EAT-18 is an essential auxiliary protein interacting with the non-alpha nAChR subunit EAT-2 to form a functional receptor
EAT-18 is an essential auxiliary protein interacting with the non-alpha nAChR subunit EAT-2 to form a functional receptor
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DOI：
10.1371/journal.ppat.1008396
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发表时间：
2020-04-01
期刊：
影响因子：
6.7
通讯作者：
Robertson, Alan P.
中科院分区：
文献类型：
--
作者：
Choudhary, Shivani;Buxton, Samuel K.;Robertson, Alan P.
线虫寄生虫感染了全球约15亿人，是一个重大的公共卫生问题。人们普遍需要新的、更有效的驱虫药。寄生虫神经和躯体肌肉上的烟碱型乙酰胆碱受体是拟胆碱类驱虫剂的靶标，而线虫咽部的谷氨酸门控氯通道则受到阿维菌素的影响。在这里，我们描述了一种新的烟碱型乙酰胆碱受体，它位于线虫咽部，是一种潜在的新药靶点。这种同聚体受体由5个非α-EAT-2亚基组成，对现有的胆碱类驱虫药不敏感。我们发现，EAT-18是一种新的辅助亚单位蛋白，对受体的功能表达是必不可少的。EAT-18直接与成熟受体相互作用，不同的同源物改变药理特性。因此，我们不仅描述了一种新的潜在的药物靶点，而且还描述了一种新型的nAChRs专有辅助蛋白。作者概述土壤传播的蠕虫影响大约四分之一的世界人口。化学驱虫剂不仅缓解了对人类和动物健康的威胁，而且还改善了农业经济和粮食安全。在这里，我们已经确定了一个“可用药的”烟碱型乙酰胆碱受体(NAChR)亚单位，EAT-2，它构成了线虫的咽胆碱能受体。该受体是摄食所必需的，也可能是蠕虫繁殖行为所必需的。针对这种nAChR的选择性治疗化合物应该要么让蠕虫挨饿，要么让它们行动迟缓，有助于更快地从宿主中排出。EAT-2咽部nAChR是一种独特的受体，由5个非α亚基组成，在配体结合环-C中缺乏邻近的半胱氨酸。到目前为止，所有的阳离子选择性nAChRs都含有至少两个α亚基。由于进化的改变，EAT-2亚基可能保留了邻近半胱氨酸的功能，并表达为一种新的nAChR亚型，与基于脊椎动物受体研究的既定教条不符。我们的发现还发现了一种新的辅助蛋白亚基，它对咽部nAChR的功能表达是必不可少的，并调节其药理学。据我们所知，这是第一次报道在任何环状配体门控离子通道中进行功能表达所必需的辅助蛋白。
Nematode parasites infect approximately 1.5 billion people globally and are a significant public health concern. There is an accepted need for new, more effective anthelmintic drugs. Nicotinic acetylcholine receptors on parasite nerve and somatic muscle are targets of the cholinomimetic anthelmintics, while glutamate-gated chloride channels in the pharynx of the nematode are affected by the avermectins. Here we describe a novel nicotinic acetylcholine receptor on the nematode pharynx that is a potential new drug target. This homomeric receptor is comprised of five non-alpha EAT-2 subunits and is not sensitive to existing cholinomimetic anthelmintics. We found that EAT-18, a novel auxiliary subunit protein, is essential for functional expression of the receptor. EAT-18 directly interacts with the mature receptor, and different homologs alter the pharmacological properties. Thus we have described not only a novel potential drug target but also a new type of obligate auxiliary protein for nAChRs.Author summarySoil-transmitted helminths affect about a quarter of the worlds' population. Chemical anthelmintics not only alleviate the threat to human and animal health but also improve agricultural economics and food security. Here we have identified a "druggable" nicotinic acetylcholine receptor (nAChR) subunit, EAT-2, that constitutes the pharyngeal cholinergic receptor in nematodes. The receptor is required for feeding and possibly for reproductive behavior in worms. A selective therapeutic compound targeting this nAChR should either starve the worms or make them sluggish, helping with faster expulsion from the host. The EAT-2 pharyngeal nAChR is a unique receptor formed by five non-alpha subunits that lack vicinal cysteines in the ligand binding loop-C. To date, all cation selective nAChRs contain at least two alpha subunits. It is possible that EAT-2 subunits have retained functionality without the vicinal cysteines due to evolutionary modifications and expresses as a new nAChR subtype which doesn't fit the established dogma based on the study of vertebrate receptors. Our findings also identified a new type of auxiliary protein subunit, which is essential for functional expression of the pharyngeal nAChR and also modulates its pharmacology. To the best of our knowledge, this is the first report of an auxiliary protein that is essential for functional expression in any cys-loop ligand-gated ion channel.