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Synaptotagmin

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https://www.readbyqxmd.com/read/28057568/localization-of-rab3a-binding-site-on-c2a-domain-of-synaptotagmin-i-to-reveal-its-regulatory-mechanism
#1
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/28026832/significance-of-syt8-for-the-detection-prediction-and-treatment-of-peritoneal-metastasis-from-gastric-cancer
#2
Mitsuro Kanda, Dai Shimizu, Haruyoshi Tanaka, Chie Tanaka, Daisuke Kobayashi, Masamichi Hayashi, Naoki Iwata, Yukiko Niwa, Suguru Yamada, Tsutomu Fujii, Hiroyuki Sugimoto, Kenta Murotani, Michitaka Fujiwara, Yasuhiro Kodera
OBJECTIVE: To develop novel diagnostic and therapeutic targets specific for peritoneal metastasis of gastric cancer (GC). BACKGROUND: Advanced GC frequently recurs because of undetected micrometastases even after curative resection. Peritoneal metastasis has been the most frequent recurrent pattern after gastrectomy and is incurable. METHODS: We conducted a recurrence pattern-specific transcriptome analysis in an independent cohort of 16 patients with stage III GC who underwent curative gastrectomy and adjuvant S-1 for screening candidate molecules specific for peritoneal metastasis of GC...
December 6, 2016: Annals of Surgery
https://www.readbyqxmd.com/read/27997124/differential-membrane-binding-mechanics-of-synaptotagmin-isoforms-observed-in-atomic-detail
#3
Josh V Vermaas, Emad Tajkhorshid
Synaptotagmin (Syt) is a membrane-associated protein involved in vesicle fusion through the SNARE complex that is found throughout the human body in 17 different isoforms. These isoforms have two membrane-binding C2 domains, which sense Ca(2+) and thereby promote anionic membrane binding and lead to vesicle fusion. Through molecular dynamics simulations using the highly mobile membrane mimetic acclerated bilayer model, we have investigated how small protein sequence changes in the Ca(2+)-binding loops of the C2 domains may give rise to the experimentally determined difference in binding kinetics between Syt-1 and Syt-7 isoforms...
December 20, 2016: Biochemistry
https://www.readbyqxmd.com/read/27988858/sequence-specific-assignment-of-methyl-groups-from-the-neuronal-snare-complex-using-lanthanide-induced-pseudocontact-shifts
#4
Yun-Zu Pan, Bradley Quade, Kyle D Brewer, Monika Szabo, James D Swarbrick, Bim Graham, Josep Rizo
Neurotransmitter release depends critically on the neuronal SNARE complex formed by syntaxin-1, SNAP-25 and synaptobrevin, as well as on other proteins such as Munc18-1, Munc13-1 and synaptotagmin-1. Although three-dimensional structures are available for these components, it is still unclear how they are assembled between the synaptic vesicle and plasma membranes to trigger fast, Ca(2+)-dependent membrane fusion. Methyl TROSY NMR experiments provide a powerful tool to study complexes between these proteins, but assignment of the methyl groups of the SNARE complex is hindered by its limited solubility...
December 17, 2016: Journal of Biomolecular NMR
https://www.readbyqxmd.com/read/27984133/perinatal-exposure-to-lead-pb-induces-ultrastructural-and-molecular-alterations-in-synapses-of-rat-offspring
#5
Magdalena Gąssowska, Irena Baranowska-Bosiacka, Joanna Moczydłowska, Małgorzata Frontczak-Baniewicz, Magdalena Gewartowska, Lidia Strużyńska, Izabela Gutowska, Dariusz Chlubek, Agata Adamczyk
Lead (Pb), environmentally abundant heavy-metal pollutant, is a strong toxicant for the developing central nervous system. Pb intoxication in children, even at low doses, is found to affect learning and memorizing, with devastating effects on cognitive function and intellectual development. However, the precise mechanism by which Pb impairs synaptic plasticity is not fully elucidated. The purpose of this study was to investigate the effect of pre- and neonatal exposure to low dose of Pb (with Pb concentrations in whole blood below 10μg/dL) on the synaptic structure and the pre- and postsynaptic proteins expression in the developing rat brain...
October 29, 2016: Toxicology
https://www.readbyqxmd.com/read/27974903/morphine-antidependence-of-erythroxylum-cuneatum-miq-kurz-in-neurotransmission-processes-in-vitro
#6
Noor Azuin Suliman, Mohamad Aris Mohd Moklas, Che Norma Mat Taib, Mohd Ilham Adenan, Mohamad Taufik Hidayat Baharuldin, Rusliza Basir, Zulkhairi Amom
Opiate abuse has been studied to cause adaptive changes observed in the presynaptic release and the mediated-synaptic plasticity proteins. The involvement of neuronal SNARE proteins reveals the role of the neurotransmitter release in expressing the opioid actions. The present study was designed to determine the effect of the alkaloid extract of Erythroxylum cuneatum (E. cuneatum) against chronic morphine and the influences of E. cuneatum on neurotransmission processes observed in vitro. The human neuroblastoma cell line, SK-N-SH, was treated with the morphine, methadone, or E...
