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Cryo-EM visualizes multiple steps of dynein's activation pathway
Agnieszka A Kendrick1,2, Kendrick H V Nguyen1, Wen Ma3
1Department of Cellular and Molecular Medicine, University of California San Diego, La Jolla, CA, USA.
Biorxiv : the Preprint Server for Biology
|October 17, 2024
Summary
Cytoplasmic dynein-1, a motor protein, is regulated by autoinhibition. Lis1 binding reveals intermediate states, advancing understanding of dynein activation and its role in lissencephaly.
Area of Science:
- Molecular Biology
- Cell Biology
- Biophysics
Background:
- Cytoplasmic dynein-1 is a crucial molecular motor.
- Dynein function is regulated by autoinhibition.
- Lis1 is a key regulator of dynein, implicated in lissencephaly.
Purpose of the Study:
- To elucidate the structural mechanisms of dynein-1 activation by Lis1.
- To identify intermediate conformational states in dynein-1 activation.
- To understand Lis1's role in relieving dynein autoinhibition.
Main Methods:
- Cryo-electron microscopy (cryo-EM) was employed.
- Structures were solved from samples with varying ATP incubation times.
- Multiple high-resolution dynein and dynein-Lis1 structures were determined.
Main Results:
- Sixteen high-resolution structures were obtained, including seven distinct dynein and dynein-Lis1 conformations.
- Novel intermediate states in dynein activation pathway were revealed.
- Lis1 was shown to increase dynein's ATP hydrolysis rate and promote motility-compatible conformations.
Conclusions:
- Lis1 relieves dynein-1 autoinhibition by modulating its ATPase activity.
- The study provides structural insights into dynein activation intermediates.
- This work enhances understanding of dynein motor regulation and Lis1 function.
