Journal Article

Structural basis of mitochondrial receptor binding and constriction by DRP1

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

2018

Overview

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. Cryo-electron microscopy is used to resolve the structure of human dynamin-related protein 1 co-assembled with its receptor mitochondrial dynamics protein of 49 kDa, along with an analysis of structure- and disease-based mutations.

• Publisher: Nature Publishing Group UK,Nature Publishing Group
• Subject: 101/28 / 631/535/1258/1259 / 631/57/2271 / 631/80/642/333 / Allosteric Regulation / Automation / 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 / Dissociation / Electron microscopy / Elongation / Extrachromosomal inheritance / Fission / Genomes / Genomics / GTP Phosphohydrolases - chemistry / GTP Phosphohydrolases - genetics / GTP Phosphohydrolases - metabolism / GTP Phosphohydrolases - ultrastructure / Guanosine triphosphatases / Guanosine triphosphate / Guanosine Triphosphate - metabolism / Humanities and Social Sciences / Humans / Hydrolysis / Metabolism / Microscopy / Mitochondria / Mitochondrial inheritance / Mitochondrial Proteins - chemistry / Mitochondrial Proteins - metabolism / Mitochondrial Proteins - ultrastructure / Models, Molecular / multidisciplinary / Mutation / Oligomers / Peptide Elongation Factors - chemistry / Peptide Elongation Factors - metabolism / Peptide Elongation Factors - ultrastructure / Phosphorylation / Polymerization / Polymers / Protein binding / Protein Domains / Protein research / Protein structure / Proteins / Receptors / Rotation / Science / Science (multidisciplinary) / Structure-Activity Relationship / Utrophin