Tethering and homotypic fusion of mitochondrial outer membranes is mediated by large GTPases of the dynamin-related proteins family called the mitofusins. The yeast mitofusin Fzo1 forms high molecular weight complexes and its assembly during membrane fusion likely involves the formation of high order complexes. Consistent with this possibility, mitofusins form oligomers in both cis (on the same lipid bilayer) and trans to mediate membrane attachment and fusion. Here, we utilize our recent Fzo1 model to investigate and discuss the formation of cis and trans mitofusin oligomers. We have built three distinct cis-assembly Fzo1 models that gave rise to three distinct trans-oligomeric models of mitofusin constructs. Each model involves two main components of mitofusin oligomerization: the GTPase and the trunk domains. The oligomeric models proposed in this study were further assessed for stability and dynamics in a membrane environment using a coarse-grained molecular dynamics (MD) simulation approach. A narrow opening 'head-to-head' cis-oligomerization (via the GTPase domain) followed by the antiparallel 'back-to-back' trans-associations (via the trunk domain) appears to be in agreement with all of the available experimental data. More broadly, this study opens new possibilities to start exploring cis and trans conformations for Fzo1 and mitofusins in general.

中文翻译：

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在膜对接的背景下，基于物理的酵母丝裂融合蛋白 Fzo1 在分子尺度上的寡聚模型

线粒体外膜的束缚和同型融合由称为线粒体融合蛋白的动力蛋白相关蛋白家族的大 GTP 酶介导。酵母丝裂融合蛋白 Fzo1 形成高分子量复合物，其在膜融合过程中的组装可能涉及高级复合物的形成。与这种可能性一致，丝裂蛋白在顺式（在同一脂质双层上）和反式中形成寡聚体以介导膜附着和融合。在这里，我们利用我们最近的 Fzo1 模型来研究和讨论顺式和反式丝裂融合蛋白寡聚体的形成。我们已经建立了三个不同的顺式组装 Fzo1 模型，这些模型产生了三个不同的 mitofusin 构建体的反式寡聚模型。每个模型都涉及线粒体融合蛋白寡聚化的两个主要组成部分：GTPase 和主干结构域。使用粗粒度分子动力学 (MD) 模拟方法进一步评估了本研究中提出的寡聚模型在膜环境中的稳定性和动力学。狭窄的开放“头对头”顺式寡聚化（通过 GTPase 域），然后是反平行的“背对背”反式关联（通过主干域）似乎与所有可用的实验一致数据。更广泛地说，这项研究为开始探索 Fzo1 和丝裂融合素的顺式和反式构象开辟了新的可能性。跨关联（通过主干域）似乎与所有可用的实验数据一致。更广泛地说，这项研究为开始探索 Fzo1 和丝裂融合素的顺式和反式构象开辟了新的可能性。跨关联（通过主干域）似乎与所有可用的实验数据一致。更广泛地说，这项研究为开始探索 Fzo1 和丝裂融合素的顺式和反式构象开辟了新的可能性。