RT Journal Article
SR Electronic
T1 Plasticity in salt bridge allows fusion-competent ubiquitylation of mitofusins and Cdc48 recognition
JF Life Science Alliance
JO Life Sci. Alliance
FD Life Science Alliance LLC
SP e201900491
DO 10.26508/lsa.201900491
VO 2
IS 6
A1 Vincent Anton
A1 Ira Buntenbroich
A1 Ramona Schuster
A1 Felix Babatz
A1 Tânia Simões
A1 Selver Altin
A1 Gaetano Calabrese
A1 Jan Riemer
A1 Astrid Schauss
A1 Mafalda Escobar-Henriques
YR 2019
UL https://www.life-science-alliance.org/content/2/6/e201900491.abstract
AB 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.