Laboratoire de Biochimie Théorique, CNRS, Université Paris Cité, 75005 Paris, France; Laboratoire des Biomolécules, LBM, Sorbonne Université, École normale supérieure, PSL University, CNRS, 75005 Paris, France.
Laboratoire de Biochimie Théorique, CNRS, Université Paris Cité, 75005 Paris, France.
Structure. 2024 Nov 7;32(11):1997-2012.e7. doi: 10.1016/j.str.2024.08.017. Epub 2024 Sep 18.
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.
外膜融合是一种重要的细胞过程，由线粒体融合蛋白（mitofusins）介导。然而，其潜在的分子机制仍不清楚。我们进行了广泛的多尺度分子动力学模拟，以预测酵母线粒体融合蛋白 Fzo1 的跨膜（TM）结构域模型。对两个 TM 结构域螺旋 TM1 和 TM2 的粗粒化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。原子替换交换模拟进一步调整了我们的模型，与独立的 AlphaFold2（AF2）预测的 Fzo1 与融合伴侣 Ugo1 的复合物具有显著的一致性，证实了该模型。此外，TM 结构域的存在会使膜不稳定，如果 Lys716 带电荷，会更不稳定，这可能有助于启动融合。酵母实验证实了 Lys716 的功能作用，表明将 Lys716 突变为疏水性残基会阻止线粒体融合。
