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Small membrane protein regulator

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https://www.readbyqxmd.com/read/28106310/mechanism-of-type-iii-protein-secretion-regulation-of-flha-conformation-by-a-functionally-critical-charged-residue-cluster
#1
Marc Erhardt, Paige Wheatley, Eun A Kim, Takanori Hirano, Yang Zhang, Mayukh K Sarkar, Kelly T Hughes, David F Blair
The bacterial flagellum contains a specialized secretion apparatus in its base that pumps certain protein subunits through the growing structure to their sites of installation beyond the membrane. A related apparatus functions in the injectisomes of gram-negative pathogens to export virulence factors into host cells. This mode of protein export is termed type-III secretion (T3S). Details of the T3S mechanism are unclear. It is energized by the proton gradient; here, a mutational approach was used to identify proton-binding groups that might function in transport...
January 20, 2017: Molecular Microbiology
https://www.readbyqxmd.com/read/28105535/the-neuropeptide-orexin-a-inhibits-the-gabaa-receptor-by-pkc-and-ca-2-camkii-dependent-phosphorylation-of-its-%C3%AE-1-subunit
#2
Divya Sachidanandan, Haritha P Reddy, Anitha Mani, Geoffrey J Hyde, Amal Kanti Bera
Orexin-A and orexin-B (Ox-A, Ox-B) are neuropeptides produced by a small number of neurons that originate in the hypothalamus and project widely in the brain. Only discovered in 1998, the orexins are already known to regulate several behaviours. Most prominently, they help to stabilise the waking state, a role with demonstrated significance in the clinical management of narcolepsy and insomnia. Orexins bind to G-protein-coupled receptors (predominantly postsynaptic) of two subtypes, OX1R and OX2R. The primary effect of Ox-OXR binding is a direct depolarising influence mediated by cell membrane cation channels, but a wide variety of secondary effects, both pre- and postsynaptic, are also emerging...
January 19, 2017: Journal of Molecular Neuroscience: MN
https://www.readbyqxmd.com/read/28104494/thoughts-on-interactions-between-pgrmc1-and-diverse-attested-and-potential-hydrophobic-ligands
#3
REVIEW
Michael A Cahill, Amy E Medlock
Progesterone Receptor Membrane Component 1 (PGRMC1) is located in many different subcellular locations with many different attested and probably location-specific functions. PGRMC1 was recently identified in the mitochondrial outer membrane where it interacts with ferrochelatase, the last enzyme in the heme synthetic pathway. It has been proposed that PGRMC1 may act as a chaperone to shuttle newly synthesized heme from the mitochondrion to cytochrome P450 (cyP450) enzymes. Here we consider potential roles that PGRMC1 may play in transferring heme, and other small hydrophobic ligands such as cholesterol and steroids, between the hydrophobic compartment of the membrane lipid bilayer interior to aqueous proteins, and perhaps to the membranes of other organelles...
January 16, 2017: Journal of Steroid Biochemistry and Molecular Biology
https://www.readbyqxmd.com/read/28099869/amitriptyline-down-regulates-coenzyme-q10-biosynthesis-in-lung-cancer-cells
#4
Tamara Ortiz, Marina Villanueva-Paz, Eduardo Díaz-Parrado, Matilde Illanes, Ana Fernández-Rodríguez, José A Sánchez-Alcázar, Manuel de Miguel
Amitriptyline, a tricyclic antidepressant, has been proposed as an antitumoral drug in oxidative therapy. Its pro-apoptotic effects, mediated by high reactive oxygen species generation, have been already described. In this study we analysed the effect of amitriptyline on the biosynthesis of coenzyme Q10 (CoQ), an essential component for electron transport and a potent membrane antioxidant involved in redox signaling. We treated H460 cells, a non-small-cell lung cancer cell line, with amitriptyline and we analyzed CoQ levels by HPLC and CoQ biosynthesis rate, as well as the enzymes involved in CoQ biosynthesis by real-time PCR and Western blot...
January 15, 2017: European Journal of Pharmacology
https://www.readbyqxmd.com/read/28096168/sk-channel-enhancers-attenuate-ca2-dependent-arrhythmia-in-hypertrophic-hearts-by-regulating-mito-ros-dependent-oxidation-and-activity-of-ryr
#5
Tae Yun Kim, Radmila Terentyeva, Karim H F Roder, Weiyan Li, Man Liu, Ian Greener, Shanna Hamilton, Iuliia Polina, Kevin R Murphy, Richard T Clements, Samuel C Dudley, Gideon Koren, Bum-Rak Choi, Dmitry Terentyev
AIM: s: Plasmamembrane small conductance Ca<su2+p>-activated K<su+ p > (SK) channels were implicated in ventricular arrhythmias in infarcted and failing hearts. Recently, SK channels were detected in the mitochondria inner membrane (mSK), and their activation protected from acute ischemia-reperfusion injury by reducing intracellular levels of reactive oxygen species (ROS). We hypothesized that mSK play an important role in regulating mitochondrial function in chronic cardiac diseases...
