Ndel1 modulates dynein activation in two distinct ways
Sharon R Garrott1,2, John P Gillies1, Aravintha Siva1
1Department of Molecular, Cellular, and Developmental Biology, University of Michigan, Ann Arbor, MI 48109, USA.
Biorxiv : the Preprint Server for Biology
|February 7, 2023
Summary
Ndel1 inhibits dynein motor activation by preventing complex formation and sequestering Lis1. This contrasts with cellular roles, suggesting Ndel1 acts as a scaffold to control timed dynein activation.
Area of Science:
- Cellular and Molecular Biology
- Motor Protein Regulation
- Cytoskeletal Dynamics
Background:
- Dynein is a crucial minus-end-directed microtubule motor essential for cellular transport.
- Lis1 protein is known to promote dynein activation by facilitating its association with dynactin and adaptor proteins.
- Ndel1 and its orthologue Nde1 bind dynein and Lis1, influencing dynein localization, but their precise role in activation remains unclear.
Approach:
- Utilized purified proteins and quantitative binding assays to investigate Ndel1-dynein-Lis1 interactions.
- Employed single-molecule imaging and protein biochemistry to elucidate the mechanism of Ndel1's influence on dynein activation.
- Examined the impact of phosphomimetic mutations in Ndel1 on complex formation.
Key Points:
- Ndel1's C-terminal region binds dynein and negatively regulates Lis1 binding.
- Ndel1 inhibits dynein activation by disfavoring the formation of the activated dynein complex.
- Ndel1 sequesters Lis1, preventing Lis1-mediated dynein activation by binding simultaneously to both proteins.
Conclusions:
- In vitro, Ndel1 acts as a negative regulator of dynein activation, contrasting with its proposed role in cellular studies.
- Ndel1 may function as a scaffold, holding dynein and Lis1 together in an inhibited state.
- Ndel1 release could be a trigger for timed dynein activation in cellular contexts.
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