1. Structural Biology and Molecular Biophysics

Conserved mechanisms of microtubule-stimulated ADP release, ATP binding, and force generation in transport kinesins

  1. Joseph Atherton
  2. Irene Farabella
  3. I-Mei Yu
  4. Steven S Rosenfeld
  5. Anne Houdusse
  6. Maya Topf
  7. Carolyn A Moores  Is a corresponding author
  1. Birkbeck College, University of London, United Kingdom
  2. Institut Curie, Centre National de la Recherche Scientifique, France
  3. Lerner Research Institute, Cleveland Clinic, United States
https://doi.org/10.7554/eLife.03680
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  1. Joseph Atherton
  2. Irene Farabella
  3. I-Mei Yu
  4. Steven S Rosenfeld
  5. Anne Houdusse
  6. Maya Topf
  7. Carolyn A Moores
(2014)
Conserved mechanisms of microtubule-stimulated ADP release, ATP binding, and force generation in transport kinesins
eLife 3:e03680.
https://doi.org/10.7554/eLife.03680
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Abstract

Kinesins are a superfamily of microtubule-based ATP-powered motors, important for multiple, essential cellular functions. How microtubule binding stimulates their ATPase and controls force generation is not understood. To address this fundamental question, we visualized microtubule-bound kinesin-1 and kinesin-3 motor domains at multiple steps in their ATPase cycles - including their nucleotide-free states - at ~7Å resolution using cryo-electron microscopy. In both motors, microtubule binding promotes ordered conformations of conserved loops that stimulate ADP release, enhance microtubule affinity and prime the catalytic site for ATP binding. ATP binding causes only small shifts of these nucleotide-coordinating loops but induces large conformational changes elsewhere that allow force generation and neck linker docking towards the microtubule plus end. Family-specific differences across the kinesin-microtubule interface account for the distinctive properties of each motor. Our data thus provide evidence for a conserved ATP-driven mechanism for kinesins and reveal the critical mechanistic contribution of the microtubule interface.

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Author details

  1. Joseph Atherton

    Birkbeck College, University of London, London, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.

  2. Irene Farabella

    Birkbeck College, University of London, London, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.

  3. I-Mei Yu

    Institut Curie, Centre National de la Recherche Scientifique, Paris, France
    Competing interests
    The authors declare that no competing interests exist.

  4. Steven S Rosenfeld

    Lerner Research Institute, Cleveland Clinic, Cleveland, United States
    Competing interests
    The authors declare that no competing interests exist.

  5. Anne Houdusse

    Institut Curie, Centre National de la Recherche Scientifique, Paris, France
    Competing interests
    The authors declare that no competing interests exist.

  6. Maya Topf

    Birkbeck College, University of London, London, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.

  7. Carolyn A Moores

    Birkbeck College, University of London, London, United Kingdom
    For correspondence
    c.moores@mail.cryst.bbk.ac.uk
    Competing interests
    The authors declare that no competing interests exist.

Copyright

© 2014, Atherton et al.

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.

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  1. Joseph Atherton
  2. Irene Farabella
  3. I-Mei Yu
  4. Steven S Rosenfeld
  5. Anne Houdusse
  6. Maya Topf
  7. Carolyn A Moores
(2014)
Conserved mechanisms of microtubule-stimulated ADP release, ATP binding, and force generation in transport kinesins
eLife 3:e03680.
https://doi.org/10.7554/eLife.03680

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https://doi.org/10.7554/eLife.03680

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Further reading

    1. Structural Biology and Molecular Biophysics

    High-resolution structures of kinesin on microtubules provide a basis for nucleotide-gated force-generation

    Zhiguo Shang, Kaifeng Zhou ... Charles V Sindelar
    Research Article Updated

    Microtubule-based transport by the kinesin motors, powered by ATP hydrolysis, is essential for a wide range of vital processes in eukaryotes. We obtained insight into this process by developing atomic models for no-nucleotide and ATP states of the monomeric kinesin motor domain on microtubules from cryo-EM reconstructions at 5–6 Å resolution. By comparing these models with existing X-ray structures of ADP-bound kinesin, we infer a mechanistic scheme in which microtubule attachment, mediated by a universally conserved ‘linchpin’ residue in kinesin (N255), triggers a clamshell opening of the nucleotide cleft and accompanying release of ADP. Binding of ATP re-closes the cleft in a manner that tightly couples to translocation of cargo, via kinesin's ‘neck linker’ element. These structural transitions are reminiscent of the analogous nucleotide-exchange steps in the myosin and F1-ATPase motors and inform how the two heads of a kinesin dimer ‘gate’ each other to promote coordinated stepping along microtubules.