Crystal structure of the dynamin tetramer

The crystal structure of the large GTPase dynamin tetramer is presented, suggesting a mechanism by which oligomerization of dynamin is regulated, and revealing how mutations that interfere with tetramer formation and autoinhibition are of relevance to understanding the congenital muscle disorders Charcot–Marie–Tooth neuropathy and centronuclear myopathy. Structure of a dynamin GTPases The large GTPase enzyme dynamin mediates the shaping and remodelling of the membranes of various organelles. To do this it forms mainly tetramers, which assemble into oligomers for subsequent constriction and scission of membranes. A new study presents the crystal structure of a dynamin tetramer. Combining this information with additional analysis, Susanne Eschenburg and co-workers identify interfaces between dynamin dimers and propose a mechanism for how oligomerization of this protein might lead to the release of intramolecular, autoinhibitory interactions. The authors' mutational analyses are of relevance to understanding the congenital muscle disorders Charcot–Marie–Tooth neuropathy and centronuclear myopathy. The mechanochemical protein dynamin is the prototype of the dynamin superfamily of large GTPases, which shape and remodel membranes in diverse cellular processes 1 . 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 1 . Previous studies have described the architecture of dynamin dimers 2 , 3 , 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 4 and centronuclear myopathy 5 , 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.