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https://www.readbyqxmd.com/read/28219929/hsp70-displaces-small-heat-shock-proteins-from-aggregates-to-initiate-protein-refolding
#1
Szymon Żwirowski, Agnieszka Kłosowska, Igor Obuchowski, Nadinath B Nillegoda, Artur Piróg, Szymon Ziętkiewicz, Bernd Bukau, Axel Mogk, Krzysztof Liberek
Small heat shock proteins (sHsps) are an evolutionary conserved class of ATP-independent chaperones that protect cells against proteotoxic stress. sHsps form assemblies with aggregation-prone misfolded proteins, which facilitates subsequent substrate solubilization and refolding by ATP-dependent Hsp70 and Hsp100 chaperones. Substrate solubilization requires disruption of sHsp association with trapped misfolded proteins. Here, we unravel a specific interplay between Hsp70 and sHsps at the initial step of the solubilization process...
February 20, 2017: EMBO Journal
https://www.readbyqxmd.com/read/28219928/mitochondria-control-store-operated-ca-2-entry-through-na-and-redox-signals
#2
Tsipi Ben-Kasus Nissim, Xuexin Zhang, Assaf Elazar, Soumitra Roy, Judith A Stolwijk, Yandong Zhou, Rajender K Motiani, Maxime Gueguinou, Nadine Hempel, Michal Hershfinkel, Donald L Gill, Mohamed Trebak, Israel Sekler
Mitochondria exert important control over plasma membrane (PM) Orai1 channels mediating store-operated Ca(2+) entry (SOCE). Although the sensing of endoplasmic reticulum (ER) Ca(2+) stores by STIM proteins and coupling to Orai1 channels is well understood, how mitochondria communicate with Orai1 channels to regulate SOCE activation remains elusive. Here, we reveal that SOCE is accompanied by a rise in cytosolic Na(+) that is critical in activating the mitochondrial Na(+)/Ca(2+) exchanger (NCLX) causing enhanced mitochondrial Na(+) uptake and Ca(2+) efflux...
February 20, 2017: EMBO Journal
https://www.readbyqxmd.com/read/28219927/molecular-role-of-the-pax5-etv6-oncoprotein-in-promoting-b-cell-acute-lymphoblastic-leukemia
#3
Leonie Smeenk, Maria Fischer, Sabine Jurado, Markus Jaritz, Anna Azaryan, Barbara Werner, Mareike Roth, Johannes Zuber, Martin Stanulla, Monique L den Boer, Charles G Mullighan, Sabine Strehl, Meinrad Busslinger
PAX5 is a tumor suppressor in B-ALL, while the role of PAX5 fusion proteins in B-ALL development is largely unknown. Here, we studied the function of PAX5-ETV6 and PAX5-FOXP1 in mice expressing these proteins from the Pax5 locus. Both proteins arrested B-lymphopoiesis at the pro-B to pre-B-cell transition and, contrary to their proposed dominant-negative role, did not interfere with the expression of most regulated Pax5 target genes. Pax5-Etv6, but not Pax5-Foxp1, cooperated with loss of the Cdkna2a/b tumor suppressors in promoting B-ALL development...
February 20, 2017: EMBO Journal
https://www.readbyqxmd.com/read/28213481/reestablishing-microglia-function-good-news-for-alzheimer-s-therapy
#4
Knut Biber
No abstract text is available yet for this article.
February 17, 2017: EMBO Journal
https://www.readbyqxmd.com/read/28188244/structural-intermediates-in-the-fusion-associated-transition-of-vesiculovirus-glycoprotein
#5
Eduard Baquero, Aurélie A Albertini, Hélène Raux, Abbas Abou-Hamdan, Elisabetta Boeri-Erba, Malika Ouldali, Linda Buonocore, John K Rose, Jean Lepault, Stéphane Bressanelli, Yves Gaudin
Vesiculoviruses enter cells by membrane fusion, driven by a large, low-pH-induced, conformational change in the fusion glycoprotein G that involves transition from a trimeric pre-fusion toward a trimeric post-fusion state via monomeric intermediates. Here, we present the structure of the G fusion protein at intermediate pH for two vesiculoviruses, vesicular stomatitis virus (VSV) and Chandipura virus (CHAV), which is responsible for deadly encephalopathies. First, a CHAV G crystal structure shows two intermediate conformations forming a flat dimer of heterodimers...