2016: Evidence-based Complementary and Alternative Medicine: ECAM
https://www.readbyqxmd.com/read/27974193/perinatal-exposure-to-lead-pb-induces-ultrastructural-and-molecular-alterations-in-synapses-of-rat-offspring
#7
Magdalena Gąssowska, Irena Baranowska-Bosiacka, Joanna Moczydłowska, Małgorzata Frontczak-Baniewicz, Magdalena Gewartowska, Lidia Strużyńska, Izabela Gutowska, Dariusz Chlubek, Agata Adamczyk
Lead (Pb), environmentally abundant heavy-metal pollutant, is a strong toxicant for the developing central nervous system. Pb intoxication in children, even at low doses, is found to affect learning and memorizing, with devastating effects on cognitive function and intellectual development. However, the precise mechanism by which Pb impairs synaptic plasticity is not fully elucidated. The purpose of this study was to investigate the effect of pre- and neonatal exposure to low dose of Pb (with Pb concentrations in whole blood below 10μg/dL) on the synaptic structure and the pre- and postsynaptic proteins expression in the developing rat brain...
December 12, 2016: Toxicology
https://www.readbyqxmd.com/read/27921176/two-feet-on-the-membrane-uptake-of-clostridial-neurotoxins
#8
Andreas Rummel
The extraordinary potency of botulinum neurotoxins (BoNT) and tetanus neurotoxin (TeNT) is mediated by their high neurospecificity, targeting peripheral cholinergic motoneurons leading to flaccid and spastic paralysis, respectively, and successive respiratory failure. Complex polysialo gangliosides accumulate BoNT and TeNT on the plasma membrane. The ganglioside binding in BoNT/A, B, E, F, G, and TeNT occurs via a conserved ganglioside-binding pocket within the most carboxyl-terminal 25 kDa domain HCC, whereas BoNT/C, DC, and D display here two different ganglioside binding sites...
December 1, 2016: Current Topics in Microbiology and Immunology
https://www.readbyqxmd.com/read/27881774/interactions-between-snap-25-and-synaptotagmin-1-are-involved-in-vesicle-priming-clamping-spontaneous-and-stimulating-evoked-neurotransmission
#9
Melanie Schupp, Jörg Malsam, Marvin Ruiter, Andrea Scheutzow, Keimpe D B Wierda, Thomas H Söllner, Jakob B Sørensen
: Whether interactions between synaptotagmin-1 (syt-1) and the soluble NSF attachment protein receptors (SNAREs) are required during neurotransmission is debated. We examined five SNAP-25 mutations designed to interfere with syt-1 interactions. One mutation, D51/E52/E55A, targeted negative charges within region II of the primary interface (Zhou et al., 2015); two mutations targeted region I (D166A and D166/E170A) and one mutation targeted both (D51/E52/E55/D166A). The final mutation (D186/D193A) targeted C-terminal residues not expected to interact with syt-1...
November 23, 2016: Journal of Neuroscience: the Official Journal of the Society for Neuroscience
https://www.readbyqxmd.com/read/27811083/arabidopsis-syt1-maintains-stability-of-cortical-endoplasmic-reticulum-networks-and-vap27-1-enriched-endoplasmic-reticulum-plasma-membrane-contact-sites
#10
Wei Siao, Pengwei Wang, Boris Voigt, Patrick J Hussey, Frantisek Baluska
Arabidopsis synaptotagmin 1 (SYT1) is localized on the endoplasmic reticulum-plasma membrane (ER-PM) contact sites in leaf and root cells. The ER-PM localization of Arabidopsis SYT1 resembles that of the extended synaptotagmins (E-SYTs) in animal cells. In mammals, E-SYTs have been shown to regulate calcium signaling, lipid transfer, and endocytosis. Arabidopsis SYT1 was reported to be essential for maintaining cell integrity and virus movement. This study provides detailed insight into the subcellular localization of SYT1 and VAP27-1, another ER-PM-tethering protein...
November 2016: Journal of Experimental Botany
https://www.readbyqxmd.com/read/27794539/human-r1441c-lrrk2-regulates-the-synaptic-vesicle-proteome-and-phosphoproteome-in-a-drosophila-model-of-parkinson-s-disease
#11
Md Shariful Islam, Hendrik Nolte, Wright Jacob, Anna B Ziegler, Stefanie Pütz, Yael Grosjean, Karolina Szczepanowska, Aleksandra Trifunovic, Thomas Braun, Hermann Heumann, Rolf Heumann, Bernhard Hovemann, Darren J Moore, Marcus Krüger
Mutations in leucine-rich repeat kinase 2 (LRRK2) cause late-onset, autosomal dominant familial Parkinson's disease (PD) and variation at the LRRK2 locus contributes to the risk for idiopathic PD. LRRK2 can function as a protein kinase and mutations lead to increased kinase activity. To elucidate the pathophysiological mechanism of the R1441C mutation in the GTPase domain of LRRK2, we expressed human wild-type or R1441C LRRK2 in dopaminergic neurons of Drosophila and observe reduced locomotor activity, impaired survival and an age-dependent degeneration of dopaminergic neurons thereby creating a new PD-like model...
