Engineered kinesin motor proteins amenable to small-molecule inhibition

Martin F. Engelke, Michael Winding, Yang Yue, Shankar Shastry, Federico Teloni, Sanjay Reddy, T. Lynne Blasius, Pushpanjali Soppina, William O. Hancock, Vladimir I. Gelfand and Kristen J. Verhey ()
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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
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

Nature Communications, 2016, vol. 7, issue 1, 1-12

Abstract: 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.

Date: 2016
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DOI: 10.1038/ncomms11159

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