title: Structural insights into oligomerization and mitochondrial remodelling of dynamin 1-like protein.
abstract: Dynamin 1-like protein (DNM1L) mediates fission of mitochondria and peroxisomes, and dysfunction of DNM1L has been implicated in several neurological disorders. To study the molecular basis of mitochondrial remodelling, we determined the crystal structure of DNM1L that is comprised of a G domain, a bundle signalling element and a stalk. DNM1L assembled via a central stalk interface, and mutations in this interface disrupted dimerization and interfered with membrane binding and mitochondrial targeting. Two sequence stretches at the tip of the stalk were shown to be required for ordered assembly of DNM1L on membranes and its function in mitochondrial fission. In the crystals, DNM1L dimers further assembled via a second, previously undescribed, stalk interface to form a linear filament. Mutations in this interface interfered with liposome tubulation and mitochondrial remodelling. Based on these results and electron microscopy reconstructions, we propose an oligomerization mode for DNM1L which differs from that of dynamin and might be adapted to the remodelling of mitochondria.
authors.affiliation: Crystallography, Max-Delbrück-Center for Molecular Medicine, Berlin, Germany.
authors.forename: Chris
authors.initials: C
authors.lastname: Fröhlich
authors.forename: Stefan
authors.initials: S
authors.lastname: Grabiger
authors.forename: David
authors.initials: D
authors.lastname: Schwefel
authors.forename: Katja
authors.initials: K
authors.lastname: Faelber
authors.forename: Eva
authors.initials: E
authors.lastname: Rosenbaum
authors.forename: Jason
authors.initials: J
authors.lastname: Mears
authors.forename: Oliver
authors.initials: O
authors.lastname: Rocks
authors.forename: Oliver
authors.initials: O
authors.lastname: Daumke
mesh_terms: D000818:Animals; D019556:COS Cells; D002522:Chlorocebus aethiops; D018360:Crystallography, X-Ray; D034281:Dynamins; D020558:GTP Phosphohydrolases / Q000037:antagonists & inhibitors / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D008869:Microtubule-Associated Proteins / Q000037:antagonists & inhibitors / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D008928:Mitochondria / Q000187:drug effects / Q000235:genetics / Q000378:metabolism* / Q000502:physiology*; D024101:Mitochondrial Proteins / Q000037:antagonists & inhibitors / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D053142:Mitochondrial Size / Q000187:drug effects / Q000235:genetics; D008954:Models, Biological; D008958:Models, Molecular; D020125:Mutation, Missense / Q000502:physiology; D017510:Protein Folding; D055503:Protein Multimerization / Q000502:physiology*; D020836:Protein Structure, Quaternary / Q000502:physiology; D017433:Protein Structure, Secondary; D034741:RNA, Small Interfering / Q000494:pharmacology
chemical_list: D008869:Microtubule-Associated Proteins; D024101:Mitochondrial Proteins; D034741:RNA, Small Interfering; D020558:GTP Phosphohydrolases; C110768:DNM1L protein, human; D034281:Dynamins