Journal Article

MFN1 structures reveal nucleotide-triggered dimerization critical for mitochondrial fusion

Yang, Jin-Yu, Gu, Dong-Dong, Cao, Yu-Lu, Feng, Jian-Xiong, Chen, Yang, Yu, Bing, Li, Yu-Jie, Meng, Shuxia, Chan, David C., Liao, Shuang, Gao, Song

2017

Overview

Crystal structures of engineered human MFN1 in different stages of GTP hydrolysis provide insights into the GTP-induced conformational changes that promote MFN1 dimerization to bring about mitochondrial fusion. Mitofusin structure provides clues to mitochondrial fusion Mitochondrial fusion, which is essential for the functionality of these organelles, requires the activity of mitofusins, which are GTPases related to dynamin. Mitofusins are found in the mitochondrial outer membrane, so the oligomerization of mitofusins on different mitochondria, together with GTPase activity, results in organelle fusion. By resolving the crystal structure of truncated human mitofusin 1, Song Gao and colleagues provide insights into the GTP-induced conformational changes that promote MFN1 dimerization to bring about mitochondrial fusion. Their observations are relevant to disorders caused by mutations in mitofusin. Mitochondria are double-membraned organelles with variable shapes influenced by metabolic conditions, developmental stage, and environmental stimuli 1 , 2 , 3 , 4 . Their dynamic morphology is a result of regulated and balanced fusion and fission processes 5 , 6 . Fusion is crucial for the health and physiological functions of mitochondria, including complementation of damaged mitochondrial DNAs and the maintenance of membrane potential 6 , 7 , 8 . Mitofusins are dynamin-related GTPases that are essential for mitochondrial fusion 9 , 10 . They are embedded in the mitochondrial outer membrane and thought to fuse adjacent mitochondria via combined oligomerization and GTP hydrolysis 11 , 12 , 13 . However, the molecular mechanisms of this process remain unknown. Here we present crystal structures of engineered human MFN1 containing the GTPase domain and a helical domain during 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 GTPase domain dimerization in the transition state. Disruption of GTPase domain dimerization abolishes the fusogenic activity of MFN1. Moreover, a conserved aspartate residue trigger was found to affect mitochondrial elongation in MFN1, probably through a GTP-loading-dependent domain rearrangement. Thus, we propose a mechanistic model for MFN1-mediated mitochondrial tethering, and our results shed light on the molecular basis of mitochondrial fusion and mitofusin-related human neuromuscular disorders 14 .

• Publisher: Nature Publishing Group UK,Nature Publishing Group
• Subject: 631/535/1266 / 631/57/2271 / 631/80/642/333 / Amino Acid Sequence / Biocatalysis / Crystal structure / Crystallography, X-Ray / Developmental stages / Enzymes / GTP Phosphohydrolases - chemistry / GTP Phosphohydrolases - genetics / GTP Phosphohydrolases - metabolism / GTPases / Guanosine Triphosphate - metabolism / Humanities and Social Sciences / Humans / Hydrolysis / letter / Membrane Fusion / Membrane Potentials / Mitochondria / Mitochondria - chemistry / Mitochondria - metabolism / Mitochondrial Dynamics / Mitochondrial Membrane Transport Proteins - chemistry / Mitochondrial Membrane Transport Proteins - genetics / Mitochondrial Membrane Transport Proteins - metabolism / Mitochondrial Membranes - chemistry / Mitochondrial Membranes - metabolism / Models, Molecular / Molecular biology / multidisciplinary / Mutation / Physiological aspects / Protein Domains / Protein Multimerization / Science / Tryptophan - metabolism