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Plasticity in salt bridge allows fusion-competent ubiquitylation of mitofusins and Cdc48 recognition.


ABSTRACT: 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.

SUBMITTER: Anton V 

PROVIDER: S-EPMC6861704 | biostudies-literature | 2019 Dec

REPOSITORIES: biostudies-literature

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Plasticity in salt bridge allows fusion-competent ubiquitylation of mitofusins and Cdc48 recognition.

Anton Vincent V   Buntenbroich Ira I   Schuster Ramona R   Babatz Felix F   Simões Tânia T   Altin Selver S   Calabrese Gaetano G   Riemer Jan J   Schauss Astrid A   Escobar-Henriques Mafalda M  

Life science alliance 20191118 6


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 sw  ...[more]

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