Mammalian mitochondrial inner membrane fusion is mediated by optic atrophy 1 (OPA1). Under physiological conditions, OPA1 undergoes proteolytic processing to form a membrane-anchored long isoform (L-OPA1) and a soluble short isoform (S-OPA1). A combination of L-OPA1 and S-OPA1 is essential for efficient membrane fusion; however, the relevant mechanism is not well understood. In this study, we investigate the cryo-electron microscopic structures of S-OPA1–coated liposomes in nucleotide-free and GTPγS-bound states. S-OPA1 exhibits a general dynamin-like structure and can assemble onto membranes in a helical array with a dimer building block. We reveal that hydrophobic residues in its extended membrane-binding domain are critical for its tubulation activity. The binding of GTPγS triggers a conformational change and results in a rearrangement of the helical lattice and tube expansion similar to that of S-Mgm1. These observations indicate that S-OPA1 adopts a dynamin-like power stroke membrane remodeling mechanism during mitochondrial inner membrane fusion.

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S-OPA1的低温-EM结构揭示其与膜的相互作用以及核苷酸结合后的变化

哺乳动物的线粒体内膜融合是由视神经萎缩1（OPA1）介导的。在生理条件下，OPA1经历蛋白水解过程，形成膜锚定的长同种型（L-OPA1）和可溶性短同种型（S-OPA1）。L-OPA1和S-OPA1的组合对于有效的膜融合至关重要。但是，相关的机制还不是很清楚。在这项研究中，我们研究了无核苷酸和GTPγS结合状态的S-OPA1涂层脂质体的冷冻电子显微结构。S-OPA1表现出一般的动力蛋白样结构，并且可以以带有二聚体构件的螺旋阵列形式组装在膜上。我们揭示了在其延伸的膜结合域中的疏水残基对其成管活性至关重要。GTPγS的结合触发构象变化，并导致螺旋晶格的重新排列和与S-Mgm1相似的管扩展。这些观察结果表明S-OPA1在线粒体内膜融合过程中采用了类似动力的中风膜重构机制。