Scramblases play a pivotal role in facilitating bidirectional lipid transport across cell membranes, thereby influencing lipid metabolism, membrane homeostasis, and cellular signaling. MTCH2, a mitochondrial outer membrane protein insertase, has a membrane-spanning hydrophilic groove resembling those that form the lipid transit pathway in known scramblases. Employing both coarse-grained and atomistic molecular dynamics simulations, we show that MTCH2 significantly reduces the free energy barrier for lipid movement along the groove and therefore can indeed function as a scramblase. Notably, the scrambling rate of MTCH2 is similar to that of voltage-dependent anion channel (VDAC), a recently discovered scramblase of the outer mitochondrial membrane, suggesting a potential complementary physiological role for these mitochondrial proteins. Finally, our findings suggest that other insertases which possess a hydrophilic path across the membrane like MTCH2, can also function as scramblases.

中文翻译：

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插入酶扰乱脂质：MTCH2 的分子模拟


Scramblases 在促进脂质跨细胞膜双向转运方面发挥着关键作用，从而影响脂质代谢、膜稳态和细胞信号传导。 MTCH2 是一种线粒体外膜蛋白插入酶，具有跨膜亲水性凹槽，类似于已知的乱序酶中形成脂质转运途径的凹槽。采用粗粒度和原子分子动力学模拟，我们表明 MTCH2 显着降低了脂质沿凹槽运动的自由能垒，因此确实可以起到扰乱酶的作用。值得注意的是，MTCH2 的扰乱速率与电压依赖性阴离子通道 (VDAC) 的扰乱速率相似，VDAC 是最近发现的线粒体外膜扰乱酶，表明这些线粒体蛋白具有潜在的互补生理作用。最后，我们的研究结果表明，具有跨膜亲水路径的其他插入酶（如 MTCH2）也可以起到扰乱酶的作用。