards eukaryotic complexity.