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https://www.readbyqxmd.com/read/28533369/phosphorylated-presenilin-1-decreases-%C3%AE-amyloid-by-facilitating-autophagosome-lysosome-fusion
#1
Victor Bustos, Maria V Pulina, Ashley Bispo, Alison Lam, Marc Flajolet, Fred S Gorelick, Paul Greengard
Presenilin 1 (PS1), the catalytic subunit of the γ-secretase complex, cleaves βCTF to produce Aβ. We have shown that PS1 regulates Aβ levels by a unique bifunctional mechanism. In addition to its known role as the catalytic subunit of the γ-secretase complex, selective phosphorylation of PS1 on Ser367 decreases Aβ levels by increasing βCTF degradation through autophagy. Here, we report the molecular mechanism by which PS1 modulates βCTF degradation. We show that PS1 phosphorylated at Ser367, but not nonphosphorylated PS1, interacts with Annexin A2, which, in turn, interacts with the lysosomal N-ethylmaleimide-sensitive factor attachment protein receptor (SNARE) Vamp8...
May 22, 2017: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/28524818/fluorescence-lifetime-imaging-microscopy-reveals-rerouting-of-snare-trafficking-driving-dendritic-cell-activation
#2
Daniëlle Rianne José Verboogen, Natalia González Mancha, Martin Ter Beest, Geert van den Bogaart
SNARE proteins play a crucial role in intracellular trafficking by catalyzing membrane fusion, but assigning SNAREs to specific intracellular transport routes is challenging with current techniques. We developed a novel Förster resonance energy transfer-fluorescence lifetime imaging microscopy (FRET-FLIM)-based technique allowing visualization of real-time local interactions of fluorescently tagged SNARE proteins in live cells. We used FRET-FLIM to delineate the trafficking steps underlying the release of the inflammatory cytokine interleukin-6 (IL-6) from human blood-derived dendritic cells...
May 19, 2017: ELife
https://www.readbyqxmd.com/read/28515322/g%C3%AE-%C3%AE-directly-modulates-vesicle-fusion-by-competing-with-synaptotagmin-for-binding-to-neuronal-snare-proteins-embedded-in-membranes
#3
Zack Zurawski, Brian Page, Michael C Chicka, Rebecca L Brindley, Christopher A Wells, Anita M Preininger, Karren Hyde, James A Gilbert, Osvaldo Cruz-Rodriguez, Kevin P M Currie, Edwin R Chapman, Simon Alford, Heidi E Hamm
Gi/o-coupled GPCRs can inhibit neurotransmitter release at synapses via multiple mechanisms. In addition to Gβγ-mediated modulation of voltage-gated calcium channels(VGCC), inhibition can also be mediated through the direct interaction of Gβγ subunits with the soluble N-ethylmaleimide attachment protein receptor (SNARE) complex of the vesicle fusion apparatus. Binding studies with soluble SNARE complexes have shown that Gβγ binds to both ternary SNARE complexes, t-SNARE heterodimers, and monomeric SNAREs, competing with synaptotagmin(syt)1 for binding sites on t-SNARE...
May 17, 2017: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/28504273/legionella-effector-lpg1137-shuts-down-er-mitochondria-communication-through-cleavage-of-syntaxin-17
#4
Kohei Arasaki, Yumi Mikami, Stephanie R Shames, Hiroki Inoue, Yuichi Wakana, Mitsuo Tagaya
During infection of macrophages, the pathogenic bacterium Legionella pneumophila secretes effector proteins that induce the conversion of the plasma membrane-derived vacuole into an endoplasmic reticulum (ER)-like replicative vacuole. These ER-like vacuoles are ultimately fused with the ER, where the pathogen replicates. Here we show that the L. pneumophila effector Lpg1137 is a serine protease that targets the mitochondria and their associated membranes. Lpg1137 binds to and cleaves syntaxin 17, a soluble N-ethylmaleimide-sensitive factor attachment protein receptor (SNARE) protein that is known to participate in the regulation of mitochondrial dynamics through interaction with the mitochondrial fission factor Drp1 in fed cells and in autophagy through interaction with Atg14L and other SNAREs in starved cells...
