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Dynactin

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https://www.readbyqxmd.com/read/28718761/the-human-cytoplasmic-dynein-interactome-reveals-novel-activators-of-motility
#1
Willam 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
#2
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...
June 12, 2017: Parkinsonism & related Disorders
https://www.readbyqxmd.com/read/28625517/reduced-tdp-43-expression-improves-neuronal-activities-in-a-drosophila-model-of-perry-syndrome
#3
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...
June 8, 2017: EBioMedicine
https://www.readbyqxmd.com/read/28602352/cryo-em-reveals-how-human-cytoplasmic-dynein-is-auto-inhibited-and-activated
#4
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
#5
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...
June 2, 2017: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/28572117/dynein-is-regulated-by-the-stability-of-its-microtubule-track
#6
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
#7
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
#8
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
https://www.readbyqxmd.com/read/28406398/lissencephaly-1-is-a-context-dependent-regulator-of-the-human-dynein-complex
#9
Janina Baumbach, Andal Murthy, Mark A McClintock, Carly I Dix, Ruta Zalyte, Ha Thi Hoang, Simon L Bullock
The cytoplasmic dynein-1 (dynein) motor plays a central role in microtubule organisation and cargo transport. These functions are spatially regulated by association of dynein and its accessory complex dynactin with dynamic microtubule plus ends. Here, we elucidate in vitro the roles of dynactin, end-binding protein-1 (EB1) and Lissencephaly-1 (LIS1) in the interaction of end tracking and minus end-directed human dynein complexes with these sites. LIS1 promotes dynactin-dependent tracking of dynein on both growing and shrinking plus ends...
April 13, 2017: ELife
https://www.readbyqxmd.com/read/28387218/retrograde-transport-of-trkb-containing-autophagosomes-via-the-adaptor-ap-2-mediates-neuronal-complexity-and-prevents-neurodegeneration
#10
Natalia L Kononenko, Gala A Claßen, Marijn Kuijpers, Dmytro Puchkov, Tanja Maritzen, Aleksandra Tempes, Anna R Malik, Agnieszka Skalecka, Sujoy Bera, Jacek Jaworski, Volker Haucke
Autophagosomes primarily mediate turnover of cytoplasmic proteins or organelles to provide nutrients and eliminate damaged proteins. In neurons, autophagosomes form in distal axons and are trafficked retrogradely to fuse with lysosomes in the soma. Although defective neuronal autophagy is associated with neurodegeneration, the function of neuronal autophagosomes remains incompletely understood. We show that in neurons, autophagosomes promote neuronal complexity and prevent neurodegeneration in vivo via retrograde transport of brain-derived neurotrophic factor (BDNF)-activated TrkB receptors...
April 7, 2017: Nature Communications
https://www.readbyqxmd.com/read/28362576/ambra1-spatially-regulates-src-activity-and-src-fak-mediated-cancer-cell-invasion-via-trafficking-networks
#11
Christina Schoenherr, Adam Byron, Emma Sandilands, Ketevan Paliashvili, George S Baillie, Amaya Garcia-Munoz, Cristina Valacca, Francesco Cecconi, Bryan Serrels, Margaret C Frame
Here, using mouse squamous cell carcinoma cells, we report a completely new function for the autophagy protein Ambra1 as the first described 'spatial rheostat' controlling the Src/FAK pathway. Ambra1 regulates the targeting of active phospho-Src away from focal adhesions into autophagic structures that cancer cells use to survive adhesion stress. Ambra1 binds to both FAK and Src in cancer cells. When FAK is present, Ambra1 is recruited to focal adhesions, promoting FAK-regulated cancer cell direction-sensing and invasion...
March 31, 2017: ELife
https://www.readbyqxmd.com/read/28320824/molecular-mechanism-of-dynein-recruitment-to-kinetochores-by-the-rod-zw10-zwilch-complex-and-spindly
#12
José B Gama, Cláudia Pereira, Patrícia A Simões, Ricardo Celestino, Rita M Reis, Daniel J Barbosa, Helena R Pires, Cátia Carvalho, João Amorim, Ana X Carvalho, Dhanya K Cheerambathur, Reto Gassmann
The molecular motor dynein concentrates at the kinetochore region of mitotic chromosomes in animals to accelerate spindle microtubule capture and to control spindle checkpoint signaling. In this study, we describe the molecular mechanism used by the Rod-Zw10-Zwilch complex and the adaptor Spindly to recruit dynein to kinetochores in Caenorhabditis elegans embryos and human cells. We show that Rod's N-terminal β-propeller and the associated Zwilch subunit bind Spindly's C-terminal domain, and we identify a specific Zwilch mutant that abrogates Spindly and dynein recruitment in vivo and Spindly binding to a Rod β-propeller-Zwilch complex in vitro...
April 3, 2017: Journal of Cell Biology
https://www.readbyqxmd.com/read/28248450/regulation-of-dynein-dynactin-driven-vesicular-transport
#13
REVIEW
Jia-Jia Liu
Most of the long-range intracellular movements of vesicles, organelles and other cargoes are driven by microtubule (MT)-based molecular motors. Cytoplasmic dynein, a multisubunit protein complex, with the aid of dynactin, drives transport of a wide variety of cargoes towards the minus end of MTs. In this article, I review our current understanding of the mechanisms underlying spatiotemporal regulation of dynein-dynactin-driven vesicular transport with a special emphasis on the many steps of directional movement along MT tracks...
