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Dynactin

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https://www.readbyqxmd.com/read/29420470/cryo-em-shows-how-dynactin-recruits-two-dyneins-for-faster-movement
#1
Linas Urnavicius, Clinton K Lau, Mohamed M Elshenawy, Edgar Morales-Rios, Carina Motz, Ahmet Yildiz, Andrew P Carter
Dynein and its cofactor dynactin form a highly processive microtubule motor in the presence of an activating adaptor, such as BICD2. Different adaptors link dynein and dynactin to distinct cargoes. Here we use electron microscopy and single-molecule studies to show that adaptors can recruit a second dynein to dynactin. Whereas BICD2 is biased towards recruiting a single dynein, the adaptors BICDR1 and HOOK3 predominantly recruit two dyneins. We find that the shift towards a double dynein complex increases both the force and speed of the microtubule motor...
February 7, 2018: Nature
https://www.readbyqxmd.com/read/29416113/cryo-electron-tomography-reveals-that-dynactin-recruits-a-team-of-dyneins-for-processive-motility
#2
Danielle A Grotjahn, Saikat Chowdhury, Yiru Xu, Richard J McKenney, Trina A Schroer, Gabriel C Lander
Cytoplasmic dynein is a protein complex that transports molecular cargo along microtubules (MTs), playing a key role in the intracellular trafficking network. Vertebrate dynein's movement becomes strikingly enhanced upon interacting with dynactin and a cargo adaptor such as BicaudalD2. However, the mechanisms responsible for increased transport activity are not well understood, largely owing to limited structural information. We used cryo-electron tomography (cryo-ET) to visualize the 3D structure of the MT-bound dynein-dynactin complex from Mus musculus and show that the dynactin-cargo adaptor complex binds two dimeric dyneins...
February 7, 2018: Nature Structural & Molecular Biology
https://www.readbyqxmd.com/read/29401420/cooperative-accumulation-of-dynein-dynactin-at-microtubule-minus-ends-drives-microtubule-network-reorganization
#3
Ruensern Tan, Peter J Foster, Daniel J Needleman, Richard J McKenney
Cytoplasmic dynein-1 is a minus-end-directed motor protein that transports cargo over long distances and organizes the intracellular microtubule (MT) network. How dynein motor activity is harnessed for these diverse functions remains unknown. Here, we have uncovered a mechanism for how processive dynein-dynactin complexes drive MT-MT sliding, reorganization, and focusing, activities required for mitotic spindle assembly. We find that motors cooperatively accumulate, in limited numbers, at MT minus-ends. Minus-end accumulations drive MT-MT sliding, independent of MT orientation, resulting in the clustering of MT minus-ends...
January 22, 2018: Developmental Cell
https://www.readbyqxmd.com/read/29273399/behavioral-defects-in-a-dctn1g71a-transgenic-mouse-model-of-perry-syndrome
#4
Takayasu Mishima, Manami Deshimaru, Takuya Watanabe, Kaori Kubota, Mariko Kinoshita-Kawada, Junichi Yuasa-Kawada, Kotaro Takasaki, Yoshinari Uehara, Shozo Jinno, Katsunori Iwasaki, Yoshio Tsuboi
Perry syndrome is a rare neurodegenerative disease characterized by parkinsonism, depression/apathy, weight loss, and central hypoventilation. Our previously-conducted genome-wide association scan and subsequent studies identified nine mutations in DCTN1, the largest protein subunit of the dynactin complex, in patients with Perry syndrome. These included G71A in the microtubule-binding cytoskeleton-associated protein Gly-rich domain of p150Glued. The dynactin complex is essential for function of the microtubule-based cytoplasmic retrograde motor dynein...
December 19, 2017: Neuroscience Letters
https://www.readbyqxmd.com/read/29222185/p37-ubxn2b-regulates-spindle-orientation-by-limiting-cortical-numa-recruitment-via-pp1-repo-man
#5
Byung Ho Lee, Francoise Schwager, Patrick Meraldi, Monica Gotta
Spindle orientation determines the axis of division and is crucial for cell fate, tissue morphogenesis, and the development of an organism. In animal cells, spindle orientation is regulated by the conserved Gαi-LGN-NuMA complex, which targets the force generator dynein-dynactin to the cortex. In this study, we show that p37/UBXN2B, a cofactor of the p97 AAA ATPase, regulates spindle orientation in mammalian cells by limiting the levels of cortical NuMA. p37 controls cortical NuMA levels via the phosphatase PP1 and its regulatory subunit Repo-Man, but it acts independently of Gαi, the kinase Aurora A, and the phosphatase PP2A...