January 17, 2017: Cardiovascular Research
https://www.readbyqxmd.com/read/28094839/improved-fluorescence-assays-to-measure-the-defects-associated-with-f508del-cftr-allow-identification-of-new-active-compounds
#6
Emily Langron, Michela I Simone, Clémence M S Delalande, Jean-Louis Reymond, David L Selwood, Paola Vergani
BACKGROUND AND PURPOSE: Cystic fibrosis (CF) is a debilitating disease caused by mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene, which codes for a Cl-/HCO3 - channel. F508del, the most common CF-associated mutation, causes both gating and biogenesis defects in the CFTR protein. This paper describes the optimisation of two fluorescence assays, capable of measuring CFTR function and cellular localisation, and their use in a pilot drug screen. EXPERIMENTAL APPROACH: HEK293 cells expressing YFP-F508del-CFTR, in which halide sensitive YFP is tagged to the N-terminal of CFTR, were used to screen a small library of compounds based on the VX-770 scaffold...
January 17, 2017: British Journal of Pharmacology
https://www.readbyqxmd.com/read/28090783/probing-the-druggability-of-membrane-bound-rab5-by-molecular-dynamics-simulations
#7
Eileen Edler, Matthias Stein
Rab5 is a small GTPase and a key regulator in early endosomal trafficking. Rab5 and its effectors are involved in a large number of infectious diseases and certain types of cancer. We performed µs atomistic molecular dynamics simulations of inactive and active full-length Rab5 anchored to a complex model bilayer with composition of the early endosome membrane. Direct interactions between the Rab5 G domain and the bilayer were observed. We found two dominant nucleotide-dependent orientations characterised by a different accessibility of the switch regions...
December 2017: Journal of Enzyme Inhibition and Medicinal Chemistry
https://www.readbyqxmd.com/read/28087700/two-small-molecules-restore-stability-to-a-sub-population-of-the-cystic-fibrosis-transmembrane-conductance-regulator-with-the-predominant-disease-causing-mutation
#8
Xin Meng, Yiting Wang, Xiaomeng Wang, Joe A Wrennall, Tracy L Rimington, Hongyu Li, Zhiwei Cai, Robert C Ford, David N Sheppard
Cystic fibrosis (CF) is caused by mutations that disrupt the plasma membrane expression, stability, and function of the cystic fibrosis transmembrane conductance regulator (CFTR) Cl- channel. Two small molecules, the CFTR corrector lumacaftor and the potentiator ivacaftor, are now used clinically to treat CF, although some studies suggest that they have counteracting effects on CFTR stability. Here, we investigated the impact of these compounds on the instability of F508del-CFTR, the most common CF mutation...
January 13, 2017: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/28078993/mirnas-new-biomarkers-and-therapeutic-targets-in-dementia
#9
Ana Teresa de Bastos Viegas, Joana Ribeiro Guedes, Ana Rafaela Oliveira, Ana Maria Sequeira Cardoso, Ana Luísa Colaço Cardoso
BACKGROUND: Dementia is a complex pathological state that affects millions of individuals worldwide and is responsible for a huge socioeconomic burden, making it a major health concern of current times. Given the impact of dementia in both patients and caregivers, it is crucial to fully clarify the molecular mechanisms underlying dementia-associated disorders, since without this knowledge our ability to correctly diagnose and treat these diseases is severely hampered. METHODS: Epigenetic mechanisms, such as miRNA-mediated post-transcriptional regulation, have been reported to play a role in dementia pathogenesis...
January 10, 2017: Current Pharmaceutical Design
https://www.readbyqxmd.com/read/28078077/a-novel-method-for-the-quantification-of-fatty-infiltration-in-skeletal-muscle
#10
Nicole K Biltz, Gretchen A Meyer
BACKGROUND: Fatty infiltration of the skeletal muscle is a common but poorly understood feature of many myopathies. It is best described in human muscle, where non-invasive imaging techniques and representative histology have been optimized to view and quantify infiltrating fat. However, human studies are limited in their ability to identify cellular and molecular mechanisms regulating fatty infiltration, a likely prerequisite to developing targeted interventions. As mechanistic investigations move to small animals, studies may benefit from new or adapted imaging tools optimized for high resolution and whole muscle quantification...
