Structural basis for regulated assembly of the mitochondrial fission GTPase Drp1

Kristy Rochon, Brianna L. Bauer, Nathaniel A. Roethler, Yuli Buckley, Chih-Chia Su, Wei Huang, Rajesh Ramachandran, Maria S. K. Stoll, Edward W. Yu, Derek J. Taylor and Jason A. Mears ()
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Kristy Rochon: Case Western Reserve University School of Medicine
Brianna L. Bauer: Case Western Reserve University School of Medicine
Nathaniel A. Roethler: Case Western Reserve University School of Medicine
Yuli Buckley: Case Western Reserve University School of Medicine
Chih-Chia Su: Case Western Reserve University School of Medicine
Wei Huang: Case Western Reserve University School of Medicine
Rajesh Ramachandran: Case Western Reserve University School of Medicine
Maria S. K. Stoll: Case Western Reserve University School of Medicine
Edward W. Yu: Case Western Reserve University School of Medicine
Derek J. Taylor: Case Western Reserve University School of Medicine
Jason A. Mears: Case Western Reserve University School of Medicine

Nature Communications, 2024, vol. 15, issue 1, 1-10

Abstract: Abstract Mitochondrial fission is a critical cellular event to maintain organelle function. This multistep process is initiated by the enhanced recruitment and oligomerization of dynamin-related protein 1 (Drp1) at the surface of mitochondria. As such, Drp1 is essential for inducing mitochondrial division in mammalian cells, and homologous proteins are found in all eukaryotes. As a member of the dynamin superfamily of proteins (DSPs), controlled Drp1 self-assembly into large helical polymers stimulates its GTPase activity to promote membrane constriction. Still, little is known about the mechanisms that regulate correct spatial and temporal assembly of the fission machinery. Here we present a cryo-EM structure of a full-length Drp1 dimer in an auto-inhibited state. This dimer reveals two key conformational rearrangements that must be unlocked through intramolecular rearrangements to achieve the assembly-competent state observed in previous structures. This structural insight provides understanding into the mechanism for regulated self-assembly of the mitochondrial fission machinery.

Date: 2024
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DOI: 10.1038/s41467-024-45524-4

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