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

Structural basis of mitochondrial receptor binding and constriction by DRP1.

Kalia R1,2,3, Wang RY1,3,4, Yusuf A1,3, Thomas PV1,3, Agard DA1,3,4, Shaw JM2,5, Frost A6,7,8,9.

Author information

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. adam.frost@ucsf.edu.
7
Department of Biochemistry, University of Utah, Salt Lake City, UT, USA. adam.frost@ucsf.edu.
8
California Institute for Quantitative Biomedical Research, San Francisco, CA, USA. adam.frost@ucsf.edu.
9
Chan Zuckerberg Biohub, San Francisco, CA, USA. adam.frost@ucsf.edu.

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.

PMID:
29899447
PMCID:
PMC6120343
DOI:
10.1038/s41586-018-0211-2
[Indexed for MEDLINE]
Free PMC Article

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