Transport and inhibition of the sphingosine-1-phosphate exporter SPNS2

IF 14.7 1区 综合性期刊 Q1 MULTIDISCIPLINARY SCIENCES Nature Communications Pub Date : 2025-01-16 DOI:10.1038/s41467-025-55942-7
Huanyu Z. Li, Ashley C. W. Pike, Yung-Ning Chang, Dheeraj Prakaash, Zuzana Gelova, Josefina Stanka, Christophe Moreau, Hannah C. Scott, Frank Wunder, Gernot Wolf, Andreea Scacioc, Gavin McKinley, Helena Batoulis, Shubhashish Mukhopadhyay, Andrea Garofoli, Adán Pinto-Fernández, Benedikt M. Kessler, Nicola A. Burgess-Brown, Saša Štefanić, Tabea Wiedmer, Katharina L. Dürr, Vera Puetter, Alexander Ehrmann, Syma Khalid, Alvaro Ingles-Prieto, Giulio Superti-Furga, David B. Sauer
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Abstract

Sphingosine-1-phosphate (S1P) is a signaling lysolipid critical to heart development, immunity, and hearing. Accordingly, mutations in the S1P transporter SPNS2 are associated with reduced white cell count and hearing defects. SPNS2 also exports the S1P-mimicking FTY720-P (Fingolimod) and thereby is central to the pharmacokinetics of this drug when treating multiple sclerosis. Here, we use a combination of cryo-electron microscopy, immunofluorescence, in vitro binding and in vivo S1P export assays, and molecular dynamics simulations to probe SPNS2’s substrate binding and transport. These results reveal the transporter’s binding mode to its native substrate S1P, the therapeutic FTY720-P, and the reported SPNS2-targeting inhibitor 33p. Further capturing an inward-facing apo state, our structures illuminate the protein’s mechanism for exchange between inward-facing and outward-facing conformations. Finally, using these structural, localization, and S1P transport results, we identify how pathogenic mutations ablate the protein’s export activity and thereby lead to hearing loss.

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鞘氨醇-1-磷酸输出基因SPNS2的转运和抑制作用
Sphingosine-1-phosphate(S1P)是一种信号溶脂,对心脏发育、免疫和听力至关重要。因此,S1P 转运体 SPNS2 的突变与白细胞数量减少和听力缺陷有关。SPNS2 还能输出模拟 S1P 的 FTY720-P(芬戈莫德),因此在治疗多发性硬化症时对该药物的药代动力学至关重要。在这里,我们结合使用了冷冻电镜、免疫荧光、体外结合和体内 S1P 输出试验以及分子动力学模拟来探究 SPNS2 的底物结合和转运。这些结果揭示了该转运体与其原生底物 S1P、治疗药物 FTY720-P 以及报道的 SPNS2 靶向抑制剂 33p 的结合模式。我们的结构进一步捕捉到了内向apo状态,阐明了蛋白质在内向构象和外向构象之间的交换机制。最后,利用这些结构、定位和 S1P 转运结果,我们确定了致病突变如何削弱该蛋白的输出活性,从而导致听力损失。
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来源期刊
Nature Communications
Nature Communications Biological Science Disciplines-
CiteScore
24.90
自引率
2.40%
发文量
6928
审稿时长
3.7 months
期刊介绍: Nature Communications, an open-access journal, publishes high-quality research spanning all areas of the natural sciences. Papers featured in the journal showcase significant advances relevant to specialists in each respective field. With a 2-year impact factor of 16.6 (2022) and a median time of 8 days from submission to the first editorial decision, Nature Communications is committed to rapid dissemination of research findings. As a multidisciplinary journal, it welcomes contributions from biological, health, physical, chemical, Earth, social, mathematical, applied, and engineering sciences, aiming to highlight important breakthroughs within each domain.
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