Publication Date:
2012-03-20
Description:
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 small-molecule 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 peroxisome motility 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.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3321072/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉 〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3321072/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉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 -- R01 CA136574/CA/NCI NIH HHS/ -- R01 GM038839/GM/NIGMS NIH HHS/ -- R01 GM052111/GM/NIGMS NIH HHS/ -- R01 GM052111-14/GM/NIGMS NIH HHS/ -- R01 GM065933/GM/NIGMS NIH HHS/ -- R01 GM52111/GM/NIGMS NIH HHS/ -- R01 GM65933/GM/NIGMS NIH HHS/ -- R01 GM71772/GM/NIGMS NIH HHS/ -- England -- Nature. 2012 Mar 18;484(7392):125-9. doi: 10.1038/nature10936.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Chemical and Systems Biology, Stanford University School of Medicine, Stanford, California 94305, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/22425997" target="_blank"〉PubMed〈/a〉
Keywords:
Animals
;
Cattle
;
Cilia/drug effects/metabolism/pathology
;
Cytoplasm/*enzymology
;
Cytoplasmic Dyneins/*antagonists & inhibitors/metabolism
;
Enzyme Inhibitors/*chemistry/*pharmacology
;
Hedgehog Proteins/metabolism
;
Kinetochores/drug effects/metabolism
;
Kruppel-Like Transcription Factors/metabolism
;
Melanosomes/drug effects/metabolism
;
Mice
;
Microtubules/drug effects/metabolism
;
Molecular Weight
;
Movement/drug effects
;
NIH 3T3 Cells
;
Peroxisomes/drug effects/physiology
;
Protein Transport/drug effects
;
Quinazolinones/*chemistry/*pharmacology
;
Signal Transduction/drug effects
;
Spindle Apparatus/drug effects/metabolism/pathology
Print ISSN:
0028-0836
Electronic ISSN:
1476-4687
Topics:
Biology
,
Chemistry and Pharmacology
,
Medicine
,
Natural Sciences in General
,
Physics
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