scholarly journals DYNLRB1 is Essential for Dynein Mediated Transport and Neuronal Survival

2019 ◽  
Author(s):  
Marco Terenzio ◽  
Agostina Di Pizio ◽  
Ida Rishal ◽  
Letizia Marvaldi ◽  
Pierluigi Di Matteo ◽  
...  
Keyword(s):  
Cytoplasmic Dynein ◽  
Cell Periphery ◽  
Dynein Light Chain ◽  
Motor Complex ◽  
Dynein Motor ◽  
Selective Depletion ◽  
Severe Impairment ◽  
Accessory Subunit ◽  
And Function

ABSTRACTThe cytoplasmic dynein motor complex transports essential signals and organelles from the cell periphery to perinuclear region, hence is critical for the survival and function of highly polarized cells such as neurons. Dynein Light Chain Roadblock-Type 1 (DYNLRB1) is thought to be an accessory subunit required for specific cargos, but here we show that it is essential for general dynein-mediated transport and sensory neuron survival. Homozygous Dynlrb1 null mice are not viable and die during early embryonic development. Furthermore, heterozygous or adult knockdown animals display reduced neuronal growth, and selective depletion of Dynlrb1 in proprioceptive neurons compromises their survival. Conditional depletion of Dynlrb1 in sensory neurons causes deficits in several signaling pathways, including β-catenin subcellular localization, and a severe impairment in the axonal transport of both lysosomes and retrograde signaling endosomes. Hence, DYNLRB1 is an essential component of the dynein complex.

scholarly journals Functional interaction between dynein light chain and intermediate chain is required for mitotic spindle positioning

2011 ◽  
Vol 22 (15) ◽  
pp. 2690-2701 ◽  
Author(s):  
Melissa D. Stuchell-Brereton ◽  
Amanda Siglin ◽  
Jun Li ◽  
Jeffrey K. Moore ◽  
Shubbir Ahmed ◽  
...  
Keyword(s):  
Light Chain ◽  
Direct Evidence ◽  
Retrograde Transport ◽  
Cytoplasmic Dynein ◽  
Dynein Light Chain ◽  
Spindle Positioning ◽  
Dynein Motor ◽  
Intermediate Chains ◽  
Activator Complex

Cytoplasmic dynein is a large multisubunit complex involved in retrograde transport and the positioning of various organelles. Dynein light chain (LC) subunits are conserved across species; however, the molecular contribution of LCs to dynein function remains controversial. One model suggests that LCs act as cargo-binding scaffolds. Alternatively, LCs are proposed to stabilize the intermediate chains (ICs) of the dynein complex. To examine the role of LCs in dynein function, we used Saccharomyces cerevisiae, in which the sole function of dynein is to position the spindle during mitosis. We report that the LC8 homologue, Dyn2, localizes with the dynein complex at microtubule ends and interacts directly with the yeast IC, Pac11. We identify two Dyn2-binding sites in Pac11 that exert differential effects on Dyn2-binding and dynein function. Mutations disrupting Dyn2 elicit a partial loss-of-dynein phenotype and impair the recruitment of the dynein activator complex, dynactin. Together these results indicate that the dynein-based function of Dyn2 is via its interaction with the dynein IC and that this interaction is important for the interaction of dynein and dynactin. In addition, these data provide the first direct evidence that LC occupancy in the dynein motor complex is important for function.

scholarly journals Nde1 is a Rab9 effector for loading late endosomes to cytoplasmic dynein motor complex

Structure ◽  
2021 ◽  
Author(s):  
Yifan Zhang ◽  
Ziyue Chen ◽  
Fang Wang ◽  
Honghua Sun ◽  
Xueliang Zhu ◽  
...  
Keyword(s):  
Cytoplasmic Dynein ◽  
Motor Complex ◽  
Dynein Motor ◽  
Late Endosomes

Opposing motor activities of dynein and kinesin determine retention and transport of MHC class II-containing compartments

1999 ◽  
Vol 112 (6) ◽  
pp. 785-795
Author(s):  
R. Wubbolts ◽  
M. Fernandez-Borja ◽  
I. Jordens ◽  
E. Reits ◽  
S. Dusseljee ◽  
...  
Keyword(s):  
Cell Surface ◽  
Mhc Class Ii ◽  
Kinase Inhibitor ◽  
Class Ii ◽  
Cytoplasmic Dynein ◽  
Retention Mechanism ◽  
Cell Periphery ◽  
Dynein Motor ◽  
Stop And Go ◽  
Motor Activities

