Structural basis of mitochondrial receptor binding and constriction by DRP1

  • Nature. 2018 Jun;558(7710):401-405. doi: 10.1038/s41586-018-0211-2.
Raghav Kalia  1  2  3 ,  Ray Yu-Ruei Wang  1  3  4 ,  Ali Yusuf  1  3 ,  Paul V Thomas  1  3 ,  David A Agard  1  3  4 ,  Janet M Shaw  2  5 ,  Adam Frost  6  7  8  9
Affiliations
  • 1. Department of Biochemistry and Biophysics, University of California, San Francisco, San Francisco, CA, USA.
  • 2. Department of Biochemistry, University of Utah, Salt Lake City, UT, USA.
  • 3. California Institute for Quantitative Biomedical Research, San Francisco, CA, USA.
  • 4. Howard Hughes Medical Institute, San Francisco, CA, USA.
  • 5. Howard Hughes Medical Institute, Salt Lake City, UT, USA.
  • 6. Department of Biochemistry and Biophysics, University of California, San Francisco, San Francisco, CA, USA. [email protected].
  • 7. Department of Biochemistry, University of Utah, Salt Lake City, UT, USA. [email protected].
  • 8. California Institute for Quantitative Biomedical Research, San Francisco, CA, USA. [email protected].
  • 9. Chan Zuckerberg Biohub, San Francisco, CA, USA. [email protected].
PMID: 29899447 DOI: 10.1038/s41586-018-0211-2
Abstract

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.