Kinesin-1, -2 and -3 motors use family-specific mechanochemical strategies to effectively compete with dynein during bidirectional transport

  1. Allison M Gicking
  2. Tzu-Chen Ma
  3. Qingzhou Feng
  4. Rui Jiang
  5. Somayesadat Badieyan
  6. Michael A Cianfrocco
  7. William O Hancock  Is a corresponding author
  1. Pennsylvania State University, United States
  2. University of Michigan-Ann Arbor, United States

Abstract

Bidirectional cargo transport in neurons requires competing activity of motors from the kinesin-1, -2 and -3 superfamilies against cytoplasmic dynein-1. Previous studies demonstrated that when kinesin-1 attached to dynein-dynactin-BicD2 (DDB) complex, the tethered motors move slowly with a slight plus-end bias, suggesting kinesin-1 overpowers DDB but DDB generates a substantial hindering load. Compared to kinesin-1, motors from the kinesin-2 and -3 families display a higher sensitivity to load in single-molecule assays and are thus predicted to be overpowered by dynein complexes in cargo transport. To test this prediction, we used a DNA scaffold to pair DDB with members of the kinesin-1, -2 and -3 families to recreate bidirectional transport in vitro, and tracked the motor pairs using two-channel TIRF microscopy. Unexpectedly, we find that when both kinesin and dynein are engaged and stepping on the microtubule, kinesin-1, -2, and -3 motors are able to effectively withstand hindering loads generated by DDB. Stochastic stepping simulations reveal that kinesin-2 and -3 motors compensate for their faster detachment rates under load with faster reattachment kinetics. The similar performance between the three kinesin transport families highlights how motor kinetics play critical roles in balancing forces between kinesin and dynein, and emphasizes the importance of motor regulation by cargo adaptors, regulatory proteins, and the microtubule track for tuning the speed and directionality of cargo transport in cells.

Data availability

Source files are included for all figures and figure supplements.Source code is included for the simulations in Fig. 6.

Article and author information

Author details

  1. Allison M Gicking

    Department of Biomedical Engineering, Pennsylvania State University, University Park, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-9287-2580
  2. Tzu-Chen Ma

    Department of Biomedical Engineering, Pennsylvania State University, University Park, United States
    Competing interests
    The authors declare that no competing interests exist.
  3. Qingzhou Feng

    Department of Biomedical Engineering, Pennsylvania State University, University Park, United States
    Competing interests
    The authors declare that no competing interests exist.
  4. Rui Jiang

    Department of Biomedical Engineering, Pennsylvania State University, University Park, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-6000-8512
  5. Somayesadat Badieyan

    Department of Biological Chemistry, University of Michigan-Ann Arbor, Ann Arbor, United States
    Competing interests
    The authors declare that no competing interests exist.
  6. Michael A Cianfrocco

    Department of Biological Chemistry, University of Michigan-Ann Arbor, Ann Arbor, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-2067-4999
  7. William O Hancock

    Department of Biomedical Engineering, Pennsylvania State University, University Park, United States
    For correspondence
    woh1@psu.edu
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-5547-8755

Funding

National Institutes of Health (R35GM139568)

  • William O Hancock

National Institutes of Health (R01GM076476)

  • William O Hancock

National Institutes of Health (R21AI152869)

  • Michael A Cianfrocco

National Institutes of Health (F32GM137487)

  • Allison M Gicking

National Institutes of Health (T32GM108563)

  • Rui Jiang

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Reviewing Editor

  1. Kassandra M Ori-McKenney, University of California, United States

Version history

  1. Received: July 27, 2022
  2. Preprint posted: August 5, 2022 (view preprint)
  3. Accepted: September 19, 2022
  4. Accepted Manuscript published: September 20, 2022 (version 1)
  5. Version of Record published: October 7, 2022 (version 2)

Copyright

© 2022, Gicking 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. Allison M Gicking
  2. Tzu-Chen Ma
  3. Qingzhou Feng
  4. Rui Jiang
  5. Somayesadat Badieyan
  6. Michael A Cianfrocco
  7. William O Hancock
(2022)
Kinesin-1, -2 and -3 motors use family-specific mechanochemical strategies to effectively compete with dynein during bidirectional transport
eLife 11:e82228.
https://doi.org/10.7554/eLife.82228

Share this article

https://doi.org/10.7554/eLife.82228

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