MHC class II molecules exert their function at the cell surface by presenting to T cells antigenic fragments that are generated in the endosomal pathway. The class II molecules are targetted to early lysosomal structures, termed MIIC, where they interact with antigenic fragments and are subsequently transported to the cell surface. We previously visualised vesicular transport of MHC class II-containing early lysosomes from the microtubule organising centre (MTOC) region towards the cell surface in living cells. Here we show that the MIIC move bidirectionally in a ‘stop-and-go’ fashion. Overexpression of a motor head-deleted kinesin inhibited MIIC motility, showing that kinesin is the motor that drives its plus end transport towards the cell periphery. Cytoplasmic dynein mediates the return of vesicles to the MTOC area and effectively retains the vesicles at this location, as assessed by inactivation of dynein by overexpression of dynamitin. Our data suggest a retention mechanism that determines the perinuclear accumulation of MIIC, which is the result of dynein activity being superior over kinesin activity. The bidirectional nature of MIIC movement is the result of both kinesin and dynein acting reciprocally on the MIIC during its transport. The motors may be the ultimate targets of regulatory kinases since the protein kinase inhibitor staurosporine induces a massive release of lysosomal vesicles from the MTOC region that is morphologically similar to that observed after inactivation of the dynein motor.

scholarly journals Dynein light chain 1 and a spindle-associated adaptor promote dynein asymmetry and spindle orientation

2012 ◽  
Vol 198 (6) ◽  
pp. 1039-1054 ◽  
Author(s):  
Anja K. Dunsch ◽  
Dean Hammond ◽  
Jennifer Lloyd ◽  
Lothar Schermelleh ◽  
Ulrike Gruneberg ◽  
...  
Keyword(s):  
Light Chain ◽  
Mitotic Spindle ◽  
Regulatory System ◽  
Cytoplasmic Dynein ◽  
Spindle Orientation ◽  
Growth Surface ◽  
Cell Cortex ◽  
Dynein Light Chain ◽  
Dynein Motor ◽  
Pulling Forces

The cytoplasmic dynein motor generates pulling forces to center and orient the mitotic spindle within the cell. During this positioning process, dynein oscillates from one pole of the cell cortex to the other but only accumulates at the pole farthest from the spindle. Here, we show that dynein light chain 1 (DYNLL1) is required for this asymmetric cortical localization of dynein and has a specific function defining spindle orientation. DYNLL1 interacted with a spindle-microtubule–associated adaptor formed by CHICA and HMMR via TQT motifs in CHICA. In cells depleted of CHICA or HMMR, the mitotic spindle failed to orient correctly in relation to the growth surface. Furthermore, CHICA TQT motif mutants localized to the mitotic spindle but failed to recruit DYNLL1 to spindle microtubules and did not correct the spindle orientation or dynein localization defects. These findings support a model where DYNLL1 and CHICA-HMMR form part of the regulatory system feeding back spindle position to dynein at the cell cortex.

scholarly journals A Role for Dynein in the Inhibition of Germ Cell Proliferative Fate

2009 ◽  
Vol 29 (22) ◽  
pp. 6128-6139 ◽  
Author(s):  
Maia Dorsett ◽  
Tim Schedl
Keyword(s):  
Cell Fate ◽  
Germ Cells ◽  
Cellular Proliferation ◽  
Germ Line ◽  
Mitotic Cell ◽  
Nuclear Accumulation ◽  
Dynein Light Chain ◽  
Motor Complex ◽  
Dynein Motor ◽  
Normal Differentiation

ABSTRACT During normal development as well as in diseased states such as cancer, extracellular “niches” often provide cues to proximal cells and activate intracellular pathways. Activation of such signaling pathways in turn instructs cellular proliferation and differentiation. In the Caenorhabditis elegans gonad, GLP-1/Notch signaling instructs germ line stem cells to self-renew through mitotic cell division. As germ cells progressively move out of the niche, they differentiate by entering meiosis and eventually form gametes. In this model system, we uncovered an unexpected role for the dynein motor complex in promoting normal differentiation of proliferating germ cells. We demonstrate that dynein light chain 1 (DLC-1) and its partner, dynein heavy chain 1, inhibit the proliferative cell fate, in part through regulation of METT-10, a conserved putative methyltransferase. We show that DLC-1 physically interacts with METT-10 and promotes both its overall levels and nuclear accumulation. Our results add a new dimension to the processes controlled by the dynein motor complex, demonstrating that dynein can act as an antiproliferative factor.

scholarly journals Analysis of Dynactin Subcomplexes Reveals a Novel Actin-Related Protein Associated with the Arp1 Minifilament Pointed End

