title: Specific interaction with cardiolipin triggers functional activation of Dynamin-Related Protein 1.
abstract: Dynamin-Related Protein 1 (Drp1), a large GTPase of the dynamin superfamily, is required for mitochondrial fission in healthy and apoptotic cells. Drp1 activation is a complex process that involves translocation from the cytosol to the mitochondrial outer membrane (MOM) and assembly into rings/spirals at the MOM, leading to membrane constriction/division. Similar to dynamins, Drp1 contains GTPase (G), bundle signaling element (BSE) and stalk domains. However, instead of the lipid-interacting Pleckstrin Homology (PH) domain present in the dynamins, Drp1 contains the so-called B insert or variable domain that has been suggested to play an important role in Drp1 regulation. Different proteins have been implicated in Drp1 recruitment to the MOM, although how MOM-localized Drp1 acquires its fully functional status remains poorly understood. We found that Drp1 can interact with pure lipid bilayers enriched in the mitochondrion-specific phospholipid cardiolipin (CL). Building on our previous study, we now explore the specificity and functional consequences of this interaction. We show that a four lysine module located within the B insert of Drp1 interacts preferentially with CL over other anionic lipids. This interaction dramatically enhances Drp1 oligomerization and assembly-stimulated GTP hydrolysis. Our results add significantly to a growing body of evidence indicating that CL is an important regulator of many essential mitochondrial functions.
authors.affiliation: Biophysics Unit (CSIC-UPV/EHU) and Department of Biochemistry and Molecular Biology, University of the Basque Country (UPV/EHU), Bilbao, Spain.
authors.forename: Itsasne
authors.initials: I
authors.lastname: Bustillo-Zabalbeitia
authors.affiliation: Department of Cell Biology, University of Geneva, Geneva, Switzerland.
authors.forename: Sylvie
authors.initials: S
authors.lastname: Montessuit
authors.affiliation: Department of Cell Biology, University of Geneva, Geneva, Switzerland.
authors.forename: Etienne
authors.initials: E
authors.lastname: Raemy
authors.affiliation: Biophysics Unit (CSIC-UPV/EHU) and Department of Biochemistry and Molecular Biology, University of the Basque Country (UPV/EHU), Bilbao, Spain.
authors.forename: Gorka
authors.initials: G
authors.lastname: Basañez
authors.affiliation: Biophysics Unit (CSIC-UPV/EHU) and Department of Biochemistry and Molecular Biology, University of the Basque Country (UPV/EHU), Bilbao, Spain.
authors.forename: Oihana
authors.initials: O
authors.lastname: Terrones
authors.affiliation: Department of Cell Biology, University of Geneva, Geneva, Switzerland.
authors.forename: Jean-Claude
authors.initials: JC
authors.lastname: Martinou
mesh_terms: D000595:Amino Acid Sequence; D002308:Cardiolipins / Q000378:metabolism*; D003600:Cytosol / Q000378:metabolism; D034281:Dynamins / Q000378:metabolism*; D004926:Escherichia coli / Q000378:metabolism; D020558:GTP Phosphohydrolases / Q000378:metabolism; D006160:Guanosine Triphosphate / Q000378:metabolism; D008051:Lipid Bilayers / Q000378:metabolism; D008869:Microtubule-Associated Proteins / Q000378:metabolism*; D008928:Mitochondria / Q000378:metabolism; D063154:Mitochondrial Dynamics / Q000502:physiology; D051336:Mitochondrial Membranes / Q000378:metabolism; D024101:Mitochondrial Proteins / Q000378:metabolism*; D008969:Molecular Sequence Data; D017434:Protein Structure, Tertiary; D016415:Sequence Alignment
chemical_list: D002308:Cardiolipins; D008051:Lipid Bilayers; D008869:Microtubule-Associated Proteins; D024101:Mitochondrial Proteins; D006160:Guanosine Triphosphate; D020558:GTP Phosphohydrolases; D034281:Dynamins