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Publication - Dr Mark Dodding

    A small-molecule activator of kinesin-1 drives remodeling of the microtubule network

    Citation

    Randall, TS, Yip, YY, Wallock-Richards, DJ, Pfisterer, K, Sanger, A, Ficek, W, Steiner, RA, Beavil, AJ, Parsons, M & Dodding, MP, 2017, ‘A small-molecule activator of kinesin-1 drives remodeling of the microtubule network’. Proceedings of the National Academy of Sciences of the United States of America, vol 114., pp. 13738-13743

    Abstract

    The microtubule motor kinesin-1 interacts via its cargo-binding domain with both microtubules and organelles, and hence plays an important role in controlling organelle transport and microtubule dynamics. In the absence of cargo, kinesin-1 is found in an autoinhibited conformation. The molecular basis of how cargo engagement affects the balance between kinesin-1's active and inactive conformations and roles in microtubule dynamics and organelle transport is not well understood. Here we describe the discovery of kinesore, a small molecule that in vitro inhibits kinesin-1 interactions with short linear peptide motifs found in organelle-specific cargo adaptors, yet activates kinesin-1's function of controlling microtubule dynamics in cells, demonstrating that these functions are mechanistically coupled. We establish a proof-of-concept that a microtubule motor-cargo interface and associated autoregulatory mechanism can be manipulated using a small molecule, and define a target for the modulation of microtubule dynamics.

    Full details in the University publications repository