Cryo-EM captures early intermediate steps in dynein activation by LIS1

Kendrick H. V. Nguyen, Eva P. Karasmanis, Agnieszka A. Kendrick, Samara L. Reck-Peterson () and Andres E. Leschziner ()
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Kendrick H. V. Nguyen: University of California San Diego
Eva P. Karasmanis: University of California San Diego
Agnieszka A. Kendrick: Salk Institute for Biological Studies
Samara L. Reck-Peterson: University of California San Diego
Andres E. Leschziner: University of California San Diego

Nature Communications, 2025, vol. 16, issue 1, 1-11

Abstract: Abstract Cytoplasmic dynein-1 (dynein) is an essential molecular motor in eukaryotic cells. Dynein primarily exists in an autoinhibited Phi state and requires conformational changes to assemble with its cofactors and form active transport complexes. LIS1, a key dynein regulator, enhances dynein activation and assembly. Using cryo-EM and a human dynein-LIS1 sample incubated with ATP, we map the conformational landscape of dynein activation by LIS1 and identify an early intermediate state that we propose precedes the previously identified dynein-LIS1 Chi state. Mutations that disrupt this species, which we termed “Pre-Chi”, lead to motility defects in vitro, emphasizing its functional importance. Together, our findings provide insights into how LIS1 relieves dynein autoinhibition during the activation pathway.

Date: 2025
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DOI: 10.1038/s41467-025-62185-z

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