Structural basis of mitochondrial receptor binding and constriction by DRP1

Nature. 2018 Jun;558(7710):401-405. doi: 10.1038/s41586-018-0211-2. Epub 2018 Jun 13.


Mitochondrial inheritance, genome maintenance and metabolic adaptation depend on organelle fission by dynamin-related protein 1 (DRP1) and its mitochondrial receptors. DRP1 receptors include the paralogues mitochondrial dynamics proteins of 49 and 51 kDa (MID49 and MID51) and mitochondrial fission factor (MFF); however, the mechanisms by which these proteins recruit and regulate DRP1 are unknown. Here we present a cryo-electron microscopy structure of full-length human DRP1 co-assembled with MID49 and an analysis of structure- and disease-based mutations. We report that GTP induces a marked elongation and rotation of the GTPase domain, bundle-signalling element and connecting hinge loops of DRP1. In this conformation, a network of multivalent interactions promotes the polymerization of a linear DRP1 filament with MID49 or MID51. After co-assembly, GTP hydrolysis and exchange lead to MID receptor dissociation, filament shortening and curling of DRP1 oligomers into constricted and closed rings. Together, these views of full-length, receptor- and nucleotide-bound conformations reveal how DRP1 performs mechanical work through nucleotide-driven allostery.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Allosteric Regulation
  • Binding Sites / genetics
  • Cryoelectron Microscopy
  • Death-Associated Protein Kinases / chemistry
  • Death-Associated Protein Kinases / genetics
  • Death-Associated Protein Kinases / metabolism*
  • Death-Associated Protein Kinases / ultrastructure*
  • GTP Phosphohydrolases / chemistry
  • GTP Phosphohydrolases / genetics
  • GTP Phosphohydrolases / metabolism
  • GTP Phosphohydrolases / ultrastructure
  • Guanosine Triphosphate / metabolism
  • Humans
  • Hydrolysis
  • Mitochondrial Proteins / chemistry
  • Mitochondrial Proteins / metabolism*
  • Mitochondrial Proteins / ultrastructure*
  • Models, Molecular
  • Mutation
  • Peptide Elongation Factors / chemistry
  • Peptide Elongation Factors / metabolism*
  • Peptide Elongation Factors / ultrastructure*
  • Phosphorylation
  • Protein Domains
  • Rotation
  • Structure-Activity Relationship


  • MIEF1 protein, human
  • MIEF2 protein, human
  • Mitochondrial Proteins
  • Peptide Elongation Factors
  • Guanosine Triphosphate
  • Death-Associated Protein Kinases
  • GTP Phosphohydrolases