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https://www.readbyqxmd.com/read/28900926/immunological-disorders-regulation-of-ca-2-signaling-in-t-lymphocytes
#1
Sonal Srikanth, Jin Seok Woo, Zuoming Sun, Yousang Gwack
Engagement of T cell receptors (TCRs) with cognate antigens triggers cascades of signaling pathways in helper T cells. TCR signaling is essential for the effector function of helper T cells including proliferation, differentiation, and cytokine production. It also modulates effector T cell fate by inducing cell death, anergy (nonresponsiveness), exhaustion, and generation of regulatory T cells. One of the main axes of TCR signaling is the Ca(2+)-calcineurin-nuclear factor of activated T cells (NFAT) signaling pathway...
2017: Advances in Experimental Medicine and Biology
https://www.readbyqxmd.com/read/28900914/stim-trp-pathways-and-microdomain-organization-contribution-of-trpc1-in-store-operated-ca-2-entry-impact-on-ca-2-signaling-and-cell-function
#2
Hwei Ling Ong, Indu S Ambudkar
Store-operated calcium entry (SOCE) is a ubiquitous Ca(2+) entry pathway that is activated in response to depletion of ER-Ca(2+) stores and critically controls the regulation of physiological functions in a wide variety of cell types. The transient receptor potential canonical (TRPC) channels (TRPCs 1-7), which are activated by stimuli leading to PIP2 hydrolysis, were first identified as molecular components of SOCE channels. While TRPC1 was associated with SOCE and regulation of function in several cell types, none of the TRPC members displayed I CRAC, the store-operated current identified in lymphocytes and mast cells...
2017: Advances in Experimental Medicine and Biology
https://www.readbyqxmd.com/read/28900912/the-stim-orai-pathway-light-operated-ca-2-entry-through-engineered-crac-channels
#3
Guolin Ma, Shufan Wen, Yun Huang, Yubin Zhou
Ca(2+) signals regulate a plethora of cellular functions that include muscle contraction, heart beating, hormone secretion, lymphocyte activation, gene expression, and metabolism. To study the impact of Ca(2+) signals on biological processes, pharmacological tools and caged compounds have been commonly applied to induce fluctuations of intracellular Ca(2+) concentrations. These conventional approaches, nonetheless, lack rapid reversibility and high spatiotemporal resolution. To overcome these disadvantages, we and others have devised a series of photoactivatable genetically encoded Ca(2+) actuators (GECAs) by installing light sensitivities into a bona fide highly selective Ca(2+) channel, the Ca(2+) release-activated Ca(2+) (CRAC) channel...
2017: Advances in Experimental Medicine and Biology
https://www.readbyqxmd.com/read/28900908/the-stim-orai-pathway-orai-the-pore-forming-subunit-of-the-crac-channel
#4
Aparna Gudlur, Patrick G Hogan
This chapter focuses on the Orai proteins, Orai1-Orai3, with special emphasis on Orai1, in humans and other mammals, and on the definitive evidence that Orai is the pore subunit of the CRAC channel. It begins by reviewing briefly the defining characteristics of the CRAC channel, then discusses the studies that implicated Orai as part of the store-operated Ca(2+) entry pathway and as the CRAC channel pore subunit, and finally examines ongoing work that is providing insights into CRAC channel structure and gating...
2017: Advances in Experimental Medicine and Biology
https://www.readbyqxmd.com/read/28863821/relevance-of-carc-and-crac-cholesterol-recognition-motifs-in-the-nicotinic-acetylcholine-receptor-and-other-membrane-bound-receptors
#5
Coralie Di Scala, Carlos J Baier, Luke S Evans, Philip T F Williamson, Jacques Fantini, Francisco J Barrantes
Cholesterol is a ubiquitous neutral lipid, which finely tunes the activity of a wide range of membrane proteins, including neurotransmitter and hormone receptors and ion channels. Given the scarcity of available X-ray crystallographic structures and the even fewer in which cholesterol sites have been directly visualized, application of in silico computational methods remains a valid alternative for the detection and thermodynamic characterization of cholesterol-specific sites in functionally important membrane proteins...
