scholarly journals Molecular models of LINC complex assembly at the nuclear envelope

2021 ◽  
Vol 134 (12) ◽  
Author(s):  
Zeinab Jahed ◽  
Nya Domkam ◽  
Jessica Ornowski ◽  
Ghafar Yerima ◽  
Mohammad R. K. Mofrad
Keyword(s):  
Nuclear Envelope ◽  
Molecular Mechanisms ◽  
Protein Complexes ◽  
Higher Order ◽  
Linc Complex ◽  
Large Protein ◽  
Ample Evidence ◽  
The Past ◽  
Force Transfer ◽  
Shed Light

ABSTRACT Large protein complexes assemble at the nuclear envelope to transmit mechanical signals between the cytoskeleton and nucleoskeleton. These protein complexes are known as the linkers of the nucleoskeleton and cytoskeleton complexes (LINC complexes) and are formed by the interaction of SUN and KASH domain proteins in the nuclear envelope. Ample evidence suggests that SUN–KASH complexes form higher-order assemblies to withstand and transfer forces across the nuclear envelope. Herein, we present a review of recent studies over the past few years that have shed light on the mechanisms of SUN–KASH interactions, their higher order assembly, and the molecular mechanisms of force transfer across these complexes.

scholarly journals Molecular requirements for the formation of a kinetochore–microtubule interface by Dam1 and Ndc80 complexes

2012 ◽  
Vol 200 (1) ◽  
pp. 21-30 ◽  
Author(s):  
Fabienne Lampert ◽  
Christine Mieck ◽  
Gregory M. Alushin ◽  
Eva Nogales ◽  
Stefan Westermann
Keyword(s):  
Chromosome Segregation ◽  
Protein Complexes ◽  
Structural Elements ◽  
Large Protein ◽  
Kinetochore Assembly ◽  
Sister Chromatids ◽  
Dam1 Complex ◽  
Shed Light ◽  
Kinetochore Function

Kinetochores are large protein complexes that link sister chromatids to the spindle and transduce microtubule dynamics into chromosome movement. In budding yeast, the kinetochore–microtubule interface is formed by the plus end–associated Dam1 complex and the kinetochore-resident Ndc80 complex, but how they work in combination and whether a physical association between them is critical for chromosome segregation is poorly understood. Here, we define structural elements required for the Ndc80–Dam1 interaction and probe their function in vivo. A novel ndc80 allele, selectively impaired in Dam1 binding, displayed growth and chromosome segregation defects. Its combination with an N-terminal truncation resulted in lethality, demonstrating essential but partially redundant roles for the Ndc80 N-tail and Ndc80–Dam1 interface. In contrast, mutations in the calponin homology domain of Ndc80 abrogated kinetochore function and were not compensated by the presence of Dam1. Our experiments shed light on how microtubule couplers cooperate and impose important constraints on structural models for outer kinetochore assembly.

scholarly journals Zebrafish and Medaka: Two Teleost Models of T-Cell and Thymic Development

2019 ◽  
Vol 20 (17) ◽  
pp. 4179 ◽  
Author(s):  
Baubak Bajoghli ◽  
Advaita M. Dick ◽  
Annisa Claasen ◽  
Larissa Doll ◽  
Narges Aghaallaei
Keyword(s):  
T Cell ◽  
Molecular Mechanisms ◽  
T Cell Development ◽  
Model Systems ◽  
Biological Processes ◽  
Direct Visualization ◽  
Thymic Development ◽  
The Past ◽  
Shed Light

Over the past two decades, studies have demonstrated that several features of T-cell and thymic development are conserved from teleosts to mammals. In particular, works using zebrafish (Danio rerio) and medaka (Oryzias latipes) have shed light on the cellular and molecular mechanisms underlying these biological processes. In particular, the ease of noninvasive in vivo imaging of these species enables direct visualization of all events associated with these processes, which are, in mice, technically very demanding. In this review, we focus on defining the similarities and differences between zebrafish and medaka in T-cell development and thymus organogenesis; and highlight their advantages as two complementary model systems for T-cell immunobiology and modeling of human diseases.

scholarly journals Tumor Cells and Cancer-Associated Fibroblasts: An Updated Metabolic Perspective

Cancers ◽  
2021 ◽  
Vol 13 (3) ◽  
pp. 399
Author(s):  
Géraldine Gentric ◽  
Fatima Mechta-Grigoriou
Keyword(s):  
Tumor Cells ◽  
Metabolic Pathways ◽  
Molecular Mechanisms ◽  
Carbon Sources ◽  
Cancer Associated Fibroblasts ◽  
The Past ◽  
Cancer Field ◽  
Metabolic Heterogeneity ◽  
The Impact ◽  
Shed Light