1999 ◽  
Vol 147 (2) ◽  
pp. 307-320 ◽  
Author(s):  
D. Mark Eckley ◽  
Steven R. Gill ◽  
Karin A. Melkonian ◽  
James B. Bingham ◽  
Holly V. Goodson ◽  
...  
Keyword(s):  
Protein Complexes ◽  
Cytoplasmic Dynein ◽  
Related Protein ◽  
Flexible Assembly ◽  
Dynein Motor ◽  
Structure Treatment ◽  
Comprehensive Picture ◽  
End Capping ◽  
And Function ◽  
Pointed End

The multisubunit protein, dynactin, is a critical component of the cytoplasmic dynein motor machinery. Dynactin contains two distinct structural domains: a projecting sidearm that interacts with dynein and an actin-like minifilament backbone that is thought to bind cargo. Here, we use biochemical, ultrastructural, and molecular cloning techniques to obtain a comprehensive picture of dynactin composition and structure. Treatment of purified dynactin with recombinant dynamitin yields two assemblies: the actin-related protein, Arp1, minifilament and the p150Glued sidearm. Both contain dynamitin. Treatment of dynactin with the chaotropic salt, potassium iodide, completely depolymerizes the Arp1 minifilament to reveal multiple protein complexes that contain the remaining dynactin subunits. The shoulder/sidearm complex contains p150Glued, dynamitin, and p24 subunits and is ultrastructurally similar to dynactin's flexible projecting sidearm. The dynactin shoulder complex, which contains dynamitin and p24, is an elongated, flexible assembly that may link the shoulder/sidearm complex to the Arp1 minifilament. Pointed-end complex contains p62, p27, and p25 subunits, plus a novel actin-related protein, Arp11. p62, p27, and p25 contain predicted cargo-binding motifs, while the Arp11 sequence suggests a pointed-end capping activity. These isolated dynactin subdomains will be useful tools for further analysis of dynactin assembly and function.

scholarly journals Crystal Structure of Dynein Light Chain TcTex-1

2005 ◽  
Vol 280 (23) ◽  
pp. 21981-21986 ◽  
Author(s):  
John C. Williams ◽  
Hui Xie ◽  
Wayne A. Hendrickson
Keyword(s):  
Crystal Structure ◽  
Light Chain ◽  
Structural Alignment ◽  
Cytoplasmic Dynein ◽  
Dynein Light Chain ◽  
Nitricoxide Synthase ◽  
Dynein Motor ◽  
Poliovirus Receptor ◽  
Dynein Intermediate Chain ◽  
Oxide Synthase

TcTex-1, one of three dynein light chains of the dynein motor complex, has been implicated in targeting and binding cargoes to cytoplasmic dynein for retrograde or apical transport. Interactions between TcTex-1 and a diverse set of proteins such as the dynein intermediate chain, Fyn, DOC2, FIP1, the poliovirus receptor, CD155, and the rhodopsin cytoplasmic tail have been reported; yet, despite the broad range of targets, a consensus binding sequence remains uncertain. Consequently, we have solved the crystal structure of the full-length Drosophila homolog of TcTex-1 to 1.7 Å resolution using MAD phasing to gain insight into its function and target specificity. The structure is homodimeric with a domain swapping of β-strand 2 and has a fold similar to the dynein light chain, LC8. Based on structural alignment, the TcTex-1 and LC8 sequences show no identity, although the root mean square deviation between secondary structural elements is less than 1.6 Å. Moreover, the N terminus, which is equivalent to β-strand 1 in LC8, is splayed out and binds to a crystallographic dimer as an anti-parallel β-strand at the same position as the neuronal nitric-oxide synthase peptide in the LC8 complex. Similarity to LC8 and comparison to the LC8-neuronal nitricoxide synthase complex suggest that TcTex-1 binds its targets in a similar manner as LC8 and provides insight to the lack of strict sequence identity among the targets for TcTex-1.

scholarly journals Ebola Virus VP35 Interaction with Dynein LC8 Regulates Viral RNA Synthesis

2015 ◽  
Vol 89 (9) ◽  
pp. 5148-5153 ◽  
Author(s):  
Priya Luthra ◽  
David S. Jordan ◽  
Daisy W. Leung ◽  
Gaya K. Amarasinghe ◽  
Christopher F. Basler
Keyword(s):  
Rna Synthesis ◽  
Ebola Virus ◽  
Mutational Analysis ◽  
Cytoplasmic Dynein ◽  
Viral Rna ◽  
Interferon Production ◽  
Dynein Light Chain ◽  
High Affinity ◽  
Functional Consequences ◽  
Oligomerization Domain