2017: Current Topics in Membranes
https://www.readbyqxmd.com/read/28851859/regulation-of-orai1-stim1-mediated-icrac-by-intracellular-ph
#6
D Gavriliouk, N R Scrimgeour, S Grigoryev, L Ma, F H Zhou, G J Barritt, G Y Rychkov
Ca(2+) release activated Ca(2+) (CRAC) channels composed of two cellular proteins, Ca(2+)-sensing stromal interaction molecule 1 (STIM1) and pore-forming Orai1, are the main mediators of the Ca(2+) entry pathway activated in response to depletion of intracellular Ca(2+) stores. Previously it has been shown that the amplitude of CRAC current (ICRAC) strongly depends on extracellular and intracellular pH. Here we investigate the intracellular pH (pHi) dependence of ICRAC mediated by Orai1 and STIM1ectopically expressed in HEK293 cells...
August 29, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28839199/the-conserved-tyrosine-residue-940-plays-a-key-structural-role-in-membrane-interaction-of-bordetella-adenylate-cyclase-toxin
#7
Jiri Masin, Jana Roderova, Adriana Osickova, Petr Novak, Ladislav Bumba, Radovan Fiser, Peter Sebo, Radim Osicka
The adenylate cyclase toxin-hemolysin (CyaA, ACT or AC-Hly) translocates its adenylate cyclase (AC) enzyme domain into target cells in a step that depends on membrane cholesterol content. We thus examined what role in toxin activities is played by the five putative cholesterol recognition amino acid consensus (CRAC) motifs predicted in CyaA hemolysin moiety. CRAC-disrupting phenylalanine substitutions had no impact on toxin activities and these were not inhibited by free cholesterol, showing that the putative CRAC motifs are not involved in cholesterol binding...
August 24, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28748221/rna-substrate-length-as-an-indicator-of-exosome-interactions-in-vivo
#8
Clémentine Delan-Forino, Claudia Schneider, David Tollervey
Background: The exosome complex plays key roles in RNA processing and degradation in Eukaryotes and Archaea. Outstanding structural studies identified multiple pathways for RNA substrates into the exosome in vitro, but identifying the pathway followed by individual RNA species in vivo remains challenging. Methods: We attempted to address this question using RNase protection. In vivo RNA-protein crosslinking (CRAC) was applied to the exosome component Rrp44/Dis3, which has both endonuclease and exonuclease activity...
2017: Wellcome Open Research
https://www.readbyqxmd.com/read/28716825/efficiency-and-safety-of-crac-inhibitors-in-human-rheumatoid-arthritis-xenograft-models
#9
Shuang Liu, Hitoshi Hasegawa, Erika Takemasa, Yasuyuki Suzuki, Keizou Oka, Takeshi Kiyoi, Hiroyuki Takeda, Tomio Ogasawara, Tatsuya Sawasaki, Masaki Yasukawa, Kazutaka Maeyama
Store-operated Ca(2+) release-activated Ca(2+) (CRAC) channels are involved in the pathogenesis of rheumatoid arthritis (RA) and have been studied as therapeutic targets in the management of RA. We investigated the efficacy and safety of CRAC inhibitors, including a neutralizing Ab (hCRACM1-IgG) and YM-58483, in the treatment of RA. Patient-derived T cell and B cell activity was suppressed by hCRACM1-IgG as well as YM-58483. Systemically constant, s.c. infused CRAC inhibitors showed anti-inflammatory activity in a human-NOD/SCID xenograft RA model as well as protective effects against the destruction of cartilage and bone...
July 17, 2017: Journal of Immunology: Official Journal of the American Association of Immunologists
https://www.readbyqxmd.com/read/28694529/the-production-of-fibroblast-growth-factor-23-is-controlled-by-tgf-%C3%AE-2
#10
Martina Feger, Philipp Hase, Bingbing Zhang, Frank Hirche, Philipp Glosse, Florian Lang, Michael Föller
Transforming growth factor-β (TGF-β) is a cytokine produced by many cell types and implicated in cell growth, differentiation, apoptosis, and inflammation. It stimulates store-operated calcium entry (SOCE) through the calcium release-activated calcium (CRAC) channel Orai1/Stim1 in endometrial Ishikawa cells. Bone cells generate fibroblast growth factor (FGF) 23, which inhibits renal phosphate reabsorption and 1,25(OH)2D3 formation in concert with its co-receptor Klotho. Moreover, Klotho and FGF23 counteract aging and age-related clinical conditions...
