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September 10, 2025Open Access

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

Puntos clave

An early intermediate state termed 'Pre-Chi' was identified during dynein activation, indicating a crucial step in the regulatory pathway.
Mutations that disrupt the 'Pre-Chi' intermediate lead to significant motility defects, highlighting its functional importance in dynein activation.
Mapping the conformational landscape of dynein activation was achieved using cryo-EM techniques with human dynein-LIS1 samples and ATP.
Findings underscore how LIS1 facilitates dynein's transition from an autoinhibited state to an active form, suggesting broader implications for cellular transport.

Resumen

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.

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