Mfn1 structures reveal nucleotide-triggered dimerization critical for mitochondrial fusion
| Autor: | David C. Chan, Dong-Dong Gu, Bing Yu, Shuang Liao, Yu-Lu Cao, Yu-Jie Li, Shuxia Meng, Song Gao, Yang Chen, Jinyu Yang, Jian-Xiong Feng |
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| Jazyk: | angličtina |
| Rok vydání: | 2017 |
| Předmět: |
0301 basic medicine
Models Molecular GTPase Mitochondrion Crystallography X-Ray Membrane Fusion Mitochondrial Dynamics Mitochondrial Membrane Transport Proteins Article GTP Phosphohydrolases Membrane Potentials 03 medical and health sciences Mitochondrial membrane transport protein 0302 clinical medicine Protein Domains MFN1 Humans Amino Acid Sequence Multidisciplinary biology Hydrolysis Tryptophan Mitochondrial carrier Cell biology Mitochondria 030104 developmental biology mitochondrial fusion Translocase of the inner membrane Mitochondrial Membranes biology.protein Biocatalysis Mitochondrial fission Guanosine Triphosphate Protein Multimerization 030217 neurology & neurosurgery |
| Zdroj: | Nature |
| ISSN: | 1476-4687 0028-0836 |
| Popis: | Mitochondria are double-membrane organelles with varying shapes influenced by metabolic conditions, developmental stage, and environmental stimuli1–4. Their dynamic morphology is realized through regulated and balanced fusion and fission processes5, 6. Fusion is crucial for the health and physiological functions of mitochondria, including complementation of damaged mitochondrial DNAs and maintenance of membrane potential6–8. Mitofusins (Mfns) are dynamin-related GTPases essential for mitochondrial fusion9, 10. They are embedded in the mitochondrial outer membrane and thought to fuse adjacent mitochondria via concerted oligomerization and GTP hydrolysis11–13. However, the molecular mechanisms behind this process remains elusive. Here we present crystal structures of engineered human Mfn1 containing the GTPase domain and a helical domain in different stages of GTP hydrolysis. The helical domain is composed of elements from widely dispersed sequence regions of Mfn1 and resembles the Neck of the bacterial dynamin-like protein. The structures reveal unique features of its catalytic machinery and explain how GTP binding induces conformational changes to promote G domain dimerization in the transition state. Disruption of G domain dimerization abolishes the fusogenic activity of Mfn1. Moreover, a conserved aspartate trigger was found in Mfn1 to affect mitochondrial elongation, likely through a GTP-loading-dependent domain rearrangement. Based on these results, we propose a mechanistic model for Mfn1-mediated mitochondrial tethering. Our study provides important insights in the molecular basis of mitochondrial fusion and mitofusin-related human neuromuscular disorders14. |
| Databáze: | OpenAIRE |
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