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

Schuster, R; Anton, V; Simoes, T; Altin, S; den Brave, F; Hermanns, T; Hospenthal, M; Komander, D; Dittmar, G; Dohmen, RJ; Escobar-Henriques, M

Author(s): Schuster, R; Anton, V; Simoes, T; Altin, S; den Brave, F; Hermanns, T; Hospenthal, M; Komander, D; Dittmar, G; Dohmen, RJ; Escobar-Henriques, M;
Details: Publication Year 2020-01,Volume 3,Issue #1,Page pii: e201900476
Journal Title: Life Sci Alliance
Publication Type: Journal Article
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 alpha4 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 alpha4. 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, alpha4 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.
Publisher: Rockefeller University Press
Research Division(s): Ubiquitin Signalling
PubMed ID: 31857350
Publisher's Version: https://doi.org/10.26508/lsa.201900476
Open Access at Publisher's Site: https://doi.org/10.26508/lsa.201900476
Terms of Use/Rights Notice: Refer to copyright notice on published article.

Creation Date: 2019-12-23 11:50:08

Last Modified: 2019-12-23 11:57:21