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  Cytoplasmic dynein regulates its attachment to microtubules via nucleotide state-switched mechanosensing at multiple AAA domains

Nicholas, M. P., Berger, F., Rao, L., Brenner, S., Cho, C., & Gennerich, A. (2015). Cytoplasmic dynein regulates its attachment to microtubules via nucleotide state-switched mechanosensing at multiple AAA domains. Proceedings of the National Academy of Sciences, 112(20), 6371-6376. doi:10.1073/pnas.1417422112.

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Item Permalink: http://hdl.handle.net/11858/00-001M-0000-0027-1325-8 Version Permalink: http://hdl.handle.net/11858/00-001M-0000-002A-C20E-5
Genre: Journal Article

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 Creators:
Nicholas, Matthew P.1, Author
Berger, Florian2, Author              
Rao, Lu, Author
Brenner, Sibylle, Author
Cho, Carol, Author
Gennerich, Arne, Author
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1External Organizations, ou_persistent22              
2Reinhard Lipowsky, Theorie & Bio-Systeme, Max Planck Institute of Colloids and Interfaces, Max Planck Society, ou_1863327              

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 Abstract: Cytoplasmic dynein is a homodimeric microtubule (MT) motor protein responsible for most MT minus-end–directed motility. Dynein contains four AAA+ ATPases (AAA: ATPase associated with various cellular activities) per motor domain (AAA1–4). The main site of ATP hydrolysis, AAA1, is the only site considered by most dynein motility models. However, it remains unclear how ATPase activity and MT binding are coordinated within and between dynein’s motor domains. Using optical tweezers, we characterize the MT-binding strength of recombinant dynein monomers as a function of mechanical tension and nucleotide state. Dynein responds anisotropically to tension, binding tighter to MTs when pulled toward the MT plus end. We provide evidence that this behavior results from an asymmetrical bond that acts as a slip bond under forward tension and a slip-ideal bond under backward tension. ATP weakens MT binding and reduces bond strength anisotropy, and unexpectedly, so does ADP. Using nucleotide binding and hydrolysis mutants, we show that, although ATP exerts its effects via binding AAA1, ADP effects are mediated by AAA3. Finally, we demonstrate “gating” of AAA1 function by AAA3. When tension is absent or applied via dynein’s C terminus, ATP binding to AAA1 induces MT release only if AAA3 is in the posthydrolysis state. However, when tension is applied to the linker, ATP binding to AAA3 is sufficient to “open” the gate. These results elucidate the mechanisms of dynein–MT interactions, identify regulatory roles for AAA3, and help define the interplay between mechanical tension and nucleotide state in regulating dynein motility.

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 Dates: 2015-05-04
 Publication Status: Published in print
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 Identifiers: DOI: 10.1073/pnas.1417422112
BibTex Citekey: Nicholas19052015
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Title: Proceedings of the National Academy of Sciences
Source Genre: Journal
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Pages: - Volume / Issue: 112 (20) Sequence Number: - Start / End Page: 6371 - 6376 Identifier: -