October 29, 2016: Human Molecular Genetics
https://www.readbyqxmd.com/read/27793683/structural-analysis-of-ca-2-binding-pocket-of-synaptotagmin-5-c2a-domain
#12
Xiaoting Qiu, Junyi Ge, Yongxiang Gao, Maikun Teng, Liwen Niu
Synaptotagmins constitute a family of multifunctional integral membrane proteins found predominantly on vesicles in neural and endocrine tissues. 17 isoforms of synaptotagmin family in mammals have been identified, 7 isoforms among them are known to be able to bind Ca(2+) via their C2 domains. This study presents the crystal structure of the first C2 domain (C2A domain) of synaptotagmin 5 complexed with Ca(2+) at 1.90Å resolution. Comparison of the Ca(2+)-binding pocket of synaptotagmin 5 C2A domain with other synaptotagmin C2 domains demonstrated that a serine residue locating at Ca(2+)-binding loop probably responsible to the conformational variation of Ca(2+)-binding pocket, and thus impacts the Ca(2+)-binding mechanism of C2 domain, which is verified by structural analysis of the serine mutant and Ca(2+)-binding assays via isothermal titration calorimetry...
February 2017: International Journal of Biological Macromolecules
https://www.readbyqxmd.com/read/27791979/ptdinsp2-and-ptdser-cooperate-to-trap-synaptotagmin-1-to-the-plasma-membrane-in-the-presence-of-calcium
#13
Ángel Pérez-Lara, Anusa Thapa, Sarah B Nyenhuis, David A Nyenhuis, Partho Halder, Michael Tietzel, Kai Tittmann, David S Cafiso, Reinhard Jahn
The Ca(2+)-sensor synaptotagmin-1 that triggers neuronal exocytosis binds to negatively charged membrane lipids (mainly phosphatidylserine (PtdSer) and phosphoinositides (PtdIns)) but the molecular details of this process are not fully understood. Using quantitative thermodynamic, kinetic and structural methods, we show that synaptotagmin-1 (from Rattus norvegicus and expressed in Escherichia coli) binds to PtdIns(4,5)P2 via a polybasic lysine patch in the C2B domain, which may promote the priming or docking of synaptic vesicles...
October 28, 2016: ELife
https://www.readbyqxmd.com/read/27771350/synaptotagmin-7-and-syncrip-proteins-are-ubiquitously-expressed-in-the-rat-brain-and-co-localize-in-purkinje-neurons
#14
Larisa Tratnjek, Marko Živin, Gordana Glavan
Synaptotagmin 7 (SYT7) is ubiquitously expressed calcium sensor, involved in neuronal membrane trafficking. Immunoprecipitation experiments demonstrated that SYT7 interacts with Synaptotagmin-binding, cytoplasmic RNA-interacting protein (SYNCRIP). SYNCRIP is a component of mRNA granules, which are transported to dendrites and are prerequisite for synaptic plasticity. Given the potential significance of SYT7 regulation in processes of neurodegeneration, which are characterized by high level of synaptic vulnerability, we aimed to analyse and compare the distribution of SYT7 and SYNCRIP proteins in the adult rat striatum, hippocampus, cerebral and cerebellar cortex...
January 2017: Journal of Chemical Neuroanatomy
https://www.readbyqxmd.com/read/27732855/the-rna-binding-protein-syncrip-is-a-component-of-the-hepatocyte-exosomal-machinery-controlling-microrna-sorting
#15
Laura Santangelo, Giorgio Giurato, Carla Cicchini, Claudia Montaldo, Carmine Mancone, Roberta Tarallo, Cecilia Battistelli, Tonino Alonzi, Alessandro Weisz, Marco Tripodi
Despite clear evidence that exosomal microRNAs (miRNAs) are able to modulate the cellular microenvironment and that exosomal RNA cargo selection is deregulated in pathological conditions, the mechanisms controlling specific RNA sorting into extracellular vesicles are still poorly understood. Here, we identified the RNA binding protein SYNCRIP (synaptotagmin-binding cytoplasmic RNA-interacting protein; also known as hnRNP-Q or NSAP1) as a component of the hepatocyte exosomal miRNA sorting machinery. SYNCRIP knockdown impairs sorting of miRNAs in exosomes...
October 11, 2016: Cell Reports
https://www.readbyqxmd.com/read/27731902/c2-domain-containing-calcium-sensors-in-neuroendocrine-secretion
#16
REVIEW
Paulo S Pinheiro, Sébastien