February 10, 2017: EMBO Journal
https://www.readbyqxmd.com/read/28179369/nmd3-is-a-structural-mimic-of-eif5a-and-activates-the-cpgtpase-lsg1-during-60s-ribosome-biogenesis
#6
Andrey G Malyutin, Sharmishtha Musalgaonkar, Stephanie Patchett, Joachim Frank, Arlen W Johnson
During ribosome biogenesis in eukaryotes, nascent subunits are exported to the cytoplasm in a functionally inactive state. 60S subunits are activated through a series of cytoplasmic maturation events. The last known events in the cytoplasm are the release of Tif6 by Efl1 and Sdo1 and the release of the export adapter, Nmd3, by the GTPase Lsg1. Here, we have used cryo-electron microscopy to determine the structure of the 60S subunit bound by Nmd3, Lsg1, and Tif6. We find that a central domain of Nmd3 mimics the translation elongation factor eIF5A, inserting into the E site of the ribosome and pulling the L1 stalk into a closed position...
February 8, 2017: EMBO Journal
https://www.readbyqxmd.com/read/28167697/prc2-is-dispensable-for-hotair-mediated-transcriptional-repression
#7
Manuela Portoso, Roberta Ragazzini, Živa Brenčič, Arianna Moiani, Audrey Michaud, Ivaylo Vassilev, Michel Wassef, Nicolas Servant, Bruno Sargueil, Raphaël Margueron
Long non-coding RNAs (lncRNAs) play diverse roles in physiological and pathological processes. Several lncRNAs have been suggested to modulate gene expression by guiding chromatin-modifying complexes to specific sites in the genome. However, besides the example of Xist, clear-cut evidence demonstrating this novel mode of regulation remains sparse. Here, we focus on HOTAIR, a lncRNA that is overexpressed in several tumor types and previously proposed to play a key role in gene silencing through direct recruitment of Polycomb Repressive Complex 2 (PRC2) to defined genomic loci...
February 6, 2017: EMBO Journal
https://www.readbyqxmd.com/read/28159860/balancing-signals-in-the-intestinal-niche
#8
Sanne M van Neerven, Louis Vermeulen
No abstract text is available yet for this article.
February 3, 2017: EMBO Journal
https://www.readbyqxmd.com/read/28137749/conformational-change-of-syntaxin-linker-region-induced-by-munc13s-initiates-snare-complex-formation-in-synaptic-exocytosis
#9
Shen Wang, Ucheor B Choi, Jihong Gong, Xiaoyu Yang, Yun Li, Austin L Wang, Xiaofei Yang, Axel T Brunger, Cong Ma
The soluble N-ethylmaleimide-sensitive factor attachment protein receptor (SNARE) protein syntaxin-1 adopts a closed conformation when bound to Munc18-1, preventing binding to synaptobrevin-2 and SNAP-25 to form the ternary SNARE complex. Although it is known that the MUN domain of Munc13-1 catalyzes the transition from the Munc18-1/syntaxin-1 complex to the SNARE complex, the molecular mechanism is unclear. Here, we identified two conserved residues (R151, I155) in the syntaxin-1 linker region as key sites for the MUN domain interaction...
January 30, 2017: EMBO Journal
https://www.readbyqxmd.com/read/28137748/cell-signaling-as-a-cognitive-process
#10
REVIEW
Aneta Koseska, Philippe Ih Bastiaens
Cellular identity as defined through morphology and function emerges from intracellular signaling networks that communicate between cells. Based on recursive interactions within and among these intracellular networks, dynamical solutions in terms of biochemical behavior are generated that can differ from those in isolated cells. In this way, cellular heterogeneity in tissues can be established, implying that cell identity is not intrinsically predetermined by the genetic code but is rather dynamically maintained in a cognitive manner...
January 30, 2017: EMBO Journal
https://www.readbyqxmd.com/read/28130247/trapping-rab18-in-lipid-droplets
#11
Francesca Zappa, Rossella Venditti, Maria Antonietta De Matteis
No abstract text is available yet for this article.
