2. Academic Validation
  3. Structural basis of mitochondrial receptor binding and constriction by DRP1

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

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.

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