MFN1 structures reveal nucleotide-triggered dimerization critical for mitochondrial fusion.
MFN1 structures reveal nucleotide-triggered dimerization critical for mitochondrial fusion.
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DOI：
10.1038/nature21077
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发表时间：
2017-02-16
期刊：
影响因子：
64.8
通讯作者：
Gao S
中科院分区：
文献类型：
--
作者：
Cao YL;Meng S;Chen Y;Feng JX;Gu DD;Yu B;Li YJ;Yang JY;Liao S;Chan DC;Gao S
线粒体是一种双膜细胞器，其形状受代谢条件、发育阶段和环境刺激的影响而变化。它们的动态形态是通过调节和平衡的聚变和裂变过程实现的。融合对于线粒体的健康和生理功能至关重要，包括受损线粒体DNA的互补和膜电位的维持。线粒体融合蛋白（Mitofusins，Mfns）是线粒体融合所必需的动力蛋白相关的GTP酶。它们嵌入线粒体外膜，并被认为通过协同寡聚化和GTP水解融合相邻的线粒体。然而，这一过程背后的分子机制仍然难以捉摸。在这里，我们提出的晶体结构的工程改造的人Mfn1含有GTP酶结构域和螺旋结构域在不同阶段的GTP水解。螺旋结构域由Mfn1广泛分布的序列区域的元件组成，类似于细菌动力蛋白样蛋白的颈部。这些结构揭示了其催化机制的独特功能，并解释了GTP结合如何诱导构象变化，以促进G结构域在过渡态的二聚化。G结构域二聚化的破坏消除了Mfn1的融合活性。此外，在Mfn1中发现了一个保守的天冬氨酸触发因子，可能通过GTP负载依赖性结构域重排影响线粒体延伸。基于这些结果，我们提出了Mfn1介导的线粒体拴系的机制模型。我们的研究为线粒体融合和线粒体融合蛋白相关的人类神经肌肉疾病的分子基础提供了重要的见解。
Mitochondria are double-membrane organelles with varying shapes influenced by metabolic conditions, developmental stage, and environmental stimuli. Their dynamic morphology is realized through regulated and balanced fusion and fission processes. Fusion is crucial for the health and physiological functions of mitochondria, including complementation of damaged mitochondrial DNAs and maintenance of membrane potential. Mitofusins (Mfns) are dynamin-related GTPases essential for mitochondrial fusion. They are embedded in the mitochondrial outer membrane and thought to fuse adjacent mitochondria via concerted oligomerization and GTP hydrolysis. However, the molecular mechanisms behind this process remains elusive. Here we present crystal structures of engineered human Mfn1 containing the GTPase domain and a helical domain in different stages of GTP hydrolysis. The helical domain is composed of elements from widely dispersed sequence regions of Mfn1 and resembles the Neck of the bacterial dynamin-like protein. The structures reveal unique features of its catalytic machinery and explain how GTP binding induces conformational changes to promote G domain dimerization in the transition state. Disruption of G domain dimerization abolishes the fusogenic activity of Mfn1. Moreover, a conserved aspartate trigger was found in Mfn1 to affect mitochondrial elongation, likely through a GTP-loading-dependent domain rearrangement. Based on these results, we propose a mechanistic model for Mfn1-mediated mitochondrial tethering. Our study provides important insights in the molecular basis of mitochondrial fusion and mitofusin-related human neuromuscular disorders.