A nucleotide code governs Lis1's ability to relieve dynein autoinhibition

Geohring, I. C.; Chai, P.; Iyer, B. R.; Ton, W. D.; Yang, J.; Ide, A. H.; George, S. C.; Bagri, J. S.; Baird, S. V.; Zhang, K.; Markus, S. M.

doi:10.1101/2024.12.30.630615

bioRxiv · 10.1101/2024.12.30.630615

A nucleotide code governs Lis1's ability to relieve dynein autoinhibition

Geohring, I. C.·Chai, P.·Iyer, B. R.·Ton, W. D.·Yang, J.·Ide, A. H.·George, S. C.·Bagri, J. S.·Baird, S. V.·Zhang, K.·Markus, S. M.

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Abstract

Dynein-1 is a microtubule motor responsible for the transport of cytoplasmic cargoes. Activation of motility requires it first overcome an autoinhibited state prior to its assembly with dynactin and a cargo adaptor. Studies suggest that Lis1 may relieve dyneins autoinhibited state. However, evidence for this mechanism is lacking. We first set out to determine the rules governing dynein-Lis1 binding, which reveals that their binding affinity is regulated by the nucleotide-bound states of each of three nucleotide-binding pockets within the dynein motor domain. We also find that distinct nucleotide codes coordinate dynein-Lis1 binding stoichiometry by impacting binding affinity at two different sites within the dynein motor domain. Electron microscopy reveals that a 1 Lis1:1 dynein complex directly promotes an open, uninhibited conformational state of dynein, whereas a 2:1 complex resembles the autoinhibited state. Cryo-EM analysis reveals the structural basis for Lis1 opening dynein relies on interactions with the linker domain.

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Geohring, I. C., Chai, P., Iyer, B. R., Ton, W. D., Yang, J., Ide, A. H., George, S. C., Bagri, J. S., Baird, S. V., Zhang, K., Markus, S. M.. 2024-12-30. A nucleotide code governs Lis1's ability to relieve dynein autoinhibition. https://doi.org/10.1101/2024.12.30.630615

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