Ndel1 disfavors dynein-dynactin-adaptor complex formation in two distinct ways.
Lis1
Nde1
Ndel1
cytoplasmic dynein-1
dynactin
microtubules
Journal
The Journal of biological chemistry
ISSN: 1083-351X
Titre abrégé: J Biol Chem
Pays: United States
ID NLM: 2985121R
Informations de publication
Date de publication:
06 2023
06 2023
Historique:
received:
26
01
2023
revised:
13
04
2023
accepted:
17
04
2023
medline:
28
6
2023
pubmed:
23
4
2023
entrez:
22
04
2023
Statut:
ppublish
Résumé
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.
Identifiants
pubmed: 37086789
pii: S0021-9258(23)01763-5
doi: 10.1016/j.jbc.2023.104735
pmc: PMC10248797
pii:
doi:
Substances chimiques
1-Alkyl-2-acetylglycerophosphocholine Esterase
EC 3.1.1.47
Dynactin Complex
0
Dyneins
EC 3.6.4.2
Microtubule-Associated Proteins
0
NDEL1 protein, human
0
PAFAH1B1 protein, human
EC 3.1.1.47
Carrier Proteins
0
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, U.S. Gov't, Non-P.H.S.
Langues
eng
Sous-ensembles de citation
IM
Pagination
104735Subventions
Organisme : NIGMS NIH HHS
ID : R00 GM127757
Pays : United States
Organisme : NIGMS NIH HHS
ID : R35 GM146739
Pays : United States
Informations de copyright
Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.
Déclaration de conflit d'intérêts
Conflict of interest The authors declare that they have no conflicts of interest with the contents of this article.
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