December 8, 2017: Journal of Cell Biology
https://www.readbyqxmd.com/read/29185983/numa-recruits-dynein-activity-to-microtubule-minus-ends-at-mitosis
#6
Christina L Hueschen, Samuel J Kenny, Ke Xu, Sophie Dumont
To build the spindle at mitosis, motors exert spatially regulated forces on microtubules. We know that dynein pulls on mammalian spindle microtubule minus-ends, and this localized activity at ends is predicted to allow dynein to cluster microtubules into poles. How dynein becomes enriched at minus-ends is not known. Here, we use quantitative imaging and laser ablation to show that NuMA targets dynactin to minus-ends, localizing dynein activity there. NuMA is recruited to new minus-ends independently of dynein and more quickly than dynactin; both NuMA and dynactin display specific, steady-state binding at minus-ends...
November 29, 2017: ELife
https://www.readbyqxmd.com/read/29184507/kir2-1-nav1-5-channel-complexes-are-differently-regulated-than-kir2-1-and-nav1-5-channels-alone
#7
Raquel G Utrilla, Paloma Nieto-Marín, Silvia Alfayate, David Tinaquero, Marcos Matamoros, Marta Pérez-Hernández, Sandra Sacristán, Lorena Ondo, Raquel de Andrés, F Javier Díez-Guerra, Juan Tamargo, Eva Delpón, Ricardo Caballero
Cardiac Kir2.1 and Nav1.5 channels generate the inward rectifier K+ (IK1) and the Na+ (INa) currents, respectively. There is a mutual interplay between the ventricular INa and IK1 densities, because Nav1.5 and Kir2.1 channels exhibit positive reciprocal modulation. Here we compared some of the biological properties of Nav1.5 and Kir2.1 channels when they are expressed together or separately to get further insights regarding their putative interaction. First we demonstrated by proximity ligation assays (PLAs) that in the membrane of ventricular myocytes Nav1...
2017: Frontiers in Physiology
https://www.readbyqxmd.com/read/29107549/myosin-2-induced-mitotic-rounding-enables-columnar-epithelial-cells-to-interpret-cortical-spindle-positioning-cues
#8
Soline Chanet, Rishabh Sharan, Zia Khan, Adam C Martin
During epithelial cell proliferation, planar alignment of the mitotic spindle allows the daughter cells to stay within the epithelium. Previous work has identified cortical cues that regulate spindle orientation and the division axis [1, 2]. One such cue is cortical Pins (LGN in vertebrates) [3-6], which recruits the conserved Mud/NuMA protein and the dynein/dynactin complex to the cortex. The dynein/dynactin motor complex pulls astral microtubules to orient the spindle. Cortical Pins can therefore dictate the division axis...
November 6, 2017: Current Biology: CB
https://www.readbyqxmd.com/read/29073112/dynein-dynactin-is-necessary-for-anterograde-transport-of-mbp-mrna-in-oligodendrocytes-and-for-myelination-in-vivo
#9
Amy L Herbert, Meng-Meng Fu, Catherine M Drerup, Ryan S Gray, Breanne L Harty, Sarah D Ackerman, Thomas O'Reilly-Pol, Stephen L Johnson, Alex V Nechiporuk, Ben A Barres, Kelly R Monk
Oligodendrocytes in the central nervous system produce myelin, a lipid-rich, multilamellar sheath that surrounds axons and promotes the rapid propagation of action potentials. A critical component of myelin is myelin basic protein (MBP), expression of which requires anterograde mRNA transport followed by local translation at the developing myelin sheath. Although the anterograde motor kinesin KIF1B is involved in mbp mRNA transport in zebrafish, it is not entirely clear how mbp transport is regulated. From a forward genetic screen for myelination defects in zebrafish, we identified a mutation in actr10, which encodes the Arp11 subunit of dynactin, a critical activator of the retrograde motor dynein...
October 24, 2017: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/29038173/combinatorial-regulation-of-the-balance-between-dynein-microtubule-end-accumulation-and-initiation-of-directed-motility
#10
Rupam Jha, Johanna Roostalu, Nicholas I Cade, Martina Trokter, Thomas Surrey
Cytoplasmic dynein is involved in a multitude of essential cellular functions. Dynein's activity is controlled by the combinatorial action of several regulatory proteins. The molecular mechanism of this regulation is still poorly understood. Using purified proteins, we reconstitute the regulation of the human dynein complex by three prominent regulators on dynamic microtubules in the presence of end binding proteins (EBs). We find that dynein can be in biochemically and functionally distinct pools: either tracking dynamic microtubule plus-ends in an EB-dependent manner or moving processively towards minus ends in an adaptor protein-dependent manner...
