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Structural Basis of Mitochondrial Receptor Binding and GTP Driven Conformational Constriction by Dynamin-Related Protein 1

By Raghav Kalia, Ray Y.-R. Wang, Ali Yusuf, Paul V. Thomas, David A. Agard, Janet M. Shaw, Adam Frost

Posted 04 Aug 2017
bioRxiv DOI: 10.1101/172809 (published DOI: 10.1038/s41586-018-0211-2)

Mitochondrial inheritance, genome maintenance, and metabolic adaptation all depend on organelle fission by Dynamin-Related Protein 1 (DRP1) and its mitochondrial receptors. DRP1 receptors include the paralogs Mitochondrial Dynamics 49 and 51 (MID49/MID51) and Mitochondrial Fission Factor (MFF), but the mechanisms by which these proteins recruit DRP1 and regulate its activities are unknown. Here we present a cryoEM structure of human, full-length DRP1 bound to MID49 and an analysis of structure- and disease-based mutations. We report that GTP binding allosterically induces a remarkable elongation and rotation of the G-domain, Bundle-Signaling Element (BSE) and connecting hinge loops of DRP1. In this nucleotide-bound conformation, a distributed network of multivalent interactions promotes DRP1 copolymerization into a linear filament with MID49, MID51 or both. Subsequent GTP hydrolysis and exchange within the filament leads to receptor dissociation, shortening through disassembly, and concomitant curling of DRP1 oligomers into closed rings. The dimensions of the closed DRP1 rings are consistent with DRP1-constricted mitochondrial tubules observed in human cells. These structures are the first views of full-length, receptor- and nucleotide-bound dynamin-family GTPases, and in comparison with nucleotide-free crystal structures, teach us how these molecular machines perform mechanical work through nucleotide-driven allostery.

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