March 1, 2017: Traffic
https://www.readbyqxmd.com/read/28218281/ubiquitination-and-dynactin-regulate-tmepai-lysosomal-trafficking
#14
Shenheng Luo, Lei Jing, Tian Zhao, Yuyin Li, Zhenxing Liu, Aipo Diao
The transmembrane prostate androgen-induced protein (TMEPAI) has been reported to be elevated in various tumor cells, is localized to the lysosome and promotes lysosome stability. The molecular mechanism of TMEPAI trafficking however to the lysosome is unknown. Here we report that clathrin and CI-M6PR mediate TMEPAI transport from the Golgi directly into the endo-lysosomal pathway. TMEPAI is ubiquitinated at its C-terminal region and ubiquitination modification of TMEPAI is a signal for its lysosomal trafficking...
February 20, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28209731/transport-of-fungal-rab11-secretory-vesicles-involves-myosin-5-dynein-dynactin-p25-and-kinesin-1-and-is-independent-of-kinesin-3
#15
Miguel A Peñalva, Jun Zhang, Xin Xiang, Areti Pantazopoulou
Hyphal tip cells of the fungus Aspergillus nidulans are useful for studying long-range intracellular traffic. Post-Golgi secretory vesicles (SVs) containing the RAB11 orthologue RabE engage myosin-5 as well as plus end- and minus end-directed microtubule motors, providing an experimental system with which to investigate the interplay between microtubule and actin motors acting on the same cargo. By exploiting the fact that depolymerization of F-actin unleashes SVs focused at the apex by myosin-5 to microtubule-dependent motors, we establish that the minus end-directed transport of SVs requires the dynein/dynactin supercomplex...
April 1, 2017: Molecular Biology of the Cell
https://www.readbyqxmd.com/read/28196890/dync1h1-mutations-associated-with-neurological-diseases-compromise-processivity-of-dynein-dynactin-cargo-adaptor-complexes
#16
Ha Thi Hoang, Max A Schlager, Andrew P Carter, Simon L Bullock
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 toward 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...
February 28, 2017: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/28162951/dynein-binding-of-competitive-regulators-dynactin-and-nude-involves-novel-interplay-between-phosphorylation-site-and-disordered-spliced-linkers
#17
Jing Jie, Frank Löhr, Elisar Barbar
Dynactin and NudE/Nudel are prominent regulators of cytoplasmic dynein motility and cargo-binding activities. Both interact with the intrinsically disordered N-terminal domain of dynein intermediate chain (IC), which also contains phosphorylation sites that apparently regulate these interactions. Nuclear magnetic resonance and isothermal calorimetry studies demonstrate that the Ser84 phosphorylation site identified in cells is in a disordered linker distant from the N-terminal helix that contains both the dynactin- and the Nudel-binding interfaces...
March 7, 2017: Structure
https://www.readbyqxmd.com/read/28131906/a-novel-hdac6-inhibitor-tubastatin-a-controls-hdac6-p97-vcp-mediated-ubiquitination-autophagy-turnover-and-reverses-temozolomide-induced-er-stress-tolerance-in-gbm-cells
#18
Zong-Yang Li, Ce Zhang, Yuan Zhang, Lei Chen, Bao-Dong Chen, Qing-Zhong Li, Xie-Jun Zhang, Wei-Ping Li
Temozolomide (TMZ) is the cornerstone of therapy for glioblastoma multiforme (GBM). However, its efficacy is limited due to the development of multidrug resistance (MDR). In this study, we first identified the occurrence of ER stress-tolerance (ERST) in glioma cells and confirmed that ERST was positively correlated with TMZ resistance. We further showed that the seesaw-effect of HDAC6-p97/VCP (increased HDAC6 and decreased p97/VCP) in glioma cells was crucial to ERST-associated TMZ resistance. Moreover, the combination treatment of Tubastatin A (TUB, a selective inhibitor of HDAC6) and TMZ synergistically overcame ERST, reduced cell viability and induced apoptosis in TMZ-resistant glioma cells...
April 10, 2017: Cancer Letters
https://www.readbyqxmd.com/read/28120201/mapping-protein-protein-interactions-by-double-redor-filtered-magic-angle-spinning-nmr-spectroscopy
#19
Changmiao Guo, Guangjin Hou, Xingyu Lu, Tatyana Polenova
REDOR-based experiments with simultaneous (1)H-(13)C and (1)H-(15)N dipolar dephasing are explored for investigating intermolecular protein-protein interfaces in complexes formed by a U-(13)C,(15)N-labeled protein and its natural abundance binding partner. The application of a double-REDOR filter (dREDOR) results in a complete dephasing of proton magnetization in the U-(13)C,(15)N-enriched molecule while the proton magnetization of the unlabeled binding partner is not dephased. This retained proton magnetization is then transferred across the intermolecular interface by (1)H-(13)C or (1)H-(15)N cross polarization, permitting to establish the residues of the U-(13)C,(15)N-labeled protein, which constitute the binding interface...
January 24, 2017: Journal of Biomolecular NMR
https://www.readbyqxmd.com/read/27976861/probing-the-energetics-of-dynactin-filament-assembly-and-the-binding-of-cargo-adaptor-proteins-using-molecular-dynamics-simulation-and-electrostatics-based-structural-modeling
#20
Wenjun Zheng
Dynactin, a large multiprotein complex, binds with the cytoplasmic dynein-1 motor and various adaptor proteins to allow recruitment and transportation of cellular cargoes toward the minus end of microtubules. The structure of the dynactin complex is built around an actin-like minifilament with a defined length, which has been visualized in a high-resolution structure of the dynactin filament determined by cryo-electron microscopy (cryo-EM). To understand the energetic basis of dynactin filament assembly, we used molecular dynamics simulation to probe the intersubunit interactions among the actin-like proteins, various capping proteins, and four extended regions of the dynactin shoulder...
January 10, 2017: Biochemistry
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