TY - JOUR T1 - Plasticity in salt bridge allows fusion-competent ubiquitylation of mitofusins and Cdc48 recognition JF - Life Science Alliance JO - Life Sci. Alliance DO - 10.26508/lsa.201900491 VL - 2 IS - 6 SP - e201900491 AU - Vincent Anton AU - Ira Buntenbroich AU - Ramona Schuster AU - Felix Babatz AU - Tânia Simões AU - Selver Altin AU - Gaetano Calabrese AU - Jan Riemer AU - Astrid Schauss AU - Mafalda Escobar-Henriques Y1 - 2019/12/01 UR - https://www.life-science-alliance.org/content/2/6/e201900491.abstract N2 - Mitofusins are dynamin-related GTPases that drive mitochondrial fusion by sequential events of oligomerization and GTP hydrolysis, followed by their ubiquitylation. Here, we show that fusion requires a trilateral salt bridge at a hinge point of the yeast mitofusin Fzo1, alternatingly forming before and after GTP hydrolysis. Mutations causative of Charcot–Marie–Tooth disease massively map to this hinge point site, underlining the disease relevance of the trilateral salt bridge. A triple charge swap rescues the activity of Fzo1, emphasizing the close coordination of the hinge residues with GTP hydrolysis. Subsequently, ubiquitylation of Fzo1 allows the AAA-ATPase ubiquitin-chaperone Cdc48 to resolve Fzo1 clusters, releasing the dynamin for the next fusion round. Furthermore, cross-complementation within the oligomer unexpectedly revealed ubiquitylated but fusion-incompetent Fzo1 intermediates. However, Cdc48 did not affect the ubiquitylated but fusion-incompetent variants, indicating that Fzo1 ubiquitylation is only controlled after membrane merging. Together, we present an integrated model on how mitochondrial outer membranes fuse, a critical process for their respiratory function but also putatively relevant for therapeutic interventions. ER -