Cryo-EM Structure of AAA + ATPase Thorase Reveals Novel Helical Filament Formation.

Autor:	Dar MA; Neuroregeneration and Stem Cell Programs, Institute for Cell Engineering, The Johns Hopkins University School of Medicine, Baltimore, Maryland, United States of America.; Department of Neurology, The Johns Hopkins University School of Medicine, Baltimore, Maryland, United States of America., Louder R; Department of Molecular Biology & Genetics, The Johns Hopkins University School of Medicine, Baltimore, Maryland, United States of America., Cortes M; Neuroregeneration and Stem Cell Programs, Institute for Cell Engineering, The Johns Hopkins University School of Medicine, Baltimore, Maryland, United States of America.; Department of Neurology, The Johns Hopkins University School of Medicine, Baltimore, Maryland, United States of America., Chen R; Neuroregeneration and Stem Cell Programs, Institute for Cell Engineering, The Johns Hopkins University School of Medicine, Baltimore, Maryland, United States of America.; Department of Neurology, The Johns Hopkins University School of Medicine, Baltimore, Maryland, United States of America., Ma Q; Department of Biological Chemistry, The Johns Hopkins University School of Medicine, Baltimore, Maryland, United States of America., Chakrabarti M; Department of Biophysics and Biological Chemistry, The Johns Hopkins University School of Medicine, Baltimore, Maryland, United States of America., Umanah GKE; Neuroregeneration and Stem Cell Programs, Institute for Cell Engineering, The Johns Hopkins University School of Medicine, Baltimore, Maryland, United States of America.; Department of Neurology, The Johns Hopkins University School of Medicine, Baltimore, Maryland, United States of America.; Present address: Division of Neuroscience, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD, USA., Dawson TM; Neuroregeneration and Stem Cell Programs, Institute for Cell Engineering, The Johns Hopkins University School of Medicine, Baltimore, Maryland, United States of America.; Department of Neurology, The Johns Hopkins University School of Medicine, Baltimore, Maryland, United States of America.; Solomon H. Snyder Department of Neuroscience, The Johns Hopkins University School of Medicine, Baltimore, Maryland, United States of America.; Department of Pharmacology and Molecular Sciences, The Johns Hopkins University School of Medicine, Baltimore, Maryland, United States of America., Dawson VL; Neuroregeneration and Stem Cell Programs, Institute for Cell Engineering, The Johns Hopkins University School of Medicine, Baltimore, Maryland, United States of America.; Department of Neurology, The Johns Hopkins University School of Medicine, Baltimore, Maryland, United States of America.; Solomon H. Snyder Department of Neuroscience, The Johns Hopkins University School of Medicine, Baltimore, Maryland, United States of America.; Department of Pharmacology and Molecular Sciences, The Johns Hopkins University School of Medicine, Baltimore, Maryland, United States of America.; Department of Physiology, Johns Hopkins University School of Medicine, Baltimore, MD, 21205, USA.
Jazyk:	angličtina
Zdroj:	BioRxiv : the preprint server for biology [bioRxiv] 2024 Nov 22. Date of Electronic Publication: 2024 Nov 22.
DOI:	10.1101/2024.11.22.624887
Abstrakt:	The AAA+ (ATPases associated with a variety of cellular activities) ATPase, Thorase, also known as ATAD1, plays multiple roles in synaptic plasticity, mitochondrial quality control and mTOR signaling through disassembling protein complexes like AMPAR and mTORC1 in an ATP-dependent manner. The Oligomerization of Thorase is crucial for its disassembly and remodeling functions. We show that wild-type Thorase forms long helical filaments in vitro , dependent on ATP binding but not hydrolysis. We report the Cryogenic Electron Microscopy (cryo-EM) structure of the Thorase filament at a resolution of 4 Å, revealing the dimeric arrangement of the basic repeating unit that is formed through a distinct interface compared to the hexameric MSP1/ATAD1E193Q assembly. Structure-guided mutagenesis confirms the role of critical amino acid residues required for filament formation, oligomerization and disassembly of mTORC1 protein complex. Together, our data reveals a novel filament structure of Thorase and provides critical information that elucidates the mechanism underlying Thorase filament formation and Thorase-mediated disassembly of the mTORC1 complex. Competing Interests: Competing interests: The authors declare no competing interests.
Databáze:	MEDLINE
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