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

Garrott, Sharon R.; Gillies, John P.; Siva, Aravintha; Little, Saffron R.; Jbeily, Rita El; DeSantis, Morgan E.

doi:10.1016/j.jbc.2023.104735

Cited by 9 publications

(4 citation statements)

References 82 publications

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“…Very recent work using human proteins have demonstrated a similar capacity for Ndel1 to inhibit the assembly of motile DDA complexes 69 , likely by competing with p150 for the ICN, as demonstrated here. However, in support of a positive role in dynein activity, another recent study found that Nde1-mediated recruitment of LIS1 to dynein indeed enhances DDA assembly 93 .…”

Section: Discussionsupporting

confidence: 71%

“…Taken together, these data indicate that the coiled-coil domain of Ndl1/Ndel1 and the dynein motor domain compete for Pac1/LIS1 binding, suggesting that Ndl1/Ndel1-recruited Pac1/LIS1 must first unbind from Ndl1/Ndel1 prior to binding dynein. Recently published data affirm this conclusion 69 .…”

Section: Resultsmentioning

confidence: 65%

“…6 ) are in part coordinated through changes in the phosphorylation status of Ndel1 and LIS1. Indeed, a recent report demonstrated that phosphorylation mimicking mutations of Ndel1 enhance its affinity for dynein, leading to enhanced disruption of DDA complexes in vitro 69 .…”

Section: Discussionmentioning

confidence: 99%

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Conserved roles for the dynein intermediate chain and Ndel1 in assembly and activation of dynein

Okada,

Iyer,

Lammers

et al. 2023

Nat Commun

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Processive transport by the microtubule motor cytoplasmic dynein requires the regulated assembly of a dynein-dynactin-adapter complex. Interactions between dynein and dynactin were initially ascribed to the dynein intermediate chain N-terminus and the dynactin subunit p150Glued. However, recent cryo-EM structures have not resolved this interaction, questioning its importance. The intermediate chain also interacts with Nde1/Ndel1, which compete with p150Glued for binding. We reveal that the intermediate chain N-terminus is a critical evolutionarily conserved hub that interacts with dynactin and Ndel1, the latter of which recruits LIS1 to drive complex assembly. In additon to revealing that the intermediate chain N-terminus is likely bound to p150Glued in active transport complexes, our data support a model whereby Ndel1-LIS1 must dissociate prior to LIS1 being handed off to dynein in temporally discrete steps. Our work reveals previously unknown steps in the dynein activation pathway, and provide insight into the integrated activities of LIS1/Ndel1 and dynactin/cargo-adapters.

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Section: Discussionsupporting

confidence: 71%

Section: Resultsmentioning

confidence: 65%

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Conserved roles for the dynein intermediate chain and Ndel1 in assembly and activation of dynein

Okada,

Iyer,

Lammers

et al. 2023

Nat Commun

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“…The interaction of DIC-N with p150 appears similar to its interaction with another dynein regulator, Ndel1 ( 39 ). This explains the proposed competition between Ndel1 and p150 for dynein binding ( 37 , 39 , 82 , 83 ) and suggests that Ndel1 will need to be displaced before DIC-N can initiate DDA assembly ( 39 , 82 , 83 ).…”

Section: Discussionmentioning

confidence: 93%

Molecular mechanism of dynein-dynactin complex assembly by LIS1

Singh,

Lau,

Manigrasso

et al. 2024

Science

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Cytoplasmic dynein is a microtubule motor vital for cellular organization and division. It functions as a ~4-megadalton complex containing its cofactor dynactin and a cargo-specific coiled-coil adaptor. However, how dynein and dynactin recognize diverse adaptors, how they interact with each other during complex formation, and the role of critical regulators such as lissencephaly-1 (LIS1) protein (LIS1) remain unclear. In this study, we determined the cryo–electron microscopy structure of dynein-dynactin on microtubules with LIS1 and the lysosomal adaptor JIP3. This structure reveals the molecular basis of interactions occurring during dynein activation. We show how JIP3 activates dynein despite its atypical architecture. Unexpectedly, LIS1 binds dynactin’s p150 subunit, tethering it along the length of dynein. Our data suggest that LIS1 and p150 constrain dynein-dynactin to ensure efficient complex formation.

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Myosin phosphatase targeting subunit1 controls localization and motility of Rab7‐containing vesicles: Is myosin phosphatase a cytoplasmic dynein regulator?

Matsumura,

Murayama,

Kuriyama

et al. 2024

Cytoskeleton

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Myosin phosphatase targeting subunit1 (MYPT1) is a critical subunit of myosin phosphatase (MP), which brings PP1Cδ phosphatase and its substrate together. We previously showed that MYPT1 depletion resulted in oblique chromatid segregation. Therefore, we hypothesized that MYPT1 may control microtubule‐dependent motor activity. Dynein, a minus‐end microtubule motor, is known to be involved in mitotic spindle assembly. We thus examined whether MYPT1 and dynein may interact. Proximity ligation assay and co‐immunoprecipitation revealed that MYPT1 and dynein intermediate chain (DIC) were associated. We found that DIC phosphorylation is increased in MYPT1‐depleted cells in vivo, and that MP was able to dephosphorylate DIC in vitro. MYPT1 depletion also altered the localization and motility of Rab7‐containing vesicles. MYPT1‐depletion dispersed the perinuclear Rab7 localization to the peripheral in interphase cells. The dispersed Rab7 localization was rescued by microinjection of a constitutively active, truncated MYPT1 mutant, supporting that MP is responsible for the altered Rab7 localization. Analyses of Rab7 vesicle trafficking also revealed that minus‐end transport was reduced in MYPT1‐depleted cells. These results suggest an unexpected role of MP: MP controls dynein activity in both mitotic and interphase cells, possibly by dephosphorylating dynein subunits including DIC.

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

Cited by 9 publications

References 82 publications

Conserved roles for the dynein intermediate chain and Ndel1 in assembly and activation of dynein

Conserved roles for the dynein intermediate chain and Ndel1 in assembly and activation of dynein

Molecular mechanism of dynein-dynactin complex assembly by LIS1

Myosin phosphatase targeting subunit1 controls localization and motility of Rab7‐containing vesicles: Is myosin phosphatase a cytoplasmic dynein regulator?

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