May 15, 2017: Nature Communications
https://www.readbyqxmd.com/read/28486561/myosin-phosphatase-and-rhoa-activated-kinase-modulate-neurotransmitter-release-by-regulating-snap-25-of-snare-complex
#5
Dániel Horváth, István Tamás, Adrienn Sipos, Zsuzsanna Darula, Bálint Bécsi, Dénes Nagy, Judit Iván, Ferenc Erdődi, Beáta Lontay
Reversible phosphorylation of neuronal proteins plays an important role in the regulation of neurotransmitter release. Myosin phosphatase holoenzyme (MP) consists of a protein phosphatase-1 (PP1) catalytic subunit (PP1c) and a regulatory subunit, termed myosin phosphatase targeting subunit (MYPT1). The primary function of MP is to regulate the phosphorylation level of contractile proteins; however, recent studies have shown that MP is localized to neurons, and is also involved in the mediation of neuronal processes...
2017: PloS One
https://www.readbyqxmd.com/read/28483976/targeting-a-potassium-channel-syntaxin-interaction-ameliorates-cell-death-in-ischemic-stroke
#6
Chung-Yang Yeh, Ashlyn M Bulas, Aubin Moutal, Jami L Saloman, Karen A Hartnett, Charles T Anderson, Thanos Tzounopoulos, Dandan Sun, Rajesh Khanna, Elias Aizenman
The voltage-gated K(+) channel Kv2.1 has been intimately linked with neuronal apoptosis. After ischemic, oxidative, or inflammatory insults, Kv2.1 mediates a pronounced, delayed enhancement of K(+) efflux, generating an optimal intracellular environment for caspase and nuclease activity, key components of programmed cell death. This apoptosis-enabling mechanism is initiated via Zn(2+)-dependent dual phosphorylation of Kv2.1, increasing the interaction between the channel's intracellular C-terminus domain and the SNARE protein syntaxin 1A...
May 8, 2017: Journal of Neuroscience: the Official Journal of the Society for Neuroscience
https://www.readbyqxmd.com/read/28476622/green-fluorescence-protein-based-content-mixing-assay-of-snare-driven-membrane-fusion
#7
Paul Heo, Byoungjae Kong, Young-Hun Jung, Joon-Bum Park, Jonghyeok Shin, Myungseo Park, Dae-Hyuk Kweon
Soluble N-ethylmaleimide-sensitive factor attachment protein receptor (SNARE) proteins mediate intracellular membrane fusion by forming a ternary SNARE complex. A minimalist approach utilizing proteoliposomes with reconstituted SNARE proteins yielded a wealth of information pinpointing the molecular mechanism of SNARE-mediated fusion and its regulation by accessory proteins. Two important attributes of a membrane fusion are lipid-mixing and the formation of an aqueous passage between apposing membranes. These two attributes are typically observed by using various fluorescent dyes...
June 17, 2017: Biochemical and Biophysical Research Communications
https://www.readbyqxmd.com/read/28471021/syntaxin-4-mediates-endosome-recycling-for-lytic-granule-exocytosis-in-cytotoxic-t-lymphocytes
#8
Waldo A Spessott, Maria L Sanmillan, Vineet V Kulkarni, Margaret E McCormick, Claudio G Giraudo
Adaptive and innate immunity utilize the perforin-killing pathway to eliminate virus-infected or cancer cells. Cytotoxic T-lymphocytes (CTLs) and Natural Killer cells mediate this process by releasing toxic proteins at the contact area with target cells known as immunological synapse (IS). Formation of a stable IS and exocytosis of toxic proteins requires persistent fusion of Rab11a recycling endosomes with the plasma membrane (PM) that may assure the delivery of key effector proteins. Despite the importance of the recycling endosomal compartment, the membrane fusion proteins that control this process at the IS remain elusive...