January 27, 2017: EMBO Journal
https://www.readbyqxmd.com/read/28122869/a-g1-like-state-allows-hiv-1-to-bypass-samhd1-restriction-in-macrophages
#12
Petra Mlcochova, Katherine A Sutherland, Sarah A Watters, Cosetta Bertoli, Rob Am de Bruin, Jan Rehwinkel, Stuart J Neil, Gina M Lenzi, Baek Kim, Asim Khwaja, Matthew C Gage, Christiana Georgiou, Alexandra Chittka, Simon Yona, Mahdad Noursadeghi, Greg J Towers, Ravindra K Gupta
An unresolved question is how HIV-1 achieves efficient replication in terminally differentiated macrophages despite the restriction factor SAMHD1. We reveal inducible changes in expression of cell cycle-associated proteins including MCM2 and cyclins A, E, D1/D3 in macrophages, without evidence for DNA synthesis or mitosis. These changes are induced by activation of the Raf/MEK/ERK kinase cascade, culminating in upregulation of CDK1 with subsequent SAMHD1 T592 phosphorylation and deactivation of its antiviral activity...
January 25, 2017: EMBO Journal
https://www.readbyqxmd.com/read/28122868/conformational-equilibria-and-intrinsic-affinities-define-integrin-activation
#13
Jing Li, Yang Su, Wei Xia, Yan Qin, Martin J Humphries, Dietmar Vestweber, Carlos Cabañas, Chafen Lu, Timothy A Springer
We show that the three conformational states of integrin α5β1 have discrete free energies and define activation by measuring intrinsic affinities for ligand of each state and the equilibria linking them. The 5,000-fold higher affinity of the extended-open state than the bent-closed and extended-closed states demonstrates profound regulation of affinity. Free energy requirements for activation are defined with protein fragments and intact α5β1 On the surface of K562 cells, α5β1 is 99.8% bent-closed. Stabilization of the bent conformation by integrin transmembrane and cytoplasmic domains must be overcome by cellular energy input to stabilize extension...
January 25, 2017: EMBO Journal
https://www.readbyqxmd.com/read/28100677/paired-siglec-receptors-generate-opposite-inflammatory-responses-to-a-human-specific-pathogen
#14
Flavio Schwarz, Corinna S Landig, Shoib Siddiqui, Ismael Secundino, Joshua Olson, Nissi Varki, Victor Nizet, Ajit Varki
Paired immune receptors display near-identical extracellular ligand-binding regions but have intracellular sequences with opposing signaling functions. While inhibitory receptors dampen cellular activation by recognizing self-associated molecules, the functions of activating counterparts are less clear. Here, we studied the inhibitory receptor Siglec-11 that shows uniquely human expression in brain microglia and engages endogenous polysialic acid to suppress inflammation. We demonstrated that the human-specific pathogen Escherichia coli K1 uses its polysialic acid capsule as a molecular mimic to engage Siglec-11 and escape killing...
January 18, 2017: EMBO Journal
https://www.readbyqxmd.com/read/28100676/gene-body-chromatin-modification-dynamics%C3%A2-mediate-epigenome-differentiation-in%C3%A2-arabidopsis
#15
Soichi Inagaki, Mayumi Takahashi, Aoi Hosaka, Tasuku Ito, Atsushi Toyoda, Asao Fujiyama, Yoshiaki Tarutani, Tetsuji Kakutani
Heterochromatin is marked by methylation of lysine 9 on histone H3 (H3K9me). A puzzling feature of H3K9me is that this modification localizes not only in promoters but also in internal regions (bodies) of silent transcription units. Despite its prevalence, the biological significance of gene-body H3K9me remains enigmatic. Here we show that H3K9me-associated removal of H3K4 monomethylation (H3K4me1) in gene bodies mediates transcriptional silencing. Mutations in an Arabidopsis H3K9 demethylase gene IBM1 induce ectopic H3K9me2 accumulation in gene bodies, with accompanying severe developmental defects...