July 10, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28575120/structural-basis-for-5-ets-recognition-by-utp4-at-the-early-stages-of-ribosome-biogenesis
#11
Fabiola R Calviño, Markus Kornprobst, Géza Schermann, Fabienne Birkle, Klemens Wild, Tamas Fischer, Ed Hurt, Yasar Luqman Ahmed, Irmgard Sinning
Eukaryotic ribosome biogenesis begins with the co-transcriptional assembly of the 90S pre-ribosome. The 'U three protein' (UTP) complexes and snoRNP particles arrange around the nascent pre-ribosomal RNA chaperoning its folding and further maturation. The earliest event in this hierarchical process is the binding of the UTP-A complex to the 5'-end of the pre-ribosomal RNA (5'-ETS). This oligomeric complex predominantly consists of β-propeller and α-solenoidal proteins. Here we present the structure of the Utp4 subunit from the thermophilic fungus Chaetomium thermophilum at 2...
2017: PloS One
https://www.readbyqxmd.com/read/28564609/sequential-steps-of-crac-channel-activation
#12
Raz Palty, Zhu Fu, Ehud Y Isacoff
Interaction between the endoplasmic reticulum protein STIM1 and the plasma membrane channel ORAI1 generates calcium signals that are central for diverse cellular functions. How STIM1 binds and activates ORAI1 remains poorly understood. Using electrophysiological, optical, and biochemical techniques, we examined the effects of mutations in the STIM1-ORAI1 activating region (SOAR) of STIM1. We find that SOAR mutants that are deficient in binding to resting ORAI1 channels are able to bind to and boost activation of partially activated ORAI1 channels...
May 30, 2017: Cell Reports
https://www.readbyqxmd.com/read/28492103/amphipathic-secondary-structure-elements-and-putative-cholesterol-recognizing-amino-acid-consensus-crac-motifs-as-governing-factors-of-highly-specific-matrix-protein-interactions-with-raft-type-membranes-in-enveloped-viruses
#13
Victor A Radyukhin, Liubov A Dadinova, Ivan A Orlov, Ludmila A Baratova
No abstract text is available yet for this article.
May 11, 2017: Journal of Biomolecular Structure & Dynamics
https://www.readbyqxmd.com/read/28400552/kinetic-crac-uncovers-a-role-for-nab3-in-determining-gene-expression-profiles-during-stress
#14
Rob van Nues, Gabriele Schweikert, Erica de Leau, Alina Selega, Andrew Langford, Ryan Franklin, Ira Iosub, Peter Wadsworth, Guido Sanguinetti, Sander Granneman
RNA-binding proteins play a key role in shaping gene expression profiles during stress, however, little is known about the dynamic nature of these interactions and how this influences the kinetics of gene expression. To address this, we developed kinetic cross-linking and analysis of cDNAs (χCRAC), an ultraviolet cross-linking method that enabled us to quantitatively measure the dynamics of protein-RNA interactions in vivo on a minute time-scale. Here, using χCRAC we measure the global RNA-binding dynamics of the yeast transcription termination factor Nab3 in response to glucose starvation...
April 11, 2017: Nature Communications
https://www.readbyqxmd.com/read/28355211/transcriptome-wide-analysis-of-alternative-routes-for-rna-substrates-into-the-exosome-complex
#15
Clémentine Delan-Forino, Claudia Schneider, David Tollervey
The RNA exosome complex functions in both the accurate processing and rapid degradation of many classes of RNA. Functional and structural analyses indicate that RNA can either be threaded through the central channel of the exosome or more directly access the active sites of the ribonucleases Rrp44 and Rrp6, but it was unclear how many substrates follow each pathway in vivo. We used CRAC (UV crosslinking and analysis of cDNA) in growing cells to identify transcriptome-wide interactions of RNAs with the major nuclear exosome-cofactor Mtr4 and with individual exosome subunits (Rrp6, Csl4, Rrp41 and Rrp44) along the threaded RNA path...