During the past decades, metabolism and redox imbalance have gained considerable attention in the cancer field. In addition to the well-known Warburg effect occurring in tumor cells, numerous other metabolic deregulations have now been reported. Indeed, metabolic reprograming in cancer is much more heterogeneous than initially thought. In particular, a high diversity of carbon sources used by tumor cells has now been shown to contribute to this metabolic heterogeneity in cancer. Moreover, the molecular mechanisms newly highlighted are multiple and shed light on novel actors. Furthermore, the impact of this metabolic heterogeneity on tumor microenvironment has also been an intense subject of research recently. Here, we will describe the new metabolic pathways newly uncovered in tumor cells. We will also have a particular focus on Cancer-Associated Fibroblasts (CAF), whose identity, function and metabolism have been recently under profound investigation. In that sense, we will discuss about the metabolic crosstalk between tumor cells and CAF.

scholarly journals Fantastic nuclear envelope herniations and where to find them

2018 ◽  
Vol 46 (4) ◽  
pp. 877-889 ◽  
Author(s):  
David J. Thaller ◽  
C. Patrick Lusk
Keyword(s):  
Nuclear Envelope ◽  
Molecular Mechanisms ◽  
Premature Aging ◽  
Nuclear Pore ◽  
Control Mechanisms ◽  
Extrinsic Factors ◽  
The Past ◽  
Nuclear Egress ◽  
Genetic Perturbations ◽  
Morphological Defects

Morphological abnormalities of the bounding membranes of the nucleus have long been associated with human diseases from cancer to premature aging to neurodegeneration. Studies over the past few decades support that there are both cell intrinsic and extrinsic factors (e.g. mechanical force) that can lead to nuclear envelope ‘herniations’, a broad catch-all term that reveals little about the underlying molecular mechanisms that contribute to these morphological defects. While there are many genetic perturbations that could ultimately change nuclear shape, here, we focus on a subset of nuclear envelope herniations that likely arise as a consequence of disrupting physiological nuclear membrane remodeling pathways required to maintain nuclear envelope homeostasis. For example, stalling of the interphase nuclear pore complex (NPC) biogenesis pathway and/or triggering of NPC quality control mechanisms can lead to herniations in budding yeast, which are remarkably similar to those observed in human disease models of early-onset dystonia. By also examining the provenance of nuclear envelope herniations associated with emerging nuclear autophagy and nuclear egress pathways, we will provide a framework to help understand the molecular pathways that contribute to nuclear deformation.

scholarly journals Identifying hetero-protein complexes in the nuclear envelope

2019 ◽  
Author(s):  
J. Hennen ◽  
K.H. Hur ◽  
J. Kohler ◽  
S.R. Karuka ◽  
I. Angert ◽  
...  
Keyword(s):  
Nuclear Envelope ◽  
Protein Complexes ◽  
Living Cells ◽  
Model Systems ◽  
Linc Complex ◽  
Oligomeric State ◽  
Subcellular Compartment ◽  
Dual Color

AbstractThe nucleus is delineated by the nuclear envelope (NE), which is a double membrane barrier composed of the inner and outer nuclear membranes as well as a ~40 nm wide lumen. In addition to its barrier function, the NE acts as a critical signaling node for a variety of cellular processes which are mediated by protein complexes within this subcellular compartment. While fluorescence fluctuation spectroscopy (FFS) is a powerful tool for characterizing protein complexes in living cells, it was recently demonstrated that conventional FFS methods are not suitable for applications in the NE because of the presence of slow nuclear membrane undulations. We previously addressed this challenge by developing time-shifted mean-segmented Q (tsMSQ) analysis and applied it to successfully characterize protein homo-oligomerization in the NE. However, many NE complexes, such as the linker of the nucleoskeleton and cytoskeleton (LINC) complex, are formed by heterotypic interactions, which single-color tsMSQ is unable to characterize. Here, we describe the development of dual-color (DC) tsMSQ to analyze NE hetero-protein complexes built from proteins that carry two spectrally distinct fluorescent labels. Experiments performed on model systems demonstrate that DC tsMSQ properly identifies hetero-protein complexes and their stoichiometry in the NE by accounting for spectral crosstalk and local volume fluctuations. Finally, we applied DC tsMSQ to study the assembly of the LINC complex, a hetero-protein complex composed of Klarsicht/ANC-1/SYNE homology (KASH) and Sad1/UNC-84 (SUN) proteins, in the NE of living cells. Using DC tsMSQ, we demonstrate the ability of the SUN protein SUN2 and the KASH protein nesprin-2 to form a hetero-complex in vivo. Our results are consistent with previously published in vitro studies and demonstrate the utility of the DC tsMSQ technique for characterizing NE hetero-protein complexes.Statement of SignificanceProtein complexes found within the nuclear envelope (NE) play a vital role in regulating cellular functions ranging from gene expression to cellular movement. However, the assembly state of these complexes within their native environment remains poorly understood, which is compounded by a general lack of fluorescence techniques suitable for quantifying the oligomeric state of NE protein complexes. This study aims at addressing this issue by introducing dual-color time-shifted mean-segmented Q analysis as a fluorescence fluctuation method specifically designed to identify the average oligomeric state of hetero-protein complexes within the NE of living cells.

