Cryo-EM structure of AAA

被引：0

作者：

Dar, Mohamad Aasif ^{[1
,2
]}

Louder, Robert ^{[3
]}

Cortes, Marisol ^{[1
,2
]}

Chen, Rong ^{[1
,2
]}

Ma, Qianqian ^{[4
]}

Chakrabarti, Mayukh ^{[5
]}

Umanah, George K. E. ^{[1
,2
,9
]}

Dawson, Ted M. ^{[1
,2
,6
,7
,10
,11
,12
,13
]}

Dawson, Valina L. ^{[1
,2
,6
,7
,8
]}

机构：

[1] Johns Hopkins Univ, Sch Med, Inst Cell Engn, Neuroregenerat & Stem Cell Programs, Baltimore, MD 21205 USA

[2] Johns Hopkins Univ, Sch Med, Dept Neurol, Baltimore, MD USA

[3] Johns Hopkins Univ, Dept Mol Biol & Genet, Sch Med, Baltimore, MD USA

[4] Johns Hopkins Univ, Sch Med, Dept Biol Chem, Baltimore, MD USA

[5] Johns Hopkins Univ, Dept Biophys & Biol Chem, Sch Med, Baltimore, MD USA

[6] Johns Hopkins Univ, Sch Med, Solomon H Snyder Dept Neurosci, Baltimore, MD USA

[7] Johns Hopkins Univ, Sch Med, Dept Pharmacol & Mol Sci, Baltimore, MD USA

[8] Johns Hopkins Univ, Sch Med, Dept Physiol, Baltimore, MD 21205 USA

[9] NIH, Div Neurosci, Natl Inst Neurol Disorders & Stroke, Bethesda, MD USA

[10] Johns Hopkins Univ, Inst Cell Engn, Sch Med, 733 North Broadway, MRB 731, Baltimore, MD 21205 USA

[11] Johns Hopkins Univ, Dept Neurol, Sch Med, 733 North Broadway,MRB 731, Baltimore, MD 21205 USA

[12] Johns Hopkins Univ, Dept Neurosci, 733 North Broadway,MRB 731, Baltimore, MD 21205 USA

[13] Johns Hopkins Univ, Dept Pharmacol & Mol Sci, 733 North Broadway,MRB 731, Baltimore, MD 21205 USA

来源：

COMPUTATIONAL AND STRUCTURAL BIOTECHNOLOGY JOURNAL | 2025年 / 27卷

关键词：

Cryo-Electron microscopy; Oligomerization; Mutagenesis; Disassembly; SYNAPTIC PLASTICITY; PROTEIN COMPLEX; VISUALIZATION;

D O I：

10.1016/j.csbj.2025.05.018

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

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 & Aring;, revealing the dimeric arrangement of the basic repeating unit that is formed through a distinct interface compared to the hexameric MSP1/Thorase E193Q 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 reveal a new filament structure of Thorase, offering insights into the mechanism of Thorase filament formation and its potential role in the disassembly of the mTORC1 complex.

引用

页码：2186 / 2198

页数：13

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