Dual role of a GTPase conformational switch for membrane fusion by mitofusin ubiquitylation
| Autor: | Fabian den Brave, Ramona Schuster, Vincent Anton, Thomas Hermanns, Selver Altin, Gunnar Dittmar, Mafalda Escobar-Henriques, David Komander, R. Juergen Dohmen, Tania Simoes, Manuela K. Hospenthal |
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| Rok vydání: | 2019 |
| Předmět: |
Protein Conformation
alpha-Helical Saccharomyces cerevisiae Proteins Health Toxicology and Mutagenesis Saccharomyces cerevisiae Plant Science GTPase Mitochondrion Biochemistry Genetics and Molecular Biology (miscellaneous) Membrane Fusion Mitochondrial Dynamics GTP Phosphohydrolases Mitochondrial Proteins 03 medical and health sciences 0302 clinical medicine Ubiquitin Protein Domains Organelle Research Articles 030304 developmental biology 0303 health sciences Ecology biology Chemistry Ubiquitination Lipid bilayer fusion Membrane Proteins biology.organism_classification Cell biology Mitochondria mitochondrial fusion Proteasome Mitochondrial Membranes biology.protein Mutant Proteins sense organs Protein Processing Post-Translational 030217 neurology & neurosurgery Plasmids Research Article |
| Zdroj: | Life Science Alliance LIFE SCIENCE ALLIANCE |
| ISSN: | 2575-1077 |
| Popis: | Mitochondrial fusion requires a conformational change in α4 of the GTPase domain, followed by AAA-ATPase regulation, thus revealing striking mechanistic similarities between small and large GTPases. 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. |
| Databáze: | OpenAIRE |
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