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.


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.

MeSH terms

  • Amino Acid Sequence
  • Animals
  • Cell Line
  • Crystallography, X-Ray
  • GTP Phosphohydrolases / chemistry*
  • GTP Phosphohydrolases / metabolism*
  • Guanosine Triphosphate / metabolism
  • Humans
  • Hydrolysis
  • Mice
  • Mitochondria / metabolism*
  • Mitochondrial Membrane Transport Proteins / chemistry*
  • Mitochondrial Membrane Transport Proteins / metabolism*
  • Protein Binding
  • Protein Domains
  • Protein Structure, Secondary


  • Mitochondrial Membrane Transport Proteins
  • Guanosine Triphosphate
  • GTP Phosphohydrolases
  • Mfn1 protein, human

Associated data

  • PDB/2J68
  • PDB/2W6D
  • PDB/5GNT
  • PDB/5GNU
  • PDB/5GNS
  • PDB/5GNR