Identification of a Novel Site in the Tail of Dynein Heavy Chain Important for Dynein Function in Vivo

Qiu, Rongde; Zhang, Jun; Xiang, Xin

doi:10.1074/jbc.m112.412403

Cited by 24 publications

(26 citation statements)

References 79 publications

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“…To do that, we examined the effect of a previously identified dynein loss-offunction mutation, nudA F208V . The nudA F208V mutation in the dynein tail impairs dynein-mediated nuclear distribution and early endosome transport but does not affect dynein-dynactin interaction or dynein-early-endosome interaction (Qiu et al, 2013), consistent with the importance of the tail in dynein motor activity (Ori-McKenney et al, 2010;Rao et al, 2013;Hoang et al, 2017). Upon overexpression of ΔC-HookA, plus-end comets formed by GFP-dynein with the nudA F208V mutation were still detected ( Fig.…”

Section: Resultssupporting

confidence: 73%

LIS1 regulates cargo-adapter–mediated activation of dynein by overcoming its autoinhibition in vivo

Qiu

Zhang

Xiang

2019

Journal of Cell Biology

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148

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Deficiency of the LIS1 protein causes lissencephaly, a brain developmental disorder. Although LIS1 binds the microtubule motor cytoplasmic dynein and has been linked to dynein function in many experimental systems, its mechanism of action remains unclear. Here, we revealed its function in cargo-adapter–mediated dynein activation in the model organism Aspergillus nidulans. Specifically, we found that overexpressed cargo adapter HookA (Hook in A. nidulans) missing its cargo-binding domain (ΔC-HookA) causes dynein and its regulator dynactin to relocate from the microtubule plus ends to the minus ends, and this relocation requires LIS1 and its binding protein, NudE. Astonishingly, the requirement for LIS1 or NudE can be bypassed to a significant extent by mutations that prohibit dynein from forming an autoinhibited conformation in which the motor domains of the dynein dimer are held close together. Our results suggest a novel mechanism of LIS1 action that promotes the switch of dynein from the autoinhibited state to an open state to facilitate dynein activation.

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Section: Resultssupporting

confidence: 73%

LIS1 regulates cargo-adapter–mediated activation of dynein by overcoming its autoinhibition in vivo

Qiu

Zhang

Xiang

2019

Journal of Cell Biology

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148

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“…To do that, we examined the effect of a previously identified dynein loss-of-function mutation, nudA F208V . The nudA F208V mutation in the dynein tail impairs dynein-mediated nuclear distribution and early endosome transport but does not affect dynein-dynactin interaction or dynein-early endosome interaction (Qiu et al, 2013), consistent with the importance of the tail in dynein motor activity (Ori-McKenney et al, 2010;Rao et al, 2013;Hoang et al, 2017). Upon overexpression of ∆C-HookA, plus-end comets formed by GFP-dynein with the nudA F208V mutation were still detected ( Figure 1I), confirming that functional dynein is needed for this relocation.…”

Section: Dynein and Dynactin Are Relocated From The Mt Plus Ends To Tsupporting

confidence: 63%

“…Quantitation of the protein band intensity was done using the IPLab software as described previously (Qiu et al, 2013). The antibody against GFP (polyclonal) was from Takara Bio Inc.…”

Section: Biochemical Pull-down Assays and Western Analysismentioning

confidence: 99%

Insights into LIS1 function in cargo-adapter-mediated dynein activation in vivo

Qiu

Zhang

Xiang

2019

Preprint

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This study reveals the role of Lissencephaly 1 (LIS1) in cargo-adapter-mediated dynein activation. Furthermore, it discovers a novel mechanism of LIS1 action involving a switch of dynein from an auto-inhibited state to an active state.2 AbstractDeficiency of the LIS1 protein causes lissencephaly, a brain developmental disorder. Although LIS1 binds the microtubule motor cytoplasmic dynein and has been linked to dynein function in many experimental systems, its mechanism of action remains unclear. Here we revealed the function of LIS1 in cargo-adapter-mediated dynein activation in the model organism Aspergillus nidulans. Specifically, we found that overexpressed cargo adapter HookA (Hook in A. nidulans) missing its cargo-binding domain (∆C-HookA) causes dynein and its regulator dynactin to relocate from the microtubule plus ends to the minus ends, and this dramatic relocation requires LIS1 and its binding protein NudE. Astonishingly, the requirement for LIS1 or NudE can be bypassed to a significant extent by specific mutations that open the auto-inhibited "phi-dynein" in which the motor domains of the dynein dimer are held close together. Our results suggest a novel mechanism of LIS1 action: it promotes the switch of dynein from the auto-inhibited state to an open state to facilitate dynein activation.

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“…Because the study was performed in the absence of processivity activators it is, however, unclear how the findings relate to our observations of the effect of the Loa mutation on dynein-dynactin-BICD2N complexes. It has also be demonstrated that a mutation in the tail of DYNC1H1 in the filamentous fungus Aspergillus nidulans (in a residue equivalent to position 186 of the human protein) reduces the frequency and velocity of minus end-directed cargo transport in vivo without affecting the composition of the dynein complex or its association with dynactin (62). Our study reveals that the ability of the tail to regulate the behavior of the motor domain is not just restricted to the regions containing the Loa and Aspergillus mutations.…”

Section: Mechanistic Effects Of Disease-associated Dync1h1 Mutationsmentioning

confidence: 99%

DYNC1H1 mutations associated with neurological diseases compromise processivity of dynein-dynactin-cargo adaptor complexes

Hoang

Schlager

Carter

et al. 2016

Preprint

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Mutations in the human DYNC1H1 gene are associated with neurological diseases. DYNC1H1 encodes the heavy chain of cytoplasmic dynein-1, a 1.4 MDa motor complex that traffics organelles, vesicles and macromolecules towards microtubule minus ends. The effects of the DYNC1H1 mutations on dynein motility, and consequently their links to neuropathology, are not understood. Here, we address this issue using a recombinant expression system for human dynein coupled to single-molecule resolution in vitro motility assays. We functionally characterise 14 DYNC1H1 mutations identified in humans diagnosed with malformations in cortical development (MCD) or spinal muscular atrophy with lower extremity predominance (SMALED), as well as three mutations that cause motor and sensory defects in mice. Two of the human mutations, R1962C and H3822P, strongly interfere with dynein's core mechanochemical properties. The remaining mutations selectively compromise the processive mode of dynein movement that is activated by binding to the accessory complex dynactin and the cargo adaptor BICD2. Mutations with the strongest effects on dynein motility in vitro are associated with MCD. The vast majority of mutations do not affect binding of dynein to dynactin and BICD2, and are therefore expected to result in linkage of cargoes to dynein-dynactin complexes that have defective long-range motility. This observation offers an explanation for the dominant effects of DYNC1H1 mutations in vivo. Collectively, our results suggest that compromised processivity of cargo-motor assemblies contributes to human neurological disease and provide insight into the influence of different regions of the heavy chain on dynein motility.

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Identification of a Novel Site in the Tail of Dynein Heavy Chain Important for Dynein Function in Vivo

Cited by 24 publications

References 79 publications

LIS1 regulates cargo-adapter–mediated activation of dynein by overcoming its autoinhibition in vivo

LIS1 regulates cargo-adapter–mediated activation of dynein by overcoming its autoinhibition in vivo

Insights into LIS1 function in cargo-adapter-mediated dynein activation in vivo

DYNC1H1 mutations associated with neurological diseases compromise processivity of dynein-dynactin-cargo adaptor complexes

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