title: The mechanoenzymatic core of dynamin-related protein 1 comprises the minimal machinery required for membrane constriction.
abstract: Mitochondria are dynamic organelles that continually undergo cycles of fission and fusion. Dynamin-related protein 1 (Drp1), a large GTPase of the dynamin superfamily, is the main mediator of mitochondrial fission. Like prototypical dynamin, Drp1 is composed of a mechanochemical core consisting of the GTPase, middle, and GTPase effector domain regions. In place of the pleckstrin homology domain in dynamin, however, Drp1 contains an unstructured variable domain, whose function is not yet fully resolved. Here, using time-resolved EM and rigorous statistical analyses, we establish the ability of full-length Drp1 to constrict lipid bilayers through a GTP hydrolysis-dependent mechanism. We also show the variable domain limits premature Drp1 assembly in solution and promotes membrane curvature. Furthermore, the mechanochemical core of Drp1, absent of the variable domain, is sufficient to mediate GTP hydrolysis-dependent membrane constriction.
authors.affiliation: From the Department of Pharmacology, Center for Mitochondrial Diseases, and Cleveland Center for Membrane and Structural Biology, and.
authors.forename: Christopher A
authors.initials: CA
authors.lastname: Francy
authors.affiliation: From the Department of Pharmacology, Center for Mitochondrial Diseases, and Cleveland Center for Membrane and Structural Biology, and.
authors.forename: Frances J D
authors.initials: FJ
authors.lastname: Alvarez
authors.affiliation: From the Department of Pharmacology, Center for Mitochondrial Diseases, and Cleveland Center for Membrane and Structural Biology, and.
authors.forename: Louie
authors.initials: L
authors.lastname: Zhou
authors.affiliation: Cleveland Center for Membrane and Structural Biology, and the Department of Physiology and Biophysics, Case Western Reserve University School of Medicine, Cleveland, Ohio 44106.
authors.forename: Rajesh
authors.initials: R
authors.lastname: Ramachandran
authors.affiliation: From the Department of Pharmacology, Center for Mitochondrial Diseases, and Cleveland Center for Membrane and Structural Biology, and jason.mears@case.edu.
authors.forename: Jason A
authors.initials: JA
authors.lastname: Mears
mesh_terms: D001696:Biomechanical Phenomena; D002308:Cardiolipins / Q000378:metabolism; D034281:Dynamins; D020558:GTP Phosphohydrolases / Q000737:chemistry / Q000378:metabolism*; D006160:Guanosine Triphosphate / Q000378:metabolism; D006801:Humans; D006868:Hydrolysis; D007700:Kinetics; D008051:Lipid Bilayers / Q000378:metabolism; D008081:Liposomes / Q000378:metabolism; D055595:Mechanical Phenomena; D008869:Microtubule-Associated Proteins / Q000737:chemistry / Q000378:metabolism*; D063154:Mitochondrial Dynamics; D051336:Mitochondrial Membranes / Q000378:metabolism*; D024101:Mitochondrial Proteins / Q000737:chemistry / Q000378:metabolism*; D008958:Models, Molecular; D055503:Protein Multimerization; D020836:Protein Structure, Quaternary; D017434:Protein Structure, Tertiary
chemical_list: D002308:Cardiolipins; D008051:Lipid Bilayers; D008081:Liposomes; D008869:Microtubule-Associated Proteins; D024101:Mitochondrial Proteins; D006160:Guanosine Triphosphate; D020558:GTP Phosphohydrolases; C110768:DNM1L protein, human; D034281:Dynamins
keywords: Dynamin; Dynamin-related Protein 1; Electron Microscopy (EM); GTPase; Mitochondria; Mitochondrial Fission; Protein Conformational Changes; Protein Self-assembly