scholarly journals Effect of Antibiotic Treatment on the Intestinal Metabolome

2011 ◽  
Vol 55 (4) ◽  
pp. 1494-1503 ◽  
Author(s):  
L. Caetano M. Antunes ◽  
Jun Han ◽  
Rosana B. R. Ferreira ◽  
Petra Lolić ◽  
Christoph H. Borchers ◽  
...  
Keyword(s):  
Antibiotic Treatment ◽  
Intestinal Microbiota ◽  
Molecular Mechanisms ◽  
Hormone Synthesis ◽  
The Past ◽  
Microbe Interactions ◽  
Host Microbe Interactions ◽  
The Impact ◽  
Shed Light ◽  
New Strategies

ABSTRACTThe importance of the mammalian intestinal microbiota to human health has been intensely studied over the past few years. It is now clear that the interactions between human hosts and their associated microbial communities need to be characterized in molecular detail if we are to truly understand human physiology. Additionally, the study of such host-microbe interactions is likely to provide us with new strategies to manipulate these complex systems to maintain or restore homeostasis in order to prevent or cure pathological states. Here, we describe the use of high-throughput metabolomics to shed light on the interactions between the intestinal microbiota and the host. We show that antibiotic treatment disrupts intestinal homeostasis and has a profound impact on the intestinal metabolome, affecting the levels of over 87% of all metabolites detected. Many metabolic pathways that are critical for host physiology were affected, including bile acid, eicosanoid, and steroid hormone synthesis. Dissecting the molecular mechanisms involved in the impact of beneficial microbes on some of these pathways will be instrumental in understanding the interplay between the host and its complex resident microbiota and may aid in the design of new therapeutic strategies that target these interactions.

scholarly journals Beyond the Black Box: Interactive Global Docking of Protein Complexes

2008 ◽  
Vol 16 (4) ◽  
pp. 6-9 ◽  
Author(s):  
Jochen Heyd ◽  
Stefan Birmanns
Keyword(s):  
Protein Complexes ◽  
Natural State ◽  
Large Protein ◽  
X Ray Crystallography ◽  
The Past ◽  
Cryo Electron Microscopy ◽  
Traditional Structure ◽  
Determination Methods ◽  
Microscopy Techniques ◽  
Structure Of Proteins

A key to understanding the function of biological systems is the visualization of their natural state, ideally in a natural environment. At a molecular level, this is challenging. Traditional experimental techniques, like X-ray crystallography, can provide the atomic structure of proteins, but only by removing them from their native surroundings and forcing them into crystals. Over the past decade, microscopy techniques have emerged as alternatives to these traditional structure determination methods, with the advantage of visualizing molecules in a near-native state. Given the current focus of structural biology on interactions between proteins and better understanding of large protein complexes, cryo-electron microscopy (cryo-EM) has become a valuable tool.

Novel Findings of Anti-cancer Property of Propofol

2018 ◽  
Vol 18 (2) ◽  
pp. 156-165 ◽  
Author(s):  
Jiaqiang Wang ◽  
Chien-shan Cheng ◽  
Yan Lu ◽  
Xiaowei Ding ◽  
Minmin Zhu ◽  
...  
Keyword(s):  
General Anesthesia ◽  
Cancer Progression ◽  
Molecular Mechanisms ◽  
Intravenous Anesthetic ◽  
The Past ◽  
Anti Cancer ◽  
Underlying Mechanisms ◽  
Recent Attention

Background: Propofol, a widely used intravenous anesthetic agent, is traditionally applied for sedation and general anesthesia. Explanation: Recent attention has been drawn to explore the effect and mechanisms of propofol against cancer progression in vitro and in vivo. Specifically, the proliferation-inhibiting and apoptosis-inducing properties of propofol in cancer have been studied. However, the underlying mechanisms remain unclear. Conclusion: This review focused on the findings within the past ten years and aimed to provide a general overview of propofol's malignance-modulating properties and the potential molecular mechanisms.

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