March 2017: PLoS Genetics
https://www.readbyqxmd.com/read/28352661/store-operated-ca-2-entry-controls-ameloblast-cell-function-and-enamel-development
#16
Miriam Eckstein, Martin Vaeth, Cinzia Fornai, Manikandan Vinu, Timothy G Bromage, Meerim K Nurbaeva, Jessica L Sorge, Paulo G Coelho, Youssef Idaghdour, Stefan Feske, Rodrigo S Lacruz
Loss-of-function mutations in stromal interaction molecule 1 (STIM1) impair the activation of Ca(2+) release-activated Ca(2+) (CRAC) channels and store-operated Ca(2+) entry (SOCE), resulting in a disease syndrome called CRAC channelopathy that is characterized by severe dental enamel defects. The cause of these enamel defects has remained unclear given a lack of animal models. We generated Stim1/2(K14cre) mice to delete STIM1 and its homolog STIM2 in enamel cells. These mice showed impaired SOCE in enamel cells...
March 23, 2017: JCI Insight
https://www.readbyqxmd.com/read/28349467/crosslinking-methods-to-identify-rna-methyltransferase-targets-in-vivo
#17
Sara Haag, Jens Kretschmer, Katherine E Sloan, Markus T Bohnsack
Several crosslinking methods have been developed to identify interacting RNAs for proteins of interest. Here, we describe variants of the UV crosslinking and analysis of cDNA (CRAC) method that allow target identification of RNA methyltransferases on a genome-wide scale. We present a detailed protocol for the application of CRAC in human cells that stably express the protein of interest fused to a tandem affinity tag. After the introduction of a covalent link between the protein and its target RNAs, protein-RNA complexes are purified and bound RNAs trimmed, ligated to adapters, reverse transcribed, and amplified...
2017: Methods in Molecular Biology
https://www.readbyqxmd.com/read/28331181/multi-walled-carbon-nanotubes-act-as-a-chemokine-and-recruit-macrophages-by-activating-the-plc-ip3-crac-channel-signaling-pathway
#18
Hui Li, Xiao-Qiu Tan, Li Yan, Bo Zeng, Jie Meng, Hai-Yan Xu, Ji-Min Cao
The impact of nanomaterials on immune cells is gaining attention but is not well documented. Here, we report a novel stimulating effect of carboxylated multi-walled carbon nanotubes (c-MWCNTs) on the migration of macrophages and uncover the underlying mechanisms, especially the upstream signaling, using a series of techniques including transwell migration assay, patch clamp, ELISA and confocal microscopy. c-MWCNTs dramatically stimulated the migration of RAW264.7 macrophages when endocytosed, and this effect was abolished by inhibiting phospholipase C (PLC) with U-73122, antagonizing the IP3 receptor with 2-APB, and blocking calcium release-activated calcium (CRAC) channels with SK&F96365...
March 22, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28294127/orai2-modulates-store-operated-calcium-entry-and-t-cell-mediated-immunity
#19
Martin Vaeth, Jun Yang, Megumi Yamashita, Isabelle Zee, Miriam Eckstein, Camille Knosp, Ulrike Kaufmann, Peter Karoly Jani, Rodrigo S Lacruz, Veit Flockerzi, Imre Kacskovics, Murali Prakriya, Stefan Feske
Store-operated Ca(2+) entry (SOCE) through Ca(2+) release-activated Ca(2+) (CRAC) channels is critical for lymphocyte function and immune responses. CRAC channels are hexamers of ORAI proteins that form the channel pore, but the contributions of individual ORAI homologues to CRAC channel function are not well understood. Here we show that deletion of Orai1 reduces, whereas deletion of Orai2 increases, SOCE in mouse T cells. These distinct effects are due to the ability of ORAI2 to form heteromeric channels with ORAI1 and to attenuate CRAC channel function...
March 15, 2017: Nature Communications
https://www.readbyqxmd.com/read/28258822/intra-articular-lentivirus-mediated-gene-therapy-targeting-cracm1-for-the-treatment-of-collagen-induced-arthritis
#20
Shuang Liu, Takeshi Kiyoi, Erika Takemasa, Kazutaka Maeyama
Abnormal store-operated calcium uptake has been observed in peripheral T lymphocytes of rheumatoid arthritis (RA) patients, and sustained intracellular calcium signalling is known to mediate the functions of many types of immune cells. Thus, it is hypothesized that regulating calcium entry through CRACM1 (the pore-forming subunit of calcium release-activated calcium (CRAC) channels; also known as ORAI1) may be beneficial for the management of RA. Localized CRACM1 knockdown in the joints and draining lymph nodes (DLNs) of mice with collagen-induced arthritis (CIA) was achieved via lentiviral-based delivery of shRNA targeting mouse CRACM1...
March 2017: Journal of Pharmacological Sciences
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