November 15, 2017: EMBO Journal
https://www.readbyqxmd.com/read/29035202/localised-dynactin-protects-growing-microtubules-to-deliver-oskar-mrna-to-the-posterior-cortex-of-the-drosophila-oocyte
#11
Ross Nieuwburg, Dmitry Nashchekin, Maximilian Jakobs, Andrew P Carter, Philipp Khuc Trong, Raymond E Goldstein, Daniel St Johnston
The localisation of oskar mRNA to the posterior of the Drosophila oocyte defines where the abdomen and germ cells form in the embryo. Kinesin 1 transports oskar mRNA to the oocyte posterior along a polarised microtubule cytoskeleton that grows from non-centrosomal microtubule organising centres (ncMTOCs) along the anterior/lateral cortex. Here, we show that the formation of this polarised microtubule network also requires the posterior regulation of microtubule growth. A missense mutation in the dynactin Arp1 subunit causes most oskar mRNA to localise in the posterior cytoplasm rather than cortically...
October 16, 2017: ELife
https://www.readbyqxmd.com/read/28901718/chondroitin-sulfate-proteoglycans-negatively-regulate-the-positioning-of-mitochondria-and-endoplasmic-reticulum-to-distal-axons
#12
Rajiv Sainath, Lorena Armijo-Weingart, Andrea Ketscheck, Zhuxuan Xu, Shuxin Li, Gianluca Gallo
Chondroitin sulfate proteoglycans (CSPGs) are components of the extracellular matrix that inhibit the extension and regeneration of axons. However, the underlying mechanism of action remains poorly understood. Mitochondria and endoplasmic reticulum (ER) are functionally inter-linked organelles important to axon development and maintenance. We report that CSPGs impair the targeting of mitochondria and ER to the growth cones of chicken embryonic sensory axons. The effect of CSPGs on the targeting of mitochondria is blocked by inhibition of the LAR receptor for CSPGs...
December 2017: Developmental Neurobiology
https://www.readbyqxmd.com/read/28883039/disease-associated-mutations-in-human-bicd2-hyperactivate-motility-of-dynein-dynactin
#13
Walter Huynh, Ronald D Vale
Bicaudal D2 (BICD2) joins dynein with dynactin into a ternary complex (termed DDB) capable of processive movement. Point mutations in the BICD2 gene have been identified in patients with a dominant form of spinal muscular atrophy, but how these mutations cause disease is unknown. To investigate this question, we have developed in vitro motility assays with purified DDB and BICD2's membrane vesicle partner, the GTPase Rab6a. Rab6a-GTP, either in solution or bound to artificial liposomes, released BICD2 from an autoinhibited state and promoted robust dynein-dynactin transport...
October 2, 2017: Journal of Cell Biology
https://www.readbyqxmd.com/read/28837701/lissencephaly-1-dependent-axonal-retrograde-transport-of-l1-type-cam-neuroglian-in-the-adult-drosophila-central-nervous-system
#14
Sirisha R Kudumala, Tyrone Penserga, Jana Börner, Olesya Slipchuk, Priyanka Kakad, LaTasha H Lee, Aater Qureshi, Jan Pielage, Tanja A Godenschwege
Here, we established the Drosophila Giant Fiber neurons (GF) as a novel model to study axonal trafficking of L1-type Cell Adhesion Molecules (CAM) Neuroglian (Nrg) in the adult CNS using live imaging. L1-type CAMs are well known for their importance in nervous system development and we previously demonstrated a role for Nrg in GF synapse formation. However, in the adult they have also been implicated in synaptic plasticity and regeneration. In addition, to its canonical role in organizing cytoskeletal elements at the plasma membrane, vertebrate L1CAM has also been shown to regulate transcription indirectly as well as directly via its import to the nucleus...
2017: PloS One
https://www.readbyqxmd.com/read/28803871/an-rnai-screen-in-a-novel-model-of-oriented-divisions-identifies-the-actin-capping-protein-z-%C3%AE-as-an-essential-regulator-of-spindle-orientation
#15
Florencia di Pietro, Léo Valon, Yingbo Li, Rosette Goïame, Auguste Genovesio, Xavier Morin
Oriented cell divisions are controlled by a conserved molecular cascade involving Gαi, LGN, and NuMA. We developed a new cellular model of oriented cell divisions combining micropatterning and localized recruitment of Gαi and performed an RNAi screen for regulators acting downstream of Gαi. Remarkably, this screen revealed a unique subset of dynein regulators as being essential for spindle orientation, shedding light on a core regulatory aspect of oriented divisions. We further analyze the involvement of one novel regulator, the actin-capping protein CAPZB...
