Universität zu Köln

Anton, Vincent ORCID: 0000-0003-3008-6346, Buntenbroich, Ira, Schuster, Ramona ORCID: 0000-0002-2227-3718, Babatz, Felix, Simoes, Tania, Altin, Selver, Calabrese, Gaetano ORCID: 0000-0002-2212-5280, Riemer, Jan, Schauss, Astrid and Escobar-Henriques, Mafalda ORCID: 0000-0002-0879-3119 (2019). Plasticity in salt bridge allows fusion-competent ubiquitylation of mitofusins and Cdc48 recognition. Life Sci. Alliance, 2 (6). COLD SPRING HARBOR: LIFE SCIENCE ALLIANCE LLC. ISSN 2575-1077

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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.

Item Type:	Journal Article
Creators:	Creators Email ORCID ORCID Put Code Anton, Vincent UNSPECIFIED orcid.org/0000-0003-3008-6346 UNSPECIFIED Buntenbroich, Ira UNSPECIFIED UNSPECIFIED UNSPECIFIED Schuster, Ramona UNSPECIFIED orcid.org/0000-0002-2227-3718 UNSPECIFIED Babatz, Felix UNSPECIFIED UNSPECIFIED UNSPECIFIED Simoes, Tania UNSPECIFIED UNSPECIFIED UNSPECIFIED Altin, Selver UNSPECIFIED UNSPECIFIED UNSPECIFIED Calabrese, Gaetano UNSPECIFIED orcid.org/0000-0002-2212-5280 UNSPECIFIED Riemer, Jan UNSPECIFIED UNSPECIFIED UNSPECIFIED Schauss, Astrid UNSPECIFIED UNSPECIFIED UNSPECIFIED Escobar-Henriques, Mafalda UNSPECIFIED orcid.org/0000-0002-0879-3119 UNSPECIFIED
URN:	urn:nbn:de:hbz:38-125737
DOI:	10.26508/lsa.201900491
Journal or Publication Title:	Life Sci. Alliance
Volume:	2
Number:	6
Date:	2019
Publisher:	LIFE SCIENCE ALLIANCE LLC
Place of Publication:	COLD SPRING HARBOR
ISSN:	2575-1077
Language:	English
Faculty:	Faculty of Mathematics and Natural Sciences
Divisions:	Faculty of Mathematics and Natural Sciences > Department of Chemistry > Institute of Biochemistry
Subjects:	no entry
Uncontrolled Keywords:	Keywords Language REGULATE MITOCHONDRIAL FUSION; STRUCTURAL BASIS; PROTEIN; REQUIRES; OUTER; MFN1; BIOGENESIS; DYNAMICS; VECTORS; FISSION Multiple languages Biology Multiple languages
Refereed:	Yes
URI:	http://kups.ub.uni-koeln.de/id/eprint/12573