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Life Sci Alliance. 2019 Dec 19;3(1). pii: e201900476. doi: 10.26508/lsa.201900476. Print 2020 Jan.

Dual role of a GTPase conformational switch for membrane fusion by mitofusin ubiquitylation.

Author information

1
Institute for Genetics, Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD), Center for Molecular Medicine Cologne, University of Cologne, Cologne, Germany.
2
Department of Molecular Cell Biology, Max Planck Institute of Biochemistry, Martinsried, Germany.
3
Institute for Genetics, University of Cologne, Cologne, Germany.
4
Institute of Molecular Biology and Biophysics, Eidgenössische Technische Hochschule Zürich, Zürich, Switzerland.
5
Medical Research Council Laboratory of Molecular Biology, Cambridge, UK.
6
Ubiquitin Signalling Division, The Walter and Eliza Hall Institute of Medical Research, Parkville, Australia.
7
Department of Medical Biology, The University of Melbourne, Melbourne, Australia.
8
Proteomics of Cellular Signalling, Luxembourg Institute of Health, Strassen, Luxembourg.
9
Institute for Genetics, Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD), Center for Molecular Medicine Cologne, University of Cologne, Cologne, Germany Mafalda.Escobar@uni-koeln.de.

Abstract

Mitochondria are essential organelles whose function is upheld by their dynamic nature. This plasticity is mediated by large dynamin-related GTPases, called mitofusins in the case of fusion between two mitochondrial outer membranes. Fusion requires ubiquitylation, attached to K398 in the yeast mitofusin Fzo1, occurring in atypical and conserved forms. Here, modelling located ubiquitylation to α4 of the GTPase domain, a critical helix in Ras-mediated events. Structure-driven analysis revealed a dual role of K398. First, it is required for GTP-dependent dynamic changes of α4. Indeed, mutations designed to restore the conformational switch, in the absence of K398, rescued wild-type-like ubiquitylation on Fzo1 and allowed fusion. Second, K398 is needed for Fzo1 recognition by the pro-fusion factors Cdc48 and Ubp2. Finally, the atypical ubiquitylation pattern is stringently required bilaterally on both involved mitochondria. In contrast, exchange of the conserved pattern with conventional ubiquitin chains was not sufficient for fusion. In sum, α4 lysines from both small and large GTPases could generally have an electrostatic function for membrane interaction, followed by posttranslational modifications, thus driving membrane fusion events.

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