Small-molecule inhibitors of the AAA1 ATPase motor cytoplasmic dynein

The conversion of chemical energy into mechanical force by AAA+ (ATPases associated with diverse cellular activities) ATPases is integral to cellular processes, including DNA replication, protein unfolding, cargo transport and membrane fusion. The AAA+ ATPase motor cytoplasmic dynein regulates cilia...

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Bibliographic Details
Published in:Nature (London) 2012-04, Vol.484 (7392), p.125
Main Authors: Firestone, Ari J, Weinger, Joshua S, Maldonado, Maria, Barlan, Kari, Langston, Lance D, O'Donnell, Michael, Gelfand, Vladimir I, Kapoor, Tarun M, Chen, James K
Format: Article
Language:English
Subjects:
Phosphorylation
Proteins
Reagents
Studies
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Summary:The conversion of chemical energy into mechanical force by AAA+ (ATPases associated with diverse cellular activities) ATPases is integral to cellular processes, including DNA replication, protein unfolding, cargo transport and membrane fusion. The AAA+ ATPase motor cytoplasmic dynein regulates ciliary trafficking, mitotic spindle formation and organelle transport, and dissecting its precise functions has been challenging because of its rapid timescale of action and the lack of cell-permeable, chemical modulators. Here we describe the discovery of ciliobrevins, the first specific smallmolecule antagonists of cytoplasmic dynein. Ciliobrevins perturb protein trafficking within the primary cilium, leading to their malformation and Hedgehog signalling blockade. Ciliobrevins also prevent spindle pole focusing, kinetochore-microtubule attachment, melanosome aggregation and peroxisomemotility in cultured cells. We further demonstrate the ability of ciliobrevins to block dynein-dependent microtubule gliding and ATPase activity in vitro. Ciliobrevins therefore will be useful reagents for studying cellular processes that require this microtubule motor and may guide the development of additional AAA+ ATPase superfamily inhibitors. [PUBLICATION ABSTRACT]
ISSN:0028-0836
1476-4687