一个以前未被识别的大锥虫毒素超家族包括感觉神经元钙通道Cav2.3抑制剂。

IF 7.8 1区 生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY PLoS Biology Pub Date : 2023-08-03 eCollection Date: 2023-08-01 DOI:10.1371/journal.pbio.3002217
Celeste M Hackney, Paula Flórez Salcedo, Emilie Mueller, Thomas Lund Koch, Lau D Kjelgaard, Maren Watkins, Linda G Zachariassen, Pernille Sønderby Tuelung, Jeffrey R McArthur, David J Adams, Anders S Kristensen, Baldomero Olivera, Rocio K Finol-Urdaneta, Helena Safavi-Hemami, Jens Preben Morth, Lars Ellgaard
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引用次数: 0

摘要

动物毒液肽是生物医学探索中有价值的化合物。海洋锥蜗牛的毒液构成了一种特别丰富的肽毒素来源,称为锥毒素。在这里,我们确定了一种异常大的芋螺毒素Mu8.1的序列,它定义了一类新的芋螺蛋白,在进化上与众所周知的芋螺素ikots和2个以前没有描述的另外的芋螺蛋白酶类有关。重组Mu8.1的晶体结构显示出saposin样折叠,并显示出与con-ikot-ikot的结构相似性。功能研究表明,Mu8.1抑制了特定类别的小鼠体感背根神经节(DRG)神经元中的钙流入。当在多种重组表达的电压门控离子通道上测试时,Mu8.1显示出对R型(Cav2.3)钙通道的最高效力。来自Mu8.1敏感DRG神经元的Ca2+信号也被SNX-482抑制,SNX-482是一种已知的Cav2.3和电压门控K+(Kv4)通道的蜘蛛肽调节剂。我们的发现强调了Mu8.1作为识别和研究表达Cav2.3的神经元亚类的分子工具的潜力。重要的是,这项多学科研究展示了在很大程度上未被探索的大锥虫毒素组中揭示新结构和生物活性的潜力。
本文章由计算机程序翻译,如有差异,请以英文原文为准。

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A previously unrecognized superfamily of macro-conotoxins includes an inhibitor of the sensory neuron calcium channel Cav2.3.

Animal venom peptides represent valuable compounds for biomedical exploration. The venoms of marine cone snails constitute a particularly rich source of peptide toxins, known as conotoxins. Here, we identify the sequence of an unusually large conotoxin, Mu8.1, which defines a new class of conotoxins evolutionarily related to the well-known con-ikot-ikots and 2 additional conotoxin classes not previously described. The crystal structure of recombinant Mu8.1 displays a saposin-like fold and shows structural similarity with con-ikot-ikot. Functional studies demonstrate that Mu8.1 curtails calcium influx in defined classes of murine somatosensory dorsal root ganglion (DRG) neurons. When tested on a variety of recombinantly expressed voltage-gated ion channels, Mu8.1 displayed the highest potency against the R-type (Cav2.3) calcium channel. Ca2+ signals from Mu8.1-sensitive DRG neurons were also inhibited by SNX-482, a known spider peptide modulator of Cav2.3 and voltage-gated K+ (Kv4) channels. Our findings highlight the potential of Mu8.1 as a molecular tool to identify and study neuronal subclasses expressing Cav2.3. Importantly, this multidisciplinary study showcases the potential of uncovering novel structures and bioactivities within the largely unexplored group of macro-conotoxins.

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来源期刊
PLoS Biology
PLoS Biology 生物-生化与分子生物学
CiteScore
14.40
自引率
2.00%
发文量
359
审稿时长
3 months
期刊介绍: PLOS Biology is an open-access, peer-reviewed general biology journal published by PLOS, a nonprofit organization of scientists and physicians dedicated to making the world's scientific and medical literature freely accessible. The journal publishes new articles online weekly, with issues compiled and published monthly. ISSN Numbers: eISSN: 1545-7885 ISSN: 1544-9173
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