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Dynactin

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https://www.readbyqxmd.com/read/29185983/numa-recruits-dynein-activity-to-microtubule-minus-ends-at-mitosis
#1
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
#2
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
#3
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
#4
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
#5
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
#6
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
#7
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
#8
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
#9
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
#10
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
#11
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
#12
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
#13
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
#14
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
#15
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
https://www.readbyqxmd.com/read/28602352/cryo-em-reveals-how-human-cytoplasmic-dynein-is-auto-inhibited-and-activated
#16
Kai Zhang, Helen E Foster, Arnaud Rondelet, Samuel E Lacey, Nadia Bahi-Buisson, Alexander W Bird, Andrew P Carter
Cytoplasmic dynein-1 binds dynactin and cargo adaptor proteins to form a transport machine capable of long-distance processive movement along microtubules. However, it is unclear why dynein-1 moves poorly on its own or how it is activated by dynactin. Here, we present a cryoelectron microscopy structure of the complete 1.4-megadalton human dynein-1 complex in an inhibited state known as the phi-particle. We reveal the 3D structure of the cargo binding dynein tail and show how self-dimerization of the motor domains locks them in a conformation with low microtubule affinity...
June 15, 2017: Cell
https://www.readbyqxmd.com/read/28576829/differential-effects-of-the-dynein-regulatory-factor-lissencephaly-1-on-processive-dynein-dynactin-motility
#17
COMPARATIVE STUDY
Pedro A Gutierrez, Bryce E Ackermann, Michael Vershinin, Richard J McKenney
Cytoplasmic dynein is the primary minus-end-directed microtubule motor protein in animal cells, performing a wide range of motile activities, including transport of vesicular cargos, mRNAs, viruses, and proteins. Lissencephaly-1 (LIS1) is a highly conserved dynein-regulatory factor that binds directly to the dynein motor domain, uncoupling the enzymatic and mechanical cycles of the motor and stalling dynein on the microtubule track. Dynactin, another ubiquitous dynein-regulatory factor, releases dynein from an autoinhibited state, leading to a dramatic increase in fast, processive dynein motility...
July 21, 2017: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/28572117/dynein-is-regulated-by-the-stability-of-its-microtubule-track
#18
Cassi Estrem, Colby P Fees, Jeffrey K Moore
How dynein motors accurately move cargoes is an important question. In budding yeast, dynein moves the mitotic spindle to the predetermined site of cytokinesis by pulling on astral microtubules. In this study, using high-resolution imaging in living cells, we discover that spindle movement is regulated by changes in microtubule plus-end dynamics that occur when dynein generates force. Mutants that increase plus-end stability increase the frequency and duration of spindle movements, causing positioning errors...
July 3, 2017: Journal of Cell Biology
https://www.readbyqxmd.com/read/28515232/the-nuclear-export-factor-crm1-controls-juxta-nuclear-microtubule-dependent-virus-transport
#19
I-Hsuan Wang, Christoph J Burckhardt, Artur Yakimovich, Matthias K Morf, Urs F Greber
Transport of large cargo through the cytoplasm requires motor proteins and polarized filaments. Viruses that replicate in the nucleus of post-mitotic cells use microtubules and the dynein-dynactin motor to traffic to the nuclear membrane and deliver their genome through nuclear pore complexes (NPCs) into the nucleus. How virus particles (virions) or cellular cargo are transferred from microtubules to the NPC is unknown. Here, we analyzed trafficking of incoming cytoplasmic adenoviruses by single-particle tracking and super-resolution microscopy...
July 1, 2017: Journal of Cell Science
https://www.readbyqxmd.com/read/28414272/regulation-of-mitochondria-dynactin-interaction-and-mitochondrial-retrograde-transport-in-axons
#20
Catherine M Drerup, Amy L Herbert, Kelly R Monk, Alex V Nechiporuk
Mitochondrial transport in axons is critical for neural circuit health and function. While several proteins have been found that modulate bidirectional mitochondrial motility, factors that regulate unidirectional mitochondrial transport have been harder to identify. In a genetic screen, we found a zebrafish strain in which mitochondria fail to attach to the dynein retrograde motor. This strain carries a loss-of-function mutation in actr10, a member of the dynein-associated complex dynactin. The abnormal axon morphology and mitochondrial retrograde transport defects observed in actr10 mutants are distinct from dynein and dynactin mutant axonal phenotypes...
April 17, 2017: ELife
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