2017: Skeletal Muscle
https://www.readbyqxmd.com/read/28077322/a-protein-kinase-a-ezrin-complex-regulates-connexin-43-gap-junction-communication-in-liver-epithelial-cells
#11
Aleksandra R Dukic, Linda Hofstad Haugen, Guillaume Pidoux, Edward Leithe, Oddmund Bakke, Kjetil Taskén
Communication between adjacent cells can occur via gap junctions (GJ) composed of connexin (Cx) hexamers that allow passage of small molecules. One of the most widely and highly expressed Cxs in human tissues is Cx43, shown to be regulated through phosphorylation by several kinases including PKA. Ezrin is a membrane associated protein that can serve as an A-kinase anchoring protein (AKAP) and hold an anchored pool of PKA. Here, we used the liver epithelial cell line IAR20, which expresses Cx43 as the predominant GJ protein, to test the hypothesis that Ezrin may associate with Cx43 in cell types that form stable GJs and serve as an AKAP...
January 8, 2017: Cellular Signalling
https://www.readbyqxmd.com/read/28073372/a-novel-method-for-the-quantification-of-fatty-infiltration-in-skeletal-muscle
#12
Nicole K Biltz, Gretchen A Meyer
BACKGROUND: Fatty infiltration of the skeletal muscle is a common but poorly understood feature of many myopathies. It is best described in human muscle, where non-invasive imaging techniques and representative histology have been optimized to view and quantify infiltrating fat. However, human studies are limited in their ability to identify cellular and molecular mechanisms regulating fatty infiltration, a likely prerequisite to developing targeted interventions. As mechanistic investigations move to small animals, studies may benefit from new or adapted imaging tools optimized for high resolution and whole muscle quantification...
January 10, 2017: Skeletal Muscle
https://www.readbyqxmd.com/read/28071848/gxxxg-mediated-parallel-and-antiparallel-dimerization-of-transmembrane-helices-and-its-inhibition-by-cholesterol-single-pair-fret-and-2d-ir-studies
#13
Yoshiaki Yano, Kotaro Kondo, Yuta Watanabe, Tianqi O Zhang, Jia-Jung Ho, Shinya Oishi, Nobutaka Fujii, Martin T Zanni, Katsumi Matsuzaki
Small-residue-mediated interhelical packings are ubiquitously found in helical membrane proteins, although their interaction dynamics and lipid dependence remain mostly uncharacterized. We used a single-pair FRET technique to examine the effect of a GXXXG motif on the association of de novo designed (AALALAA)3 helices in liposomes. Dimerization occurred with sub-second lifetimes, which was abolished by cholesterol. Utilizing the nearly instantaneous time-resolution of 2D IR spectroscopy, parallel and antiparallel helix associations were identified by vibrational couplings across helices at their interface...
January 10, 2017: Angewandte Chemie
https://www.readbyqxmd.com/read/28068084/molecular-modeling-evaluation-of-the-enantiomers-of-a-novel-adenylyl-cyclase-2-inhibitor
#14
Neha Rana, Jason M Conley, Monica Soto-Velasquez, Francisco Leon, Stephen J Cutler, Val J Watts, Markus A Lill
Adenylyl cyclase 2 (AC2) is one of nine membrane-bound isoforms of adenylyl cyclase that converts ATP into cyclic AMP (cAMP), an important second messenger molecule. Up-regulation of AC2 is linked to cancers like pancreatic and small intestinal neuroendocrine tumors (NETs). The structures of the various isoforms of adenylyl cyclases are highly homologous, posing a significant challenge to drug discovery efforts for an effective, isoform-selective modulator of AC2. In a previous study, a screen identified a potential isoform-selective and non-competitive inhibitor of AC2, SKF83566...
January 9, 2017: Journal of Chemical Information and Modeling
https://www.readbyqxmd.com/read/28065784/role-of-phosphatidylserine-in-the-activation-of-rho1-related-pkc1-signaling-in-saccharomyces-cerevisiae
#15
Wataru Nomura, Yusuke Ito, Yoshiharu Inoue
Protein kinase C (PKC) belongs to a family of serine/threonine kinases and is evolutionary conserved among eukaryotes. It contains several functional domains, with the C1 domain being identified as a membrane-targeting module. Diacylglycerol (DAG) and phorbol esters bind to the C1 domain to enhance its kinase activity. The C1 domain is conserved in PKC (Pkc1) in the budding yeast Saccharomyces cerevisiae; however, its kinase activity does not respond to DAG. Although the C1 domain of Pkc1 physically interacts with the small GTPase Rho1, the interaction between C1 domain and lipids has not yet been characterized...
