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Cited by 22Microtubule and mitosis dynamicsGenetic and Kidney Cyst DiseasesBiotin and Related Studies

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Ndel1 disfavors dynein–dynactin–adaptor complex formation in two distinct ways

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Garrott, Sharon R., Gillies, John P., Siva, Aravintha, Little, Saffron R., El Jbeily, Rita, DeSantis, Morgan E.·2023·Journal of Biological Chemistry
DOI 10.1016/j.jbc.2023.104735PMC PMC10248797

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Abstract

Dynein is the primary minus-end-directed microtubule motor protein. To achieve activation, dynein binds to the dynactin complex and an adaptor to form the "activated dynein complex." The protein Lis1 aids activation by binding to dynein and promoting its association with dynactin and the adaptor. Ndel1 and its paralog Nde1 are dynein- and Lis1-binding proteins that help control dynein localization within the cell. Cell-based assays suggest that Ndel1-Nde1 also work with Lis1 to promote dynein activation, although the underlying mechanism is unclear. Using purified proteins and quantitative binding assays, here we found that the C-terminal region of Ndel1 contributes to dynein binding and negatively regulates binding to Lis1. Using single-molecule imaging and protein biochemistry, we observed that Ndel1 inhibits dynein activation in two distinct ways. First, Ndel1 disfavors the formation of the activated dynein complex. We found that phosphomimetic mutations in the C-terminal domain of Ndel1 increase its ability to inhibit dynein-dynactin-adaptor complex formation. Second, we observed that Ndel1 interacts with dynein and Lis1 simultaneously and sequesters Lis1 away from its dynein-binding site. In doing this, Ndel1 prevents Lis1-mediated dynein activation. Together, our work suggests that in vitro, Ndel1 is a negative regulator of dynein activation, which contrasts with cellular studies where Ndel1 promotes dynein activity. To reconcile our findings with previous work, we posit that Ndel1 functions to scaffold dynein and Lis1 together while keeping dynein in an inhibited state. We speculate that Ndel1 release can be triggered in cellular settings to allow for timed dynein activation.

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Metadata

Authors
Garrott, S. R., Gillies, J. P., Siva, A., Little, S. R., El Jbeily, R., & DeSantis, M. E.
Affiliations
University of Michigan (US)
Corresponding author
DeSantis, Morgan E.
ORCID
Venue
Journal of Biological Chemistry
Publisher
Elsevier BV
Published
2023-06
Volume
299
Issue
6
Pages
104735
ISSN
0021-9258 (ISSN-L)
DOI
10.1016/j.jbc.2023.104735
PMC
PMC10248797
OpenAlex
W4366607404
Cited by
22
References
1
Citations by year
2026: 3 · 2025: 5 · 2024: 10 · 2023: 4
FWCI
3.33
Type
journal article
Language
en
Open access
Licence
Locations
  • Journal of Biological Chemistry (publishedVersion, cc-by)
  • bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion, cc-by-nc-nd)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • PubMed Central (submittedVersion, cc-by-nc-nd)
Funders
  • National Institutes of Health
  • National Institute of General Medical Sciences (R00GM127757, R35GM146739)
  • National Science Foundation (2142670)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Microtubule and mitosis dynamics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic and Kidney Cyst Diseases
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Biotin and Related Studies
Keywords
Ndel1, NDE1, dynein activation, LIS1, dynactin, microtubule motor proteins, protein-protein binding, phosphomimetic mutations, single-molecule imaging

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