May 4, 2017: Traffic
https://www.readbyqxmd.com/read/28461216/disruption-of-kv2-1-somato-dendritic-clusters-prevents-the-apoptogenic-increase-of-potassium-currents
#9
Jason A Justice, Anthony J Schulien, Kai He, Karen A Hartnett, Elias Aizenman, Niyathi H Shah
As the predominant mediator of the delayed rectifier current, KV2.1 is an important regulator of neuronal excitability. KV2.1, however, also plays a well-established role in apoptotic cell death. Apoptogenic stimuli induce syntaxin-dependent trafficking of KV2.1, resulting in an augmented delayed rectifier current that acts as a conduit for K(+) efflux required for pro-apoptotic protease/nuclease activation. Recent evidence suggests that KV2.1 somato-dendritic clusters regulate the formation of endoplasmic reticulum-plasma membrane junctions that function as scaffolding sites for plasma membrane trafficking of ion channels, including KV2...
April 28, 2017: Neuroscience
https://www.readbyqxmd.com/read/28456331/complexin-binding-to-membranes-and-acceptor-t-snares-explains-its-clamping-effect-on-fusion
#10
Rafal Zdanowicz, Alex Kreutzberger, Binyong Liang, Volker Kiessling, Lukas K Tamm, David S Cafiso
Complexin-1 is a SNARE effector protein that decreases spontaneous neurotransmitter release and enhances evoked release. Complexin binds to the fully assembled four-helical neuronal SNARE core complex as revealed in competing molecular models derived from x-ray crystallography. Presently, it is unclear how complexin binding to the postfusion complex accounts for its effects upon spontaneous and evoked release in vivo. Using a combination of spectroscopic and imaging methods, we characterize in molecular detail how complexin binds to the 1:1 plasma membrane t-SNARE complex of syntaxin-1a and SNAP-25 while simultaneously binding the lipid bilayer at both its N- and C-terminal ends...
April 26, 2017: Biophysical Journal
https://www.readbyqxmd.com/read/28449010/excess-of-a-rassf1-targeting-microrna-mir-193a-3p-perturbs-cell-division-fidelity
#11
Sofia Pruikkonen, Marko J Kallio
BACKGROUND: Several microRNA (miRNA) molecules have emerged as important post-transcriptional regulators of tumour suppressor and oncogene expression. Ras association domain family member 1 (RASSF1) is a critical tumour suppressor that controls multiple aspects of cell proliferation such as cell cycle, cell division and apoptosis. The expression of RASSF1 is lost in a variety of cancers due to the promoter hypermethylation. METHODS: miR-193a-3p was identified as a RASSF1-targeting miRNA by a dual screening approach...
May 23, 2017: British Journal of Cancer
https://www.readbyqxmd.com/read/28433799/affinity-proteomics-exploration-of-melanoma-identifies-proteins-in-serum-with-associations-to-t-stage-and-recurrence
#12
Sanna Byström, Claudia Fredolini, Per-Henrik Edqvist, Etienne-Nicholas Nyaiesh, Kimi Drobin, Mathias Uhlén, Michael Bergqvist, Fredrik Pontén, Jochen M Schwenk
BACKGROUND: Blood-based proteomic profiling may aid and expand our understanding of diseases and their different phenotypes. The aim of the presented study was to profile serum samples from patients with malignant melanoma using affinity proteomic assays to describe proteins in the blood stream that are associated to stage or recurrence of melanoma. MATERIAL AND METHODS: Multiplexed protein analysis was conducted using antibody suspension bead arrays. A total of 232 antibodies against 132 proteins were selected from (i) a screening with 4595 antibodies and 32 serum samples from melanoma patients and controls, (ii) antibodies used for immunohistochemistry, (iii) protein targets previously related with melanoma...
