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Engineered kinesin motor proteins amenable to small-molecule inhibition

Author

Listed:
  • Martin F. Engelke

    (University of Michigan, 109 Zina Pitcher Place)

  • Michael Winding

    (Feinberg School of Medicine, Northwestern University)

  • Yang Yue

    (University of Michigan, 109 Zina Pitcher Place)

  • Shankar Shastry

    (Penn State University
    Present Address: Department of Chemistry and Biochemistry, UC Santa Cruz, Santa Cruz, California 95064, USA.)

  • Federico Teloni

    (University of Michigan, 109 Zina Pitcher Place)

  • Sanjay Reddy

    (University of Michigan, 109 Zina Pitcher Place)

  • T. Lynne Blasius

    (University of Michigan, 109 Zina Pitcher Place)

  • Pushpanjali Soppina

    (University of Michigan, 109 Zina Pitcher Place)

  • William O. Hancock

    (Penn State University)

  • Vladimir I. Gelfand

    (Feinberg School of Medicine, Northwestern University)

  • Kristen J. Verhey

    (University of Michigan, 109 Zina Pitcher Place)

Abstract

The human genome encodes 45 kinesin motor proteins that drive cell division, cell motility, intracellular trafficking and ciliary function. Determining the cellular function of each kinesin would benefit from specific small-molecule inhibitors. However, screens have yielded only a few specific inhibitors. Here we present a novel chemical-genetic approach to engineer kinesin motors that can carry out the function of the wild-type motor yet can also be efficiently inhibited by small, cell-permeable molecules. Using kinesin-1 as a prototype, we develop two independent strategies to generate inhibitable motors, and characterize the resulting inhibition in single-molecule assays and in cells. We further apply these two strategies to create analogously inhibitable kinesin-3 motors. These inhibitable motors will be of great utility to study the functions of specific kinesins in a dynamic manner in cells and animals. Furthermore, these strategies can be used to generate inhibitable versions of any motor protein of interest.

Suggested Citation

  • Martin F. Engelke & Michael Winding & Yang Yue & Shankar Shastry & Federico Teloni & Sanjay Reddy & T. Lynne Blasius & Pushpanjali Soppina & William O. Hancock & Vladimir I. Gelfand & Kristen J. Verhe, 2016. "Engineered kinesin motor proteins amenable to small-molecule inhibition," Nature Communications, Nature, vol. 7(1), pages 1-12, September.
    • Handle: RePEc:nat:natcom:v:7:y:2016:i:1:d:10.1038_ncomms11159
    DOI: 10.1038/ncomms11159
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    Cited by:

    1. Alex Albaugh & Todd R. Gingrich, 2022. "Simulating a chemically fueled molecular motor with nonequilibrium molecular dynamics," Nature Communications, Nature, vol. 13(1), pages 1-10, December.

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