Nature communications, 2019-10, Vol.10 (1), p.4914-14, Article 4914
2019
Volltextzugriff (PDF)
Details
- Autor(en) / Beteiligte
- Titel
- Structural insights of human mitofusin-2 into mitochondrial fusion and CMT2A onset
- Ist Teil von
- Nature communications, 2019-10, Vol.10 (1), p.4914-14, Article 4914
- Ort / Verlag
- England: Nature Publishing Group
- Erscheinungsjahr
- 2019
- Quelle
- MEDLINE
- Beschreibungen/Notizen
- Mitofusin-2 (MFN2) is a dynamin-like GTPase that plays a central role in regulating mitochondrial fusion and cell metabolism. Mutations in MFN2 cause the neurodegenerative disease Charcot-Marie-Tooth type 2A (CMT2A). The molecular basis underlying the physiological and pathological relevance of MFN2 is unclear. Here, we present crystal structures of truncated human MFN2 in different nucleotide-loading states. Unlike other dynamin superfamily members including MFN1, MFN2 forms sustained dimers even after GTP hydrolysis via the GTPase domain (G) interface, which accounts for its high membrane-tethering efficiency. The biochemical discrepancy between human MFN2 and MFN1 largely derives from a primate-only single amino acid variance. MFN2 and MFN1 can form heterodimers via the G interface in a nucleotide-dependent manner. CMT2A-related mutations, mapping to different functional zones of MFN2, lead to changes in GTP hydrolysis and homo/hetero-association ability. Our study provides fundamental insight into how mitofusins mediate mitochondrial fusion and the ways their disruptions cause disease.
- Sprache
- Englisch
- Identifikatoren
- ISSN: 2041-1723eISSN: 2041-1723DOI: 10.1038/s41467-019-12912-0Titel-ID: cdi_doaj_primary_oai_doaj_org_article_20184dcb3f0a4e0db34a9f78850e0d8f
- Format
- –
- Schlagworte
- Amino acids, Cell fusion, Charcot-Marie-Tooth disease, Charcot-Marie-Tooth Disease - enzymology, Charcot-Marie-Tooth Disease - genetics, Charcot-Marie-Tooth Disease - physiopathology, Crystal structure, Dimerization, Dimers, Dynamin, GTP Phosphohydrolases - chemistry, GTP Phosphohydrolases - genetics, GTP Phosphohydrolases - metabolism, Guanosine triphosphatases, Guanosine triphosphate, Guanosine Triphosphate - metabolism, Humans, Hydrolysis, Mapping, Metabolism, Mitochondria, Mitochondria - chemistry, Mitochondria - enzymology, Mitochondria - genetics, Mitochondrial Dynamics, Mitochondrial Membrane Transport Proteins - chemistry, Mitochondrial Membrane Transport Proteins - genetics, Mitochondrial Membrane Transport Proteins - metabolism, Mitochondrial Proteins - chemistry, Mitochondrial Proteins - genetics, Mitochondrial Proteins - metabolism, Mutation, Neurodegenerative diseases, Nucleotides, Protein Domains, Tethering