N-myristoylation is a ubiquitous class of protein lipidation across eukaryotes and N-myristoyl transferase (NMT) has been proposed as an attractive drug target in several pathogens. Myristoylation often primes for subsequent palmitoylation and stable membrane attachment, however, growing evidence suggests additional regulatory roles for myristoylation on proteins. Here we describe the myristoylated proteome of Toxoplasma gondii using chemoproteomic methods and show that a small-molecule NMT inhibitor developed against related Plasmodium spp. is also functional in Toxoplasma. We identify myristoylation on a transmembrane protein, the microneme protein 7 (MIC7), which enters the secretory pathway in an unconventional fashion with the myristoylated N-terminus facing the lumen of the micronemes. MIC7 and its myristoylation play a crucial role in the initial steps of invasion, likely during the interaction with and penetration of the host cell. Myristoylation of secreted eukaryotic proteins represents a substantial expansion of the functional repertoire of this co-translational modification.

中文翻译：

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弓形虫肉豆蔻酰化分析揭示了一种对宿主细胞渗透很重要的 N-肉豆蔻酰化蛋白


N-肉豆蔻酰化是真核生物中普遍存在的一类蛋白质脂化，N-肉豆蔻酰转移酶（NMT）已被提议作为多种病原体中有吸引力的药物靶标。肉豆蔻酰化通常为随后的棕榈酰化和稳定的膜附着做好准备，然而，越来越多的证据表明肉豆蔻酰化对蛋白质具有额外的调节作用。在这里，我们使用化学蛋白质组学方法描述了弓形虫的肉豆蔻酰化蛋白质组，并表明针对相关疟原虫属开发了一种小分子 NMT 抑制剂。对弓形虫也有作用。我们鉴定了跨膜蛋白微线体蛋白 7 (MIC7) 上的肉豆蔻酰化，该蛋白以非常规方式进入分泌途径，肉豆蔻酰化的 N 末端面向微线体的内腔。 MIC7 及其肉豆蔻酰化在入侵的初始步骤中发挥着至关重要的作用，可能是在与宿主细胞相互作用和渗透过程中。分泌性真核蛋白的肉豆蔻酰化代表了这种共翻译修饰的功能库的实质性扩展。