Structures of human mitofusin 1 provide insight into mitochondrial tethering

  • J Cell Biol. 2016 Dec 5;215(5):621-629. doi: 10.1083/jcb.201609019.
Yuanbo Qi  1  2 ,  Liming Yan  3 ,  Caiting Yu  3 ,  Xiangyang Guo  1  2 ,  Xin Zhou  1  2 ,  Xiaoyu Hu  1  2 ,  Xiaofang Huang  1  2 ,  Zihe Rao  4  5 ,  Zhiyong Lou  4 ,  Junjie Hu  6
Affiliations
  • 1. Department of Genetics and Cell Biology, College of Life Sciences, Nankai University, Tianjin 300071, China.
  • 2. Tianjin Key Laboratory of Protein Sciences, Nankai University, Tianjin 300071, China.
  • 3. School of Medicine, Tsinghua University, Beijing 100084, China.
  • 4. School of Medicine, Tsinghua University, Beijing 100084, China [email protected] [email protected] [email protected].
  • 5. National Laboratory of Macromolecules, Institute of Biophysics, Chinese Academy of Science, Beijing 100101, China.
  • 6. National Laboratory of Macromolecules, Institute of Biophysics, Chinese Academy of Science, Beijing 100101, China [email protected] [email protected] [email protected].
PMID: 27920125 DOI: 10.1083/jcb.201609019
Abstract

Mitochondria undergo fusion and fission. The merging of outer mitochondrial membranes requires mitofusin (MFN), a dynamin-like GTPase. How exactly MFN mediates membrane fusion is poorly understood. Here, we determined crystal structures of a minimal GTPase domain (MGD) of human MFN1, including the predicted GTPase and the distal part of the C-terminal tail (CT). The structures revealed that a helix bundle (HB) formed by three helices extending from the GTPase and one extending from the CT closely attaches to the GTPase domain, resembling the configuration of Bacterial dynamin-like protein. We show that the nucleotide-binding pocket is shallow and narrow, rendering weak hydrolysis and less dependence on magnesium ion, and that association of HB affects GTPase activity. MFN1 forms a dimer when GTP or GDP/BeF3-, but not GDP or Other analogs, is added. In addition, clustering of vesicles containing membrane-anchored MGD requires continuous GTP hydrolysis. These results suggest that MFN tethers apposing membranes, likely through nucleotide-dependent dimerization.