August 21, 2017: Current Biology: CB
https://www.readbyqxmd.com/read/28759579/dynactin-binding-to-tyrosinated-microtubules-promotes-centrosome-centration-in-c-elegans-by-enhancing-dynein-mediated-organelle-transport
#16
Daniel J Barbosa, Joana Duro, Bram Prevo, Dhanya K Cheerambathur, Ana X Carvalho, Reto Gassmann
The microtubule-based motor dynein generates pulling forces for centrosome centration and mitotic spindle positioning in animal cells. How the essential dynein activator dynactin regulates these functions of the motor is incompletely understood. Here, we dissect the role of dynactin's microtubule binding activity, located in the p150 CAP-Gly domain and an adjacent basic patch, in the C. elegans zygote. Analysis of p150 mutants engineered by genome editing suggests that microtubule tip tracking of dynein-dynactin is dispensable for targeting the motor to the cell cortex and for generating robust cortical pulling forces...
July 2017: PLoS Genetics
https://www.readbyqxmd.com/read/28747439/diverse-mitotic-functions-of-the-cytoskeletal-cross-linking-protein-shortstop-suggest-a-role-in-dynein-dynactin-activity
#17
Evan B Dewey, Christopher A Johnston
Proper assembly and orientation of the bipolar mitotic spindle is critical to the fidelity of cell division. Mitotic precision fundamentally contributes to cell fate specification, tissue development and homeostasis, and chromosome distribution within daughter cells. Defects in these events are thought to contribute to several human diseases. The underlying mechanisms that function in spindle morphogenesis and positioning remain incompletely defined, however. Here we describe diverse roles for the actin-microtubule cross-linker Shortstop (Shot) in mitotic spindle function in Drosophila Shot localizes to mitotic spindle poles, and its knockdown results in an unfocused spindle pole morphology and a disruption of proper spindle orientation...
September 15, 2017: Molecular Biology of the Cell
https://www.readbyqxmd.com/read/28718761/the-human-cytoplasmic-dynein-interactome-reveals-novel-activators-of-motility
#18
William B Redwine, Morgan E DeSantis, Ian Hollyer, Zaw Min Htet, Phuoc Tien Tran, Selene K Swanson, Laurence Florens, Michael P Washburn, Samara L Reck-Peterson
In human cells, cytoplasmic dynein-1 is essential for long-distance transport of many cargos, including organelles, RNAs, proteins, and viruses, towards microtubule minus ends. To understand how a single motor achieves cargo specificity, we identified the human dynein interactome by attaching a promiscuous biotin ligase ('BioID') to seven components of the dynein machinery, including a subunit of the essential cofactor dynactin. This method reported spatial information about the large cytosolic dynein/dynactin complex in living cells...
July 18, 2017: ELife
https://www.readbyqxmd.com/read/28625595/dctn1-related-neurodegeneration-perry-syndrome-and-beyond
#19
REVIEW
Takuya Konno, Owen A Ross, Hélio A G Teive, Jarosław Sławek, Dennis W Dickson, Zbigniew K Wszolek
Perry syndrome (PS) is a rare hereditary neurodegenerative disease characterized by autosomal dominant parkinsonism, psychiatric symptoms, weight loss, central hypoventilation, and distinct TDP-43 pathology. The mutated causative gene for PS is DCTN1, which encodes the dynactin subunit p150(Glued). Dynactin is a motor protein involved in axonal transport; the p150(Glued) subunit has a critical role in the overall function. Since the discovery of DCTN1 in PS, it has been increasingly recognized that DCTN1 mutations can exhibit more diverse phenotypes than previously thought...
August 2017: Parkinsonism & related Disorders
https://www.readbyqxmd.com/read/28625517/reduced-tdp-43-expression-improves-neuronal-activities-in-a-drosophila-model-of-perry-syndrome
#20
Yuka Hosaka, Tsuyoshi Inoshita, Kahori Shiba-Fukushima, Changxu Cui, Taku Arano, Yuzuru Imai, Nobutaka Hattori
Parkinsonian Perry syndrome, involving mutations in the dynein motor component dynactin or p150(Glued), is characterized by TDP-43 pathology in affected brain regions, including the substantia nigra. However, the molecular relationship between p150(Glued) and TDP-43 is largely unknown. Here, we report that a reduction in TDP-43 protein levels alleviates the synaptic defects of neurons expressing the Perry mutant p150(G50R) in Drosophila. Dopaminergic expression of p150(G50R), which decreases dopamine release, disrupts motor ability and reduces the lifespan of Drosophila...
July 2017: EBioMedicine
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