Ebola virus VP35 inhibits alpha/beta interferon production and functions as a viral polymerase cofactor. Previously, the 8-kDa cytoplasmic dynein light chain (LC8) was demonstrated to interact with VP35, but the functional consequences were unclear. Here we demonstrate that the interaction is direct and of high affinity and that binding stabilizes the VP35 N-terminal oligomerization domain and enhances viral RNA synthesis. Mutational analysis demonstrates that VP35 interaction is required for the functional effects of LC8.

scholarly journals The traditional experience strategy (TES) and combined ultrasonography examination (CUE) for the treatment of lateral compression type 1 pelvic fractures: a historical control study

2021 ◽  
Vol 22 (1) ◽  
Author(s):  
Hai Huang ◽  
Bin-Fei Zhang ◽  
Ping Liu ◽  
Hong-Li Deng ◽  
Peng-Fei Wang ◽  
...  
Keyword(s):  
Pelvic Fractures ◽  
Definitive Treatment ◽  
Lateral Compression ◽  
Level Of Evidence ◽  
Conservative Group ◽  
Medical Records System ◽  
The Stability ◽  
And Function ◽  
Compression Type

Abstract Background It is difficult to judge the stability of lateral compression type-1 (LC-1) pelvic fracture, as it is often based on static images of the pelvis. Compared with the traditional experience strategy, ultrasonography examination may be able to distinguish operative and conservative patients before definitive treatment. However, in previous studies, we have not compared the outcomes between traditional experience strategy (TES group) and combined ultrasonography examination (CUE group). Thus, the aim of the study is comparing the differences between TES and CUE strategy, to identify the value of ultrasonography examination. Methods Medical records system for patients with LC-1 pelvic fractures who were treated with TES and CUE strategy were included. Patients’ baseline characteristics, treatment strategy, and function were recorded at follow-up. Functional outcomes were evaluated using the Majeed grading system. Results In total, 77 patients with LC-1 pelvic fractures were included in the study. There were 42 and 35 patients in TES and CUE group, respectively. Compared to TES group (69 %), there were less proportion patients chosen the operative treatment in CUE group (43 %, P = 0.021). The volume of intraoperative blood loss in CUE operative group was more than TES operative group (P = 0.037). There were more patients with complete sacral fracture in CUE operative group than TES operative group (P = 0.002). The Majeed scores in CUE conservative group was higher than TES conservative group (P = 0.008). The overall Majeed scores in CUE group was higher than that in TES group (P = 0.039). Conclusions The ultrasonography examination could relatively accurately identify the unstable LC-1 pelvis than the traditional experience strategy, the operative rate could be reduced and the overall function of LC-1 patients could be improved under the ultrasonography examination. Level of evidence Level III.

scholarly journals Cardiac Manifestations in a Group of Romanian Patients with Gaucher Disease Type 1 (a Monocentric Study)

Diagnostics ◽  
2021 ◽  
Vol 11 (6) ◽  
pp. 989
Author(s):  
Cecilia Lazea ◽  
Simona Bucerzan ◽  
Camelia Al-Khzouz ◽  
Anca Zimmermann ◽  
Ștefan Cristian Vesa ◽  
...  
Keyword(s):  
Gaucher Disease ◽  
Cardiac Involvement ◽  
Disease Type ◽  
Clinical Onset ◽  
Lysosomal Disorders ◽  
Electrocardiographic Changes ◽  
Gaucher Disease Type 1 ◽  
And Function ◽  
Cardiac Manifestations

Gaucher disease (GD), one of the most common lysosomal disorders, is characterised by clinical heterogeneity. Cardiac involvement is rare and refers to pulmonary hypertension (PH), valvular abnormalities and myocardial infiltrative damage. The aim of this study was to evaluate cardiac involvement in a group of Romanian GD patients. Phenotypic and genotypic characterisation was carried out in 69 patients with GD type 1. Annual echocardiography and electrocardiography were performed to assess pulmonary pressure, morphology and function of the valves and electrocardiographic changes. Nine patients (13%) exhibited baseline echocardiographic signs suggesting PH. Mitral regurgitation was present in 33 patients (48%) and aortic regurgitation in 11 patients (16%). One patient presented aortic stenosis. Significant valvular dysfunction was diagnosed in 10% of patients. PH was associated with greater age (p < 0.001), longer time since splenectomy (p = 0.045) and longer time between clinical onset and the start of enzyme replacing therapy (p < 0.001). Electrocardiographic changes were present in five patients (7%).

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