Mitochondrial inheritance, genome maintenance and metabolic adaptation depend on organelle fission by dynamin-related protein 1 (DRP1) and its mitochondrial receptors. DRP1 receptors include the paralogues mitochondrial dynamics proteins of 49 and 51 kDa (MID49 and MID51) and mitochondrial fission factor (MFF); however, the mechanisms by which these proteins recruit and regulate DRP1 are unknown. Here we present a cryo-electron microscopy structure of full-length human DRP1 co-assembled with MID49 and an analysis of structure- and disease-based mutations. We report that GTP induces a marked elongation and rotation of the GTPase domain, bundle-signalling element and connecting hinge loops of DRP1. In this conformation, a network of multivalent interactions promotes the polymerization of a linear DRP1 filament with MID49 or MID51. After co-assembly, GTP hydrolysis and exchange lead to MID receptor dissociation, filament shortening and curling of DRP1 oligomers into constricted and closed rings. Together, these views of full-length, receptor- and nucleotide-bound conformations reveal how DRP1 performs mechanical work through nucleotide-driven allostery.Cryo-electron microscopy is used to resolve the structure of human dynamin-related protein 1 co-assembled with its receptor mitochondrial dynamics protein of 49 kDa, along with an analysis of structure- and disease-based mutations.

中文翻译：

---

DRP1结合和收缩线粒体受体的结构基础

线粒体遗传、基因组维持和代谢适应取决于动力蛋白相关蛋白 1 (DRP1) 及其线粒体受体的细胞器裂变。DRP1受体包括49和51 kDa的旁系同源物线粒体动力学蛋白（MID49和MID51）和线粒体裂变因子（MFF）；然而，这些蛋白质募集和调节 DRP1 的机制尚不清楚。在这里，我们展示了与 MID49 共同组装的全长人类 DRP1 的冷冻电子显微镜结构，以及基于结构和疾病的突变分析。我们报告 GTP 诱导 GTPase 域、束信号元件和 DRP1 的连接铰链环的显着伸长和旋转。在这种构象中，多价相互作用网络促进了线性 DRP1 细丝与 MID49 或 MID51 的聚合。共同组装后，GTP 水解和交换导致 MID 受体解离、细丝缩短和 DRP1 寡聚体卷曲成收缩和闭合的环。总之，这些全长、受体和核苷酸结合构象的观点揭示了 DRP1 如何通过核苷酸驱动的变构来执行机械工作。冷冻电子显微镜用于解析人类动力相关蛋白 1 与其共组装的结构49 kDa 的受体线粒体动力学蛋白，以及基于结构和疾病的突变分析。