Microtubule binding-induced allostery promotes LIS1 dissociation from dynein prior to cargo transport
Ton, W. D.; Wang, Y.; Chai, P.; Beauchamp-Perez, C.; Flint, N. T.; Lammers, L. G.; Xiong, H.; Zhang, K.; Markus, S. M.
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The lissencephaly-related protein LIS1 is a critical regulator of cytoplasmic dynein that governs motor function and intracellular localization (e.g., to microtubule plus-ends). Although LIS1 binding is required for dynein activity, its unbinding prior to initiation of cargo transport is equally important, since preventing dissociation leads to dynein dysfunction. To understand whether and how dynein-LIS1 binding is modulated, we engineered dynein mutants locked in a microtubule-bound (MT-B) or -unbound (MT-U) state. Whereas the MT-B mutant exhibits low LIS1 affinity, the MT-U mutant binds LIS1 with high affinity, and as a consequence remains almost irreversibly bound to microtubule plus-ends. We find that a monomeric motor domain is sufficient to exhibit these opposing LIS1 affinities, and that this is an evolutionarily conserved phenomenon. Three cryo-EM structures of dynein with and without LIS1 reveal microtubule-binding induced conformational changes responsible for this regulation. Our work reveals key biochemical and structural insight into LIS1-mediated dynein activation.
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