Coil-to-α-helix transition at the Nup358-BicD2 interface activates BicD2 for dynein recruitment

Gibson, James M.; Cui, Haixia; Ali, M. Yusuf; Zhao, Xioaxin; Debler, Erik; Zhao, Jing; Trybus, Kathleen M.; Solmaz, Sozanne R.; Wang, Chunyu

doi:10.7554/elife.74714

Cited by 16 publications

(48 citation statements)

References 112 publications

(433 reference statements)

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“…Nonetheless, based on our in vivo and immunoprecipitation results, we hypothesized that JIP3 can form a tripartite complex with dynein and dynactin, possibly through a transition of its disordered domain into a more ordered conformation upon binding to dynein/dynactin. A similar disorder-to-order transition has been recently reported for Nup358, which changed a random coil into an α-helix upon binding to BicD2 ( Gibson et al, 2022 ).…”

Section: Resultssupporting

confidence: 80%

Doublecortin and JIP3 are neural-specific counteracting regulators of dynein-mediated retrograde trafficking

Rao

Liu

et al. 2022

eLife

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Mutations in the microtubule (MT)-binding protein doublecortin (DCX) or in the MT-based molecular motor dynein result in lissencephaly. However, a functional link between DCX and dynein has not been defined. Here, we demonstrate that DCX negatively regulates dynein-mediated retrograde transport in neurons from Dcx-/y or Dcx-/y;Dclk1-/- mice by reducing dynein's association with MTs and by disrupting the composition of the dynein motor complex. Previous work showed an increased binding of the adaptor protein C-Jun-amino-terminal kinase-interacting protein 3 (JIP3) to dynein in the absence of DCX. Using purified components, we demonstrate that JIP3 forms an active motor complex with dynein and its cofactor dynactin with two dyneins per complex. DCX competes with the binding of the second dynein, resulting in a velocity reduction of the complex. We conclude that DCX negatively regulates dynein-mediated retrograde transport through two critical interactions by regulating dynein binding to MTs and by regulating the composition of the dynein motor complex.

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Section: Resultssupporting

confidence: 80%

Doublecortin and JIP3 are neural-specific counteracting regulators of dynein-mediated retrograde trafficking

Rao

Liu

et al. 2022

eLife

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“…In comparison, activation of the DDT complex may block the entire kinesin binding site, and thereby, exclude kinesin from motile DDT complexes. Alternatively, TRAK may coordinate motor binding through a registry shift of its coiled coils, as proposed for the BicD2 adaptor 49 . These possibilities could be best distinguished by future cryo-electron imaging of reconstituted DDKT complexes at near-atomic resolution.…”

Section: Discussionmentioning

confidence: 99%

TRAK adaptors regulate the recruitment and activation of dynein and kinesin in mitochondrial transport

Canty¹,

Hensley

Aslan³

et al. 2023

Nat Commun

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Mitochondrial transport along microtubules is mediated by Miro1 and TRAK adaptors that recruit kinesin-1 and dynein-dynactin. To understand how these opposing motors are regulated during mitochondrial transport, we reconstitute the bidirectional transport of Miro1/TRAK along microtubules in vitro. We show that the coiled-coil domain of TRAK activates dynein-dynactin and enhances the motility of kinesin-1 activated by its cofactor MAP7. We find that TRAK adaptors that recruit both motors move towards kinesin-1’s direction, whereas kinesin-1 is excluded from binding TRAK transported by dynein-dynactin, avoiding motor tug-of-war. We also test the predictions of the models that explain how mitochondrial transport stalls in regions with elevated Ca2+. Transport of Miro1/TRAK by kinesin-1 is not affected by Ca2+. Instead, we demonstrate that the microtubule docking protein syntaphilin induces resistive forces that stall kinesin-1 and dynein-driven motility. Our results suggest that mitochondrial transport stalls by Ca2+-mediated recruitment of syntaphilin to the mitochondrial membrane, not by disruption of the transport machinery.

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“…In view of these data, we tested whether BICD2 can accommodate both NE-binding cargo proteins at once (Fig 2A). We note that the RanBP2 fragment (aa 2148-2240) is the minimal BICD2-binding fragment, which can bind to the full-length BICD2 to form processive dynein/ dynactin/BICD2/RanBP2 complexes in in vitro assays [40] The experiment was repeated with the RanBP2 fragment, which also clearly interacted with BICD2-CC3, since the elution volumes of both RanBP2 and BICD2-CC3 were shifted towards higher mass when the complex was analyzed compared to the individual proteins ( , and 2H). We have previously determined the molar masses of the RanBP2/BICD2-CC3 complex and the individual proteins by size-exclusion chromatography coupled to multi-angle light scattering, which is highly accurate (<5% error) and by smallangle X-ray scattering.…”

Section: Overlapping But Distinct Nesprin-2 Vs Ranbp2 Binding To Regi...mentioning

confidence: 92%

“…In brief, all expression constructs were obtained from commercial gene synthesis and codon optimized for expression in E. coli (Genscript). For sequences of Ms BICD2-CC3 (aa 711-800) and Hs RanBP2 (aa 2148-2240) see [40]. For the sequence of Ms Nesprin-2, see S1A Fig.…”

Section: Plos Geneticsmentioning

confidence: 99%

Role of Nesprin-2 and RanBP2 in BICD2-associated brain developmental disorders

Zhao

Noell

et al. 2023

PLoS Genet

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Bicaudal D2 (BICD2) is responsible for recruiting cytoplasmic dynein to diverse forms of subcellular cargo for their intracellular transport. Mutations in the human BICD2 gene have been found to cause an autosomal dominant form of spinal muscular atrophy (SMA-LED2), and brain developmental defects. Whether and how the latter mutations are related to roles we and others have identified for BICD2 in brain development remains little understood. BICD2 interacts with the nucleoporin RanBP2 to recruit dynein to the nuclear envelope (NE) of Radial Glial Progenitor cells (RGPs) to mediate their well-known but mysterious cell-cycle-regulated interkinetic nuclear migration (INM) behavior, and their subsequent differentiation to form cortical neurons. We more recently found that BICD2 also mediates NE dynein recruitment in migrating post-mitotic neurons, though via a different interactor, Nesprin-2. Here, we report that Nesprin-2 and RanBP2 compete for BICD2-binding in vitro. To test the physiological implications of this behavior, we examined the effects of known BICD2 mutations using in vitro biochemical and in vivo electroporation-mediated brain developmental assays. We find a clear relationship between the ability of BICD2 to bind RanBP2 vs. Nesprin-2 in controlling of nuclear migration and neuronal migration behavior. We propose that mutually exclusive RanBP2-BICD2 vs. Nesprin-2-BICD2 interactions at the NE play successive, critical roles in INM behavior in RGPs and in post-mitotic neuronal migration and errors in these processes contribute to specific human brain malformations.

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Coil-to-α-helix transition at the Nup358-BicD2 interface activates BicD2 for dynein recruitment

Cited by 16 publications

References 112 publications

Doublecortin and JIP3 are neural-specific counteracting regulators of dynein-mediated retrograde trafficking

Doublecortin and JIP3 are neural-specific counteracting regulators of dynein-mediated retrograde trafficking

TRAK adaptors regulate the recruitment and activation of dynein and kinesin in mitochondrial transport

Role of Nesprin-2 and RanBP2 in BICD2-associated brain developmental disorders

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