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Sci Rep. 2017 Aug 31;7(1):10217. doi: 10.1038/s41598-017-10687-2.

A membrane-inserted structural model of the yeast mitofusin Fzo1.

Author information

1
Institut de Biologie Physico-Chimique, Laboratoire de Biochimie Théorique, UPR 9080, Centre National de la Recherche Scientifique, Paris, France.
2
Institut de Biologie Physico-Chimique, Laboratoire de Biologie Cellulaire et Moléculaire des Eucaryotes, UMR 8226, Centre National de la Recherche Scientifique, Sorbonne Universités, UPMC University of Paris 06, Paris, France.
3
Institut de Biologie Physico-Chimique, Laboratoire de Biologie Cellulaire et Moléculaire des Eucaryotes, UMR 8226, Centre National de la Recherche Scientifique, Sorbonne Universités, UPMC University of Paris 06, Paris, France. cohen@ibpc.fr.
4
Institut de Biologie Physico-Chimique, Laboratoire de Biochimie Théorique, UPR 9080, Centre National de la Recherche Scientifique, Paris, France. taly@ibpc.fr.

Abstract

Mitofusins are large transmembrane GTPases of the dynamin-related protein family, and are required for the tethering and fusion of mitochondrial outer membranes. Their full-length structures remain unknown, which is a limiting factor in the study of outer membrane fusion. We investigated the structure and dynamics of the yeast mitofusin Fzo1 through a hybrid computational and experimental approach, combining molecular modelling and all-atom molecular dynamics simulations in a lipid bilayer with site-directed mutagenesis and in vivo functional assays. The predicted architecture of Fzo1 improves upon the current domain annotation, with a precise description of the helical spans linked by flexible hinges, which are likely of functional significance. In vivo site-directed mutagenesis validates salient aspects of this model, notably, the long-distance contacts and residues participating in hinges. GDP is predicted to interact with Fzo1 through the G1 and G4 motifs of the GTPase domain. The model reveals structural determinants critical for protein function, including regions that may be involved in GTPase domain-dependent rearrangements.

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