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Cryo-EM captures early intermediate steps in dynein activation by LIS1
Kendrick H V Nguyen1, Eva P Karasmanis1, Agnieszka A Kendrick2
1Department of Cellular and Molecular Medicine, University of California San Diego, La Jolla, CA, USA.
Nature Communications
|August 1, 2025
Summary
Cytoplasmic dynein-1 (dynein) activation by LIS1 involves a novel "Pre-Chi" intermediate state. This finding reveals how LIS1 regulates dynein motor function and assembly for cellular transport.
Area of Science:
- Molecular biology
- Cell biology
- Biochemistry
Background:
- Cytoplasmic dynein-1 is a crucial molecular motor for intracellular transport in eukaryotic cells.
- Dynein typically exists in an autoinhibited state, requiring regulation for activation and complex assembly.
Purpose of the Study:
- To investigate the role of LIS1 in the conformational changes and activation pathway of cytoplasmic dynein-1.
- To identify and characterize intermediate states in dynein activation mediated by LIS1.
Main Methods:
- Cryo-electron microscopy (cryo-EM) was used to analyze human dynein-LIS1 complexes.
- Biochemical assays were performed to assess the functional impact of mutations on dynein motility.
Main Results:
- A novel intermediate state, termed "Pre-Chi", was identified preceding the known dynein-LIS1 Chi state.
- Mutations disrupting the "Pre-Chi" state resulted in significant in vitro motility defects.
- LIS1 was shown to facilitate the transition of dynein from its autoinhibited state.
Conclusions:
- LIS1 plays a critical role in relieving dynein autoinhibition by stabilizing early activation intermediates.
- The identified "Pre-Chi" state is functionally important for dynein motor activity and assembly.
- This study provides new insights into the mechanism of dynein regulation by LIS1.