January 5, 2017: Cellular Signalling
https://www.readbyqxmd.com/read/28062165/daboialectin-a-c-type-lectin-from-russell-s-viper-venom-induces-cytoskeletal-damage-and-apoptosis-in-human-lung-cancer-cells-in%C3%A2-vitro
#16
Jigni Pathan, Sukanta Mondal, Angshuman Sarkar, Dibakar Chakrabarty
'Daboialectin', a low molecular weight C-type lectin (18.5 kDa) isolated from Russell's viper venom showed cytotoxic effects on human broncho-alveolar carcinoma derived (A549) cell lines. Daboialectin induced inhibition of A549 cell growth was time and concentration dependent with severe morphological changes by altering the functions of small GTPases such as Rac, Rho and cdc42. ROS induced DNA damage may result in apoptosis by inducing disruption of membrane integrity, blebbing and nuclear disintegration by activating caspases...
January 3, 2017: Toxicon: Official Journal of the International Society on Toxinology
https://www.readbyqxmd.com/read/28060560/harnessing-membrane-trafficking-to-promote-cancer-spreading-and-invasion-the-case-of-rab2a
#17
Hiroaki Kajiho, Yuko Kajiho, Giorgio Scita
How cancer disseminates and metastasizes remains an outstanding open question. Emerging evidence indicates that membrane trafficking is frequently harnessed by tumours of epithelial origin to acquire a mesenchymal program of invasiveness. However, the critical molecular hubs utilized by cancer cells this context have only began to be elucidated. Here, we discussed the results of a recent phenotypic screening that led to the identification of the small GTPase RAB2A, not previously involved in cancer dissemination, as pivotal for the acquisition of pericellular proteolysis, cell dissemination and distant metastatic spreading of human breast cancer...
January 6, 2017: Small GTPases
https://www.readbyqxmd.com/read/28057568/localization-of-rab3a-binding-site-on-c2a-domain-of-synaptotagmin-i-to-reveal-its-regulatory-mechanism
#18
Xia Tang, Chunliang Xie, Ying Wang, Xianchun Wang
Synaptotagmin I (Syt I) functions in the regulation of neurotransmitter release and multiple other cellular processes through its C2 domain binding to other molecules. Our previous study demonstrated that Rab3A, a small GTP-binding protein, is a new interacting partner of Syt I and could bind to both of the C2 domains; the polylysine motif in C2B is a key site for Rab3A binding, but the binding site on C2A is not clear. In order to localize Rab3-binding site on C2A and reveal the relevant regulatory mechanism, in the present study we investigated the interaction between recombinant Rab3A and various C2A mutants...
January 3, 2017: International Journal of Biological Macromolecules
https://www.readbyqxmd.com/read/28057533/presynaptic-pick1-facilitates-trafficking-of-ampa-receptors-between-active-zone-and-synaptic-vesicle-pool
#19
C Haglerød, S Hussain, Y Nakamura, J Xia, F-M S Haug, O P Ottersen, J M Henley, S Davanger
Previous studies have indicated that presynaptic α-amino-3-hydroxy-5-methyl-4-isoxazole propionate receptors (AMPARs) contribute to the regulation of neurotransmitter release. In hippocampal synapses, the presynaptic surface expression of several AMPAR subunits, including GluA2, is regulated in a ligand-dependent manner. However, the molecular mechanisms underlying the presynaptic trafficking of AMPARs are still unknown. Here, using bright-field immunocytochemistry, western blots, and quantitative immunogold electron microscopy of the hippocampal CA1 area from intact adult rat brain, we demonstrate the association of AMPA receptors with the presynaptic active zone and with small presynaptic vesicles, in Schaffer collateral synapses in CA1 of the hippocampus...
January 3, 2017: Neuroscience
https://www.readbyqxmd.com/read/28052479/a-thioredoxin-nbtrxh2-from-nicotiana-benthamiana-negatively-regulates-the-movement-of-bamboo-mosaic-virus
#20
I-Hsuan Chen, Hui-Ting Chen, Ying-Ping Huang, Hweng-Jan Huang, Lin-Ling Shenkwen, Yau-Heiu Hsu, Ching-Hsiu Tsai
An upregulated gene derived from Bamboo mosaic virus (BaMV)-infected Nicotiana benthamiana plant was cloned and characterized in this study; BaMV is a single-stranded positive-sense RNA virus. This gene product, designated as NbTRXh2, was matched with sequences of thioredoxin h proteins, a group of small proteins with a conserved active-site motif WCXPC conferring disulfide reductase activity. To examine how NbTRXh2 is involved in the infection cycle of BaMV, we used the virus-induced gene silencing technique to knock down NbTRXh2 expression in N...
January 3, 2017: Molecular Plant Pathology
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