Regulators of the cytoplasmic dynein motor. Nat Rev Mol Cell Biol

Department of Biology, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, USA.
Nature Reviews Molecular Cell Biology (Impact Factor: 37.81). 12/2009; 10(12):854-65. DOI: 10.1038/nrm2804
Source: PubMed


Eukaryotic cells use cytoskeletal motor proteins to transport many different intracellular cargos. Numerous kinesins and myosins have evolved to cope with the various transport needs that have arisen during eukaryotic evolution. Surprisingly, a single cytoplasmic dynein (a minus end-directed microtubule motor) carries out similarly diverse transport activities as the many different types of kinesin. How is dynein coupled to its wide range of cargos and how is it spatially and temporally regulated? The answer could lie in the several multifunctional adaptors, including dynactin, lissencephaly 1, nuclear distribution protein E (NUDE) and NUDE-like, Bicaudal D, Rod-ZW10-Zwilch and Spindly, that regulate dynein function and localization.

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Available from: Julia R Kardon, Dec 18, 2013
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    • "Dynein forms a multiprotein complex consisting of two heavy chains and several subunits, intermediate, light intermediate, and light chains, and interacts with additional regulatory protein complexes such as the dynactin complex. These interactions are thought to target dynein to subcellular structures and cargos and to regulate dynein motor activity (Kardon and Vale, 2009; Vallee et al., 2012; Roberts et al., 2013). In fission yeast, the intermediate chain Dic1, the light intermediate chain Dli1 and the dynactin component Ssm4, homologous to Glued, are all absolutely required to generate dynein-dependent pulling forces during horsetail nuclear movement because dynein localization to MTs is disrupted in their absence (Niccoli et al., 2004; Fujita et al., 2010). "
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    ABSTRACT: Microtubules (MTs) and associated motors play a central role in nuclear migration, which is crucial for diverse biological functions including cell division, polarity, and sexual reproduction. In this paper, we report a dual mechanism underlying nuclear congression during fission yeast karyogamy upon mating of haploid cells. Using microfluidic chambers for long-term imaging, we captured the precise timing of nuclear congression and identified two minus end-directed motors operating in parallel in this process. Kinesin-14 Klp2 associated with MTs may cross-link and slide antiparallel MTs emanating from the two nuclei, whereas dynein accumulating at spindle pole bodies (SPBs) may pull MTs nucleated from the opposite SPB. Klp2-dependent nuclear congression proceeds at constant speed, whereas dynein accumulation results in an increase of nuclear velocity over time. Surprisingly, the light intermediate chain Dli1, but not dynactin, is required for this previously unknown function of dynein. We conclude that efficient nuclear congression depends on the cooperation of two minus end-directed motors. © 2015 Scheffler et al.
    The Journal of Cell Biology 04/2015; 209(1):47-58. DOI:10.1083/jcb.201409087 · 9.83 Impact Factor
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    • "Overall these findings suggest that mutations in BICD2 predominantly affect dynein function in motor neurons and that the effect of mutant DYNC1H1 on cortical development and neuronal migration is largely independent of BICD2. This notion is compatible with the finding that the dynein motor uses multiple adaptors, including different BICD family members (Kardon and Vale, 2009; Terenzio and Schiavo, 2010) to associate with different cargos. "
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    ABSTRACT: Spinal muscular atrophy is a disorder of lower motor neurons, most commonly caused by recessive mutations in SMN1 on chromosome 5q. Cases without SMN1 mutations are subclassified according to phenotype. Spinal muscular atrophy, lower extremity-predominant, is characterized by lower limb muscle weakness and wasting, associated with reduced numbers of lumbar motor neurons and is caused by mutations in DYNC1H1, which encodes a microtubule motor protein in the dynein-dynactin complex and one of its cargo adaptors, BICD2. We have now identified 32 patients with BICD2 mutations from nine different families, providing detailed insights into the clinical phenotype and natural history of BICD2 disease. BICD2 spinal muscular atrophy, lower extremity predominant most commonly presents with delayed motor milestones and ankle contractures. Additional features at presentation include arthrogryposis and congenital dislocation of the hips. In all affected individuals, weakness and wasting is lower-limb predominant, and typically involves both proximal and distal muscle groups. There is no evidence of sensory nerve involvement. Upper motor neuron signs are a prominent feature in a subset of individuals, including one family with exclusively adult-onset upper motor neuron features, consistent with a diagnosis of hereditary spastic paraplegia. In all cohort members, lower motor neuron features were static or only slowly progressive, and the majority remained ambulant throughout life. Muscle MRI in six individuals showed a common pattern of muscle involvement with fat deposition in most thigh muscles, but sparing of the adductors and semitendinosus. Muscle pathology findings were highly variable and included pseudomyopathic features, neuropathic features, and minimal change. The six causative mutations, including one not previously reported, result in amino acid changes within all three coiled-coil domains of the BICD2 protein, and include a possible 'hot spot' mutation, p.Ser107Leu present in four families. We used the recently solved crystal structure of a highly conserved region of the Drosophila orthologue of BICD2 to further-explore how the p.Glu774Gly substitution inhibits the binding of BICD2 to Rab6. Overall, the features of BICD2 spinal muscular atrophy, lower extremity predominant are consistent with a pathological process that preferentially affects lumbar lower motor neurons, with or without additional upper motor neuron involvement. Defining the phenotypic features in this, the largest BICD2 disease cohort reported to date, will facilitate focused genetic testing and filtering of next generation sequencing-derived variants in cases with similar features. © 2014 The Author (2014). Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For Permissions, please email: [email protected] /* */
    Brain 02/2015; DOI:10.1093/brain/awu356 · 9.20 Impact Factor
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    • "One potential advantage of directing vesicles toward the minus ends of microtubules is that they are likely to form a single aggregate near the cell center, which should provide a strong signal. We adapted the strategy developed by Kapitein et al., 2010a,b, who investigated dynein-driven peroxisome transport by inducibly linking BicD2, a dynein cargo adaptor, to peroxisomes (Dienstbier and Li, 2009; Kardon and Vale, 2009). We expressed a protein, tandem dimer Tomato (tdTM)–BicD2 594 –FK506 binding protein (FKBP), consisting of FKBP fused to the dynein-binding fragment of BicD2, which was coexpressed with FRB-Rab5 (Fig. 1 A). "
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    ABSTRACT: Identifying the proteins that regulate vesicle trafficking is a fundamental problem in cell biology. In this paper, we introduce a new assay that involves the expression of an FKBP12-rapamycin-binding domain-tagged candidate vesicle-binding protein, which can be inducibly linked to dynein or kinesin. Vesicles can be labeled by any convenient method. If the candidate protein binds the labeled vesicles, addition of the linker drug results in a predictable, highly distinctive change in vesicle localization. This assay generates robust and easily interpretable results that provide direct experimental evidence of binding between a candidate protein and the vesicle population of interest. We used this approach to compare the binding of Kinesin-3 family members with different endosomal populations. We found that KIF13A and KIF13B bind preferentially to early endosomes and that KIF1A and KIF1Bβ bind preferentially to late endosomes and lysosomes. This assay may have broad utility for identifying the trafficking proteins that bind to different vesicle populations. © 2015 Bentley et al.
    The Journal of Cell Biology 01/2015; 208(3). DOI:10.1083/jcb.201408056 · 9.83 Impact Factor
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