1. The heptad repeat domain 1 of Mitofusin has membrane destabilization function in mitochondrial fusion
- Author
-
David Tareste, Claudine David, Fabienne Pierre, Manuel Rojo, Frédéric Daste, Patrick F.J. Fuchs, Cécile Sauvanet, Rémi Le Borgne, Andrej Bavdek, James Baye, Martinez Rico, Clara, Institut Jacques Monod (IJM (UMR_7592)), Université Paris Diderot - Paris 7 (UPD7)-Centre National de la Recherche Scientifique (CNRS), Trafic Membranaire et Morphogenèse Neuronale & Epithéliale, Institut National de la Santé et de la Recherche Médicale (INSERM), Institut de biochimie et génétique cellulaires (IBGC), Université Bordeaux Segalen - Bordeaux 2-Centre National de la Recherche Scientifique (CNRS), Institut de psychiatrie et neurosciences (U894 / UMS 1266), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), and This work was supported by the 'Agence Nationale de la Recherche' (ANR-09-JCJC-0062-01), the 'Association Française contre les Myopathies' (AFM Trampoline grant 16799 and AFM Research grant 20123), the 'Fondation pour la Recherche Médicale' (FRM), and funds by the 'Who am I?' Labex to DT. FD received a PhD fellowship from Paris Descartes University, an 'End of Thesis Grant' from the FRM, and funds by the PhD Program 'Frontières du Vivant (FdV)—Cursus Bettencourt'. CS received a 'Bourse de Doctorat pour Ingénieur' (BDI) fellowship from the Centre National de la Recherche Scientifique (CNRS) and an 'End of Thesis Grant' from the FRM.
- Subjects
0301 basic medicine ,Atlastin ,fusion ,viruses ,Lipid Bilayers ,GTPase ,Mitochondrion ,Membrane Fusion ,Mitochondrial Dynamics ,Mitochondrial Membrane Transport Proteins ,Biochemistry ,GTP Phosphohydrolases ,Mitochondrial Proteins ,Mice ,03 medical and health sciences ,Protein Domains ,[SDV.BBM] Life Sciences [q-bio]/Biochemistry, Molecular Biology ,Genetics ,Animals ,[SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology ,Lipid bilayer ,membrane ,Molecular Biology ,Cells, Cultured ,amphipathic helix ,Chemistry ,Lipid bilayer fusion ,Articles ,mitochondria ,Heptad repeat ,Transmembrane domain ,030104 developmental biology ,mitochondrial fusion ,Biophysics ,Mitofusin Subject Categories Membrane & Intracellular Transport - Abstract
International audience; Mitochondria are double-membrane-bound organelles that constantly change shape through membrane fusion and fission. Outer mitochondrial membrane fusion is controlled by Mitofusin, whose molecular architecture consists of an N-terminal GTPase domain, a first heptad repeat domain (HR1), two transmembrane domains, and a second heptad repeat domain (HR2). The mode of action of Mitofusin and the specific roles played by each of these functional domains in mitochondrial fusion are not fully understood. Here, using a combination of in situ and in vitro fusion assays, we show that HR1 induces membrane fusion and possesses a conserved amphipathic helix that folds upon interaction with the lipid bilayer surface. Our results strongly suggest that HR1 facilitates membrane fusion by destabilizing the lipid bilayer structure, notably in membrane regions presenting lipid packing defects. This mechanism for fusion is thus distinct from that described for the heptad repeat domains of SNARE and viral proteins, which assemble as membrane-bridging complexes, triggering close membrane apposition and fusion, and is more closely related to that of the C-terminal amphipathic tail of the Atlastin protein.
- Published
- 2018