title: Crystal structure of the dynamin tetramer.
abstract: 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.
authors: Institut für Biophysikalische Chemie, Medizinische Hochschule Hannover, Carl-Neuberg-Str. 1, 30625 Hannover, Germany.
authors: Thomas F
authors: TF
authors: Reubold
authors: Max-Delbrück-Centrum für Molekulare Medizin, Kristallographie, Robert-Rössle-Straße 10, 13125 Berlin, Germany.
authors: Katja
authors: K
authors: Faelber
authors: Institut für Mathematik, Freie Universität Berlin, Arnimallee 6, 14195 Berlin, Germany.
authors: Nuria
authors: N
authors: Plattner
authors: Leibniz-Institut für Molekulare Pharmakologie, Robert-Rössle-Straße 10, 13125 Berlin, Germany.
authors: York
authors: Y
authors: Posor
authors: Leibniz-Institut für Molekulare Pharmakologie, Robert-Rössle-Straße 10, 13125 Berlin, Germany.
authors: Katharina
authors: K
authors: Ketel
authors: Institut für Biophysikalische Chemie, Medizinische Hochschule Hannover, Carl-Neuberg-Str. 1, 30625 Hannover, Germany.|Forschungseinrichtung Strukturanalyse, Medizinische Hochschule Hannover, Carl-Neuberg-Str. 1, 30625 Hannover, Germany.
authors: Ute
authors: U
authors: Curth
authors: Max-Delbrück-Centrum für Molekulare Medizin, Kristallographie, Robert-Rössle-Straße 10, 13125 Berlin, Germany.
authors: Jeanette
authors: J
authors: Schlegel
authors: Institut für Biophysikalische Chemie, Medizinische Hochschule Hannover, Carl-Neuberg-Str. 1, 30625 Hannover, Germany.
authors: Roopsee
authors: R
authors: Anand
authors: Institut für Biophysikalische Chemie, Medizinische Hochschule Hannover, Carl-Neuberg-Str. 1, 30625 Hannover, Germany.|Forschungseinrichtung Strukturanalyse, Medizinische Hochschule Hannover, Carl-Neuberg-Str. 1, 30625 Hannover, Germany.
authors: Dietmar J
authors: DJ
authors: Manstein
authors: Institut für Mathematik, Freie Universität Berlin, Arnimallee 6, 14195 Berlin, Germany.
authors: Frank
authors: F
authors: Noé
authors: Leibniz-Institut für Molekulare Pharmakologie, Robert-Rössle-Straße 10, 13125 Berlin, Germany.|Institut für Chemie und Biochemie, Freie Universität Berlin, Takustraße 6, 14195 Berlin, Germany.
authors: Volker
authors: V
authors: Haucke
authors: Max-Delbrück-Centrum für Molekulare Medizin, Kristallographie, Robert-Rössle-Straße 10, 13125 Berlin, Germany.|Institut für Chemie und Biochemie, Freie Universität Berlin, Takustraße 6, 14195 Berlin, Germany.
authors: Oliver
authors: O
authors: Daumke
authors: Institut für Biophysikalische Chemie, Medizinische Hochschule Hannover, Carl-Neuberg-Str. 1, 30625 Hannover, Germany.
authors: Susanne
authors: S
authors: Eschenburg
mesh_terms: D002607:Charcot-Marie-Tooth Disease; D018360:Crystallography, X-Ray; D034281:Dynamins / Q000037:antagonists & inhibitors* / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D006801:Humans; D008390:Markov Chains; D008958:Models, Molecular; D056004:Molecular Dynamics Simulation; D050505:Mutant Proteins / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D009154:Mutation / Q000235:genetics; D020914:Myopathies, Structural, Congenital; D009711:Nucleotides; D055503:Protein Multimerization / Q000235:genetics; D013329:Structure-Activity Relationship
chemical_list: D050505:Mutant Proteins; D009711:Nucleotides; D034281:Dynamins