Scorpion α-toxin LqhαIT specifically interacts with a glycan at the pore domain of voltage-gated sodium channels

IF 4.4 2区生物学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY Structure Pub Date : 2024-08-23 DOI:10.1016/j.str.2024.07.021

Swastik Phulera, Callum J. Dickson, Christopher J. Schwalen, Maryam Khoshouei, Samantha J. Cassell, Yishan Sun, Tara Condos, Jonathan Whicher, Wilhelm A. Weihofen

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Abstract

Voltage-gated sodium (Nav) channels sense membrane potential and drive cellular electrical activity. The deathstalker scorpion α-toxin LqhαIT exerts a strong action potential prolonging effect on Nav channels. To elucidate the mechanism of action of LqhαIT, we determined a 3.9 Å cryoelectron microscopy (cryo-EM) structure of LqhαIT in complex with the Nav channel from Periplaneta americana (NavPas). We found that LqhαIT binds to voltage sensor domain 4 and traps it in an “S4 down” conformation. The functionally essential C-terminal epitope of LqhαIT forms an extensive interface with the glycan scaffold linked to Asn330 of NavPas that augments a small protein-protein interface between NavPas and LqhαIT. A combination of molecular dynamics simulations, structural comparisons, and prior mutagenesis experiments demonstrates the functional importance of this toxin-glycan interaction. These findings establish a structural basis for the specificity achieved by scorpion α-toxins and reveal the conserved glycan as an essential component of the toxin-binding epitope.

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蝎子α毒素 LqhαIT 与电压门控钠通道孔域的聚糖发生特异性相互作用

电压门控钠（Nav）通道能感知膜电位并驱动细胞电活动。死亡潜行者蝎子α毒素 LqhαIT 对 Nav 通道具有很强的延长动作电位的作用。为了阐明 LqhαIT 的作用机理，我们测定了 LqhαIT 与 Periplaneta americana 的 Nav 通道（NavPas）复合物的 3.9 Å 冷冻电镜（cryo-EM）结构。我们发现，LqhαIT 与电压传感器结构域 4 结合，并将其困在 "S4 向下 "构象中。LqhαIT 在功能上必不可少的 C 端表位与连接到 NavPas Asn330 的糖支架形成了一个广泛的界面，从而增强了 NavPas 与 LqhαIT 之间的小蛋白-蛋白界面。分子动力学模拟、结构比较和先前的诱变实验相结合，证明了这种毒素与聚糖相互作用的功能重要性。这些发现为蝎子α-毒素的特异性奠定了结构基础，并揭示了保守的聚糖是毒素结合表位的重要组成部分。

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来源期刊

Structure 生物-生化与分子生物学

CiteScore

8.90

自引率

1.80%

发文量

155

审稿时长

3-8 weeks

期刊介绍： Structure aims to publish papers of exceptional interest in the field of structural biology. The journal strives to be essential reading for structural biologists, as well as biologists and biochemists that are interested in macromolecular structure and function. Structure strongly encourages the submission of manuscripts that present structural and molecular insights into biological function and mechanism. Other reports that address fundamental questions in structural biology, such as structure-based examinations of protein evolution, folding, and/or design, will also be considered. We will consider the application of any method, experimental or computational, at high or low resolution, to conduct structural investigations, as long as the method is appropriate for the biological, functional, and mechanistic question(s) being addressed. Likewise, reports describing single-molecule analysis of biological mechanisms are welcome. In general, the editors encourage submission of experimental structural studies that are enriched by an analysis of structure-activity relationships and will not consider studies that solely report structural information unless the structure or analysis is of exceptional and broad interest. Studies reporting only homology models, de novo models, or molecular dynamics simulations are also discouraged unless the models are informed by or validated by novel experimental data; rationalization of a large body of existing experimental evidence and making testable predictions based on a model or simulation is often not considered sufficient.