June 2017: Translational Oncology
https://www.readbyqxmd.com/read/28426820/the-influence-of-cell-membrane-and-snap25-linker-loop-on-the-dynamics-and-unzipping-of-snare-complex
#13
Yi Shi, Yong Zhang, Jizhong Lou
The soluble N-ethylmaleimide-sensitive factor attachment protein receptor (SNARE) complex is composed of three neuronal proteins VAMP2, Syntaxin and SNAP25, which plays a core role during the process of membrane fusion. The zipping assembly of the SNARE complex releases energies and drives the vesicle and cell membrane into close proximity. In this study, we use all-atom molecular dynamics simulations to probe the dynamics of SNARE and its unzipping process in the context of membrane at the atomistic details...
2017: PloS One
https://www.readbyqxmd.com/read/28398146/protective-action-of-b1r-antagonist-against-cerebral-ischemia-reperfusion-injury-through-suppressing-mir-200c-expression-of-microglia-derived-microvesicles
#14
Min Tang, Ping Liu, Xia Li, Jian-Wen Wang, Xiong-Chao Zhu, Fang-Ping He
BACKGROUND AND OBJECTIVE: Cerebral ischemia-reperfusion (I/R) injury is a common side-effect for cerebral ischemic disease and its therapeutic regimen is limited. Kinin is pro-inflammatory peptide that is released and acts at the site of injury and inflammation such as brain and it works through bradykinin 1 receptor (B1R). The present study was to examine the effect of B1R antagonist on cerebral I/R injury and the potential mechanism. METHODS: Cerebral I/R injury was induced in mice by transient middle cerebral artery occlusion (MCAO)...
April 11, 2017: Neurological Research
https://www.readbyqxmd.com/read/28396819/rab11-fip1-phosphorylation-by-mark2-regulates-polarity-in-mdck-cells
#15
Rebecca McRae, Lynne A Lapierre, Elizabeth H Manning, James R Goldenring
MARK2/Par1b/EMK1, a serine/threonine kinase, is required for correct apical/basolateral membrane polarization in epithelial cells. However, the specific substrates mediating MARK2 action are less well understood. We have now found that MARK2 phosphorylates Rab11-FIP1B/C at serine 234 in a consensus site similar to that previously identified in Rab11-FIP2. In MDCK cells undergoing repolarization after a calcium switch, antibodies specific for pS234-Rab11-FIP1 or pS227-Rab11-FIP2 demonstrate that the spatial and temporal activation of Rab11-FIP1 phosphorylation is distinct from that for Rab11-FIP2...
2017: Cellular Logistics
https://www.readbyqxmd.com/read/28392696/compound-porcine-cerebroside-and-ganglioside-injection-attenuates-cerebral-ischemia-reperfusion-injury-in-rats-by-targeting-multiple-cellular-processes
#16
Mingyang Wang, Yi Zhang, Lu Feng, Ji Zheng, Shujie Fan, Junya Liu, Nan Yang, Yanyong Liu, Pingping Zuo
BACKGROUND: Compound porcine cerebroside and ganglioside injection (CPCGI) is a neurotrophic drug used clinically to treat certain functional disorders of brain. Despite its extensive usage throughout China, the exact mechanistic targets of CPCGI are unknown. This study was carried out to investigate the protective effect of CPCGI against ischemic neuronal damage in rats with middle cerebral artery occlusion (MCAO) reperfusion injury and to investigate the neuroprotective mechanisms of CPCGI...
