Department of Biochemistry and Biophysics, University of California, San Francisco, San Francisco, CA, USA.
Department of Biochemistry, University of Utah, Salt Lake City, UT, USA.
Nature. 2018 Jun;558(7710):401-405. doi: 10.1038/s41586-018-0211-2. Epub 2018 Jun 13.
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.
线粒体的遗传、基因组的维护和代谢的适应都依赖于动力相关蛋白 1（DRP1）及其线粒体受体的分裂。DRP1 的受体包括线粒体动力学蛋白 49 和 51kDa（MID49 和 MID51）和线粒体分裂因子（MFF）的异构体；然而，这些蛋白招募和调节 DRP1 的机制尚不清楚。在这里，我们展示了全长人 DRP1 与 MID49 组装在一起的冷冻电子显微镜结构，并对基于结构和疾病的突变进行了分析。我们报告说，GTP 诱导 DRP1 的 GTP 酶结构域、束信号元件和连接铰链环的明显伸长和旋转。在这种构象中，一个多价相互作用网络促进了线性 DRP1 细丝与 MID49 或 MID51 的聚合。在组装后，GTP 水解和交换导致 MID 受体解离，细丝缩短，DRP1 寡聚物卷曲成收缩和封闭的环。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作用来完成机械工作。
