Institut für Biophysikalische Chemie, Medizinische Hochschule Hannover, Carl-Neuberg-Str. 1, 30625 Hannover, Germany.
Max-Delbrück-Centrum für Molekulare Medizin, Kristallographie, Robert-Rössle-Straße 10, 13125 Berlin, Germany.
Nature. 2015 Sep 17;525(7569):404-8. doi: 10.1038/nature14880. Epub 2015 Aug 24.
The mechanochemical protein dynamin is the prototype of the dynamin superfamily of large GTPases, which shape and remodel membranes in diverse cellular processes. Dynamin forms predominantly tetramers in the cytosol, which oligomerize at the neck of clathrin-coated vesicles to mediate constriction and subsequent scission of the membrane. Previous studies have described the architecture of dynamin dimers, but the molecular determinants for dynamin assembly and its regulation have remained unclear. Here we present the crystal structure of the human dynamin tetramer in the nucleotide-free state. Combining structural data with mutational studies, oligomerization measurements and Markov state models of molecular dynamics simulations, we suggest a mechanism by which oligomerization of dynamin is linked to the release of intramolecular autoinhibitory interactions. We elucidate how mutations that interfere with tetramer formation and autoinhibition can lead to the congenital muscle disorders Charcot-Marie-Tooth neuropathy and centronuclear myopathy, respectively. Notably, the bent shape of the tetramer explains how dynamin assembles into a right-handed helical oligomer of defined diameter, which has direct implications for its function in membrane constriction.
机械化学蛋白 dynamin 是 dynamin 大家族中大型 GTPase 的原型,该家族在多种细胞过程中塑造和重塑膜。dynamin 在细胞质中主要形成四聚体,在网格蛋白包被小泡的颈部寡聚化,介导膜的收缩和随后的断裂。先前的研究描述了 dynamin 二聚体的结构,但 dynamin 组装及其调节的分子决定因素仍不清楚。在这里,我们展示了核苷酸非结合状态下的人源 dynamin 四聚体的晶体结构。我们将结构数据与突变研究、寡聚化测量和分子动力学模拟的 Markov 状态模型相结合,提出了一种机制,即 dynamin 的寡聚化与分子内自动抑制相互作用的释放相关联。我们阐明了如何干扰四聚体形成和自动抑制的突变分别导致先天性肌肉疾病遗传性运动感觉神经病和中轴核肌病。值得注意的是,四聚体的弯曲形状解释了 dynamin 如何组装成具有特定直径的右手螺旋寡聚体,这对其在膜收缩中的功能有直接影响。