4.8 Article

Molecular mechanism of cytoplasmic dynein tension sensing

Journal

NATURE COMMUNICATIONS
Volume 10, Issue -, Pages -

Publisher

NATURE PUBLISHING GROUP
DOI: 10.1038/s41467-019-11231-8

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Funding

  1. National Institutes of Health (NIH) [R01GM098469]
  2. NIH-funded Medical Scientist Training and Molecular Biophysics Training programs at the Albert Einstein College of Medicine (NIH) [T32GM007288, T32GM008572]
  3. Alexander von Humboldt Foundation

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Cytoplasmic dynein is the most complex cytoskeletal motor protein and is responsible for numerous biological functions. Essential to dynein's function is its capacity to respond anisotropically to tension, so that its microtubule-binding domains bind microtubules more strongly when under backward load than forward load. The structural mechanisms by which dynein senses directional tension, however, are unknown. Using a combination of optical tweezers, mutagenesis, and chemical cross-linking, we show that three structural elements protruding from the motor domain-the linker, buttress, and stalk-together regulate directional tension-sensing. We demonstrate that dynein's anisotropic response to directional tension is mediated by sliding of the coiled-coils of the stalk, and that coordinated conformational changes of dynein's linker and buttress control this process. We also demonstrate that the stalk coiled-coils assume a previously undescribed registry during dynein's stepping cycle. We propose a revised model of dynein's mechanochemical cycle which accounts for our findings.

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