Profiling of myristoylation in Toxoplasma gondii reveals an N-myristoylated protein important for host cell penetration
Profiling of myristoylation in Toxoplasma gondii reveals an N-myristoylated protein important for host cell penetration
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DOI：
10.7554/elife.57861
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发表时间：
2020-07-03
期刊：
影响因子：
7.7
通讯作者：
Treeck, Moritz
中科院分区：
文献类型：
--
作者：
Broncel, Malgorzata;Dominicus, Caia;Treeck, Moritz
N-肉豆蔻酰化是真核生物中普遍存在的一类蛋白质脂化反应，N-肉豆蔻酰转移酶(NMT)已被认为是多种病原体的药物靶点。肉豆蔻化通常是随后的棕榈酰化和稳定的膜附着的基础，然而，越来越多的证据表明，肉豆蔻化对蛋白质具有额外的调节作用。在这里，我们用化学蛋白质组学的方法描述了弓形虫的肉豆蔻酰化蛋白质组，并展示了一种小分子NMT抑制剂对相关疟原虫的抑制作用。在弓形虫中也有作用。我们鉴定了一种跨膜蛋白--微线蛋白7(MIC7)上的肉豆蔻酰化，它以一种非常规的方式进入分泌途径，肉豆蔻化的N-末端面对微线条的管腔。MIC7及其肉豆蔻酰化在侵袭的最初步骤中起着至关重要的作用，可能是在与宿主细胞相互作用和穿透的过程中。分泌的真核蛋白的肉豆蔻酰化代表了这种共翻译修饰的功能谱的实质性扩展。
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.