Structural basis for GTP hydrolysis and conformational change of MFN1 in mediating membrane fusion

Nat Struct Mol Biol. 2018 Mar;25(3):233-243. doi: 10.1038/s41594-018-0034-8. Epub 2018 Feb 26.


Fusion of the outer mitochondrial membrane is mediated by the dynamin-like GTPase mitofusin (MFN). Here, we determined the structure of the minimal GTPase domain (MGD) of human MFN1 in complex with GDP-BeF3-. The MGD folds into a canonical GTPase fold with an associating four-helix bundle, HB1, and forms a dimer. A potassium ion in the catalytic core engages GDP and BeF3- (GDP-BeF3-). Enzymatic analysis has confirmed that efficient GTP hydrolysis by MFN1 requires potassium. Compared to previously reported MGD structures, the HB1 structure undergoes a major conformational change relative to the GTPase domains, as they move from pointing in opposite directions to point in the same direction, suggesting that a swing of the four-helix bundle can pull tethered membranes closer to achieve fusion. The proposed model is supported by results from in vitro biochemical assays and mitochondria morphology rescue assays in MFN1-deleted cells. These findings offer an explanation for how Charcot-Marie-Tooth neuropathy type 2 A (CMT2A)-causing mutations compromise MFN-mediated fusion.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • GTP Phosphohydrolases / chemistry*
  • GTP Phosphohydrolases / genetics
  • GTP Phosphohydrolases / metabolism
  • Guanosine Triphosphate / chemistry*
  • Guanosine Triphosphate / metabolism
  • Humans
  • Hydrolysis
  • Membrane Fusion
  • Mitochondrial Membrane Transport Proteins / chemistry*
  • Mitochondrial Membrane Transport Proteins / genetics
  • Mitochondrial Membrane Transport Proteins / metabolism
  • Models, Molecular
  • Mutation
  • Protein Conformation
  • Protein Domains
  • Protein Multimerization


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