January 18, 2017: EMBO Journal
https://www.readbyqxmd.com/read/28100675/protein-synthesis-inhibition-and-gadd34-control-ifn-%C3%AE-heterogeneous-expression-in-response-to%C3%A2-dsrna
#16
Alexandre Dalet, Rafael J Argüello, Alexis Combes, Lionel Spinelli, Sebastien Jaeger, Mathieu Fallet, Thien-Phong Vu Manh, Andreia Mendes, Jessica Perego, Marisa Reverendo, Voahirana Camosseto, Marc Dalod, Tobias Weil, Manuel A Santos, Evelina Gatti, Philippe Pierre
In innate immune responses, induction of type-I interferons (IFNs) prevents virus spreading while viral replication is delayed by protein synthesis inhibition. We asked how cells perform these apparently contradictory activities. Using single fibroblast monitoring by flow cytometry and mathematical modeling, we demonstrate that type-I IFN production is linked to cell's ability to enter dsRNA-activated PKR-dependent translational arrest and then overcome this inhibition by decreasing eIF2α phosphorylation through phosphatase 1c cofactor GADD34 (Ppp1r15a) expression...
January 18, 2017: EMBO Journal
https://www.readbyqxmd.com/read/28096180/nutrient-sensing-and-tor-signaling-in-yeast-and-mammals
#17
REVIEW
Asier González, Michael N Hall
Coordinating cell growth with nutrient availability is critical for cell survival. The evolutionarily conserved TOR (target of rapamycin) controls cell growth in response to nutrients, in particular amino acids. As a central controller of cell growth, mTOR (mammalian TOR) is implicated in several disorders, including cancer, obesity, and diabetes. Here, we review how nutrient availability is sensed and transduced to TOR in budding yeast and mammals. A better understanding of how nutrient availability is transduced to TOR may allow novel strategies in the treatment for mTOR-related diseases...
January 17, 2017: EMBO Journal
https://www.readbyqxmd.com/read/28096179/dbf4-dependent-kinase-and-the-rtt107-scaffold-promote-mus81-mms4-resolvase-activation-during-mitosis
#18
Lissa N Princz, Philipp Wild, Julia Bittmann, F Javier Aguado, Miguel G Blanco, Joao Matos, Boris Pfander
DNA repair by homologous recombination is under stringent cell cycle control. This includes the last step of the reaction, disentanglement of DNA joint molecules (JMs). Previous work has established that JM resolving nucleases are activated specifically at the onset of mitosis. In case of budding yeast Mus81-Mms4, this cell cycle stage-specific activation is known to depend on phosphorylation by CDK and Cdc5 kinases. Here, we show that a third cell cycle kinase, Cdc7-Dbf4 (DDK), targets Mus81-Mms4 in conjunction with Cdc5-both kinases bind to as well as phosphorylate Mus81-Mms4 in an interdependent manner...
January 17, 2017: EMBO Journal
https://www.readbyqxmd.com/read/28093501/discrete-cytosolic-macromolecular-braf-complexes-exhibit-distinct-activities-and-composition
#19
Britta Diedrich, Kristoffer Tg Rigbolt, Michael Röring, Ricarda Herr, Stephanie Kaeser-Pebernard, Christine Gretzmeier, Robert F Murphy, Tilman Brummer, Jörn Dengjel
As a central element within the RAS/ERK pathway, the serine/threonine kinase BRAF plays a key role in development and homeostasis and represents the most frequently mutated kinase in tumors. Consequently, it has emerged as an important therapeutic target in various malignancies. Nevertheless, the BRAF activation cycle still raises many mechanistic questions as illustrated by the paradoxical action and side effects of RAF inhibitors. By applying SEC-PCP-SILAC, we analyzed protein-protein interactions of hyperactive BRAF(V)(600E) and wild-type BRAF (BRAF(WT))...
January 16, 2017: EMBO Journal
https://www.readbyqxmd.com/read/28093500/cytosolic-thioredoxin-reductase-1-is-required-for-correct-disulfide-formation-in-the-er
#20
Greg J Poet, Ojore Bv Oka, Marcel van Lith, Zhenbo Cao, Philip J Robinson, Marie Anne Pringle, Elias Sj Arnér, Neil J Bulleid
Folding of proteins entering the secretory pathway in mammalian cells frequently requires the insertion of disulfide bonds. Disulfide insertion can result in covalent linkages found in the native structure as well as those that are not, so-called non-native disulfides. The pathways for disulfide formation are well characterized, but our understanding of how non-native disulfides are reduced so that the correct or native disulfides can form is poor. Here, we use a novel assay to demonstrate that the reduction in non-native disulfides requires NADPH as the ultimate electron donor, and a robust cytosolic thioredoxin system, driven by thioredoxin reductase 1 (TrxR1 or TXNRD1)...
January 16, 2017: EMBO Journal
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