2017: Neuropsychiatric Disease and Treatment
https://www.readbyqxmd.com/read/28391067/n-type-ca-2-channels-are-affected-by-full-length-mutant-huntingtin-expression-in-a-mouse-model-of-huntington-s-disease
#17
Flavia R Silva, Artur S Miranda, Rebeca P M Santos, Isabella G Olmo, Gerald W Zamponi, Tomas Dobransky, Jader S Cruz, Luciene B Vieira, Fabiola M Ribeiro
Huntington's disease (HD) is an autosomal dominant neurodegenerative disorder caused by a polyglutamine expansion in the amino-terminal region of the huntingtin (htt) protein. In addition to facilitating neurodegeneration, mutant htt is implicated in HD-related alterations of neurotransmission. Previous data showed that htt can modulate N-type voltage-gated Ca(2+) channels (Cav2.2), which are essential for presynaptic neurotransmitter release. Thus, to elucidate the mechanism underlying mutant htt-mediated alterations in neurotransmission, we investigated how Cav2...
March 18, 2017: Neurobiology of Aging
https://www.readbyqxmd.com/read/28381425/an-endosomal-syntaxin-and-the-ap-3-complex-are-required-for-formation-and-maturation-of-candidate-lysosome-related-secretory-organelles-mucocysts-in-tetrahymena-thermophila
#18
Harsimran Kaur, Daniela Sparvoli, Hiroko Osakada, Masaaki Iwamoto, Tokuko Haraguchi, Aaron P Turkewitz
The ciliate Tetrahymena thermophila synthesizes large secretory vesicles called mucocysts. Mucocyst biosynthesis shares features with dense core granules (DCGs) in animal cells, including proteolytic processing of cargo proteins during maturation. However, other molecular features have suggested relatedness to lysosome-related organelles (LROs). LROs, which include diverse organelles in animals, are formed via convergence of secretory and endocytic trafficking. Here we analyzed Tetrahymena Stx7l1p (syntaxin 7-like 1), a Qa SNARE whose homologs in other lineages are linked with vacuoles/LROs...
April 5, 2017: Molecular Biology of the Cell
https://www.readbyqxmd.com/read/28368721/cellular-and-molecular-mechanism-for-secretory-autophagy
#19
Tomonori Kimura, Jingyue Jia, Aurore Claude-Taupin, Suresh Kumar, Seong Won Choi, Yuexi Gu, Michal Mudd, Nicolas Dupont, Shanya Jiang, Ryan Peters, Farzin Farzam, Ashish Jain, Keith A Lidke, Christopher M Adams, Terje Johansen, Vojo Deretic
Macroautophagy/autophagy plays a role in unconventional secretion of leaderless cytosolic proteins. Whether and how secretory autophagy diverges from conventional degradative autophagy is unclear. We have shown that the prototypical secretory autophagy cargo IL1B/IL-1β (interleukin 1 β) is recognized by TRIM16, and that this first to be identified secretory autophagy receptor interacts with the R-SNARE SEC22B to jointly deliver cargo to the MAP1LC3B-II-positive sequestration membranes. Cargo secretion is unaffected by knockdowns of STX17, a SNARE catalyzing autophagosome-lysosome fusion as a prelude to cargo degradation...
April 3, 2017: Autophagy
https://www.readbyqxmd.com/read/28367336/evidence-of-presynaptic-localization-and-function-of-the-c-jun-n-terminal-kinase
#20
Silvia Biggi, Lucia Buccarello, Alessandra Sclip, Pellegrino Lippiello, Noemi Tonna, Cristiano Rumio, Daniele Di Marino, Maria Concetta Miniaci, Tiziana Borsello
The c-Jun N-terminal kinase (JNK) is part of a stress signalling pathway strongly activated by NMDA-stimulation and involved in synaptic plasticity. Many studies have been focused on the post-synaptic mechanism of JNK action, and less is known about JNK presynaptic localization and its physiological role at this site. Here we examined whether JNK is present at the presynaptic site and its activity after presynaptic NMDA receptors stimulation. By using N-SIM Structured Super Resolution Microscopy as well as biochemical approaches, we demonstrated that presynaptic fractions contained significant amount of JNK protein and its activated form...
2017: Neural Plasticity
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