本期文章：《自然》：Online/在线发表

美国国立卫生研究院Jenny E. Hinshaw小组发现，神经萎缩蛋白1（OPA1）螺旋结构揭示线粒体功能障碍。2023年8月23日，《自然》杂志在线发表了这项成果。

研究人员使用冷冻电镜方法来解析了在核苷酸存在和不存在的情况下，OPA1在脂膜管上组装的螺旋结构问题。这些螺旋装配组织成密集的蛋白质梯级，梯级间的连接极少，并表现出GTP酶结构域的核苷酸依赖性二聚化，这是dynamin超家族蛋白质的特征。OPA1的桨叶结构域还含有几种独特的二级结构，包括膜插入螺旋，这些结构加强了其与膜的结合。

这些结构特征揭示了致病点突变对蛋白质折叠、蛋白质间组装和膜相互作用的影响。此外，在基于细胞的实验中，破坏OPA1组装界面和膜结合的突变会导致线粒体破碎，从而为这些相互作用的生物学相关性提供了证据。

据介绍，显性视神经萎缩是导致儿童失明的主要原因之一。约60-80%的病例是由编码OPA1的基因突变引起的，该蛋白在线粒体内膜融合和嵴重塑中起关键作用，对线粒体的动态组织和调节至关重要。OPA1基因突变会导致线粒体内膜和外膜在GTP酶介导下的融合过程失调。

附：英文原文

Title: OPA1 helical structures give perspective to mitochondrial dysfunction

Author: Nyenhuis, Sarah B., Wu, Xufeng, Strub, Marie-Paule, Yim, Yang-In, Stanton, Abigail E., Baena, Valentina, Syed, Zulfeqhar A., Canagarajah, Bertram, Hammer, John A., Hinshaw, Jenny E.

Issue&Volume: 2023-08-23

Abstract: Dominant optic atrophy is one of the leading causes of childhood blindness. Around 60–80% of cases1 are caused by mutations of the gene that encodes optic atrophy protein 1 (OPA1), a protein that has a key role in inner mitochondrial membrane fusion and remodelling of cristae and is crucial for the dynamic organization and regulation of mitochondria2. Mutations in OPA1 result in the dysregulation of the GTPase-mediated fusion process of the mitochondrial inner and outer membranes3. Here we used cryo-electron microscopy methods to solve helical structures of OPA1 assembled on lipid membrane tubes, in the presence and absence of nucleotide. These helical assemblies organize into densely packed protein rungs with minimal inter-rung connectivity, and exhibit nucleotide-dependent dimerization of the GTPase domains—a hallmark of the dynamin superfamily of proteins4. OPA1 also contains several unique secondary structures in the paddle domain that strengthen its membrane association, including membrane-inserting helices. The structural features identified in this study shed light on the effects of pathogenic point mutations on protein folding, inter-protein assembly and membrane interactions. Furthermore, mutations that disrupt the assembly interfaces and membrane binding of OPA1 cause mitochondrial fragmentation in cell-based assays, providing evidence of the biological relevance of these interactions.

DOI: 10.1038/s41586-023-06462-1