Lys716 in the transmembrane domain of yeast mitofusin Fzo1 modulates anchoring and fusion

IF 4.4 2区生物学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY Structure Pub Date : 2024-09-18 DOI:10.1016/j.str.2024.08.017

Raphaëlle Versini, Marc Baaden, Laetitia Cavellini, Mickaël M. Cohen, Antoine Taly, Patrick F.J. Fuchs

引用次数: 0

Abstract

Outer mitochondrial membrane fusion, a vital cellular process, is mediated by mitofusins. However, the underlying molecular mechanism remains elusive. We have performed extensive multiscale molecular dynamics simulations to predict a model of the transmembrane (TM) domain of the yeast mitofusin Fzo1. Coarse-grained simulations of the two TM domain helices, TM1 and TM2, reveal a stable interface, which is controlled by the charge status of residue Lys716. Atomistic replica-exchange simulations further tune our model, which is confirmed by a remarkable agreement with an independent AlphaFold2 (AF2) prediction of Fzo1 in complex with its fusion partner Ugo1. Furthermore, the presence of the TM domain destabilizes the membrane, even more if Lys716 is charged, which can be an asset for initiating fusion. The functional role of Lys716 was confirmed with yeast experiments, which show that mutating Lys716 to a hydrophobic residue prevents mitochondrial fusion.

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酵母丝裂蛋白Fzo1跨膜结构域中的Lys716调节锚定和融合

线粒体外膜融合是一个重要的细胞过程，它由丝裂蛋白介导。然而，其潜在的分子机制仍然难以捉摸。我们进行了大量的多尺度分子动力学模拟，以预测酵母丝裂蛋白 Fzo1 的跨膜（TM）结构域模型。对两个 TM 结构域螺旋（TM1 和 TM2）的粗粒度模拟揭示了一个稳定的界面，该界面由残基 Lys716 的电荷状态控制。原子论复制交换模拟进一步调整了我们的模型，这一点通过 Fzo1 与其融合伙伴 Ugo1 复合物的独立 AlphaFold2（AF2）预测结果的显著一致性得到了证实。此外，TM 结构域的存在破坏了膜的稳定性，如果 Lys716 带有电荷，则破坏程度更大，而这正是启动融合的有利条件。酵母实验证实了 Lys716 的功能作用，实验表明，将 Lys716 突变为疏水残基会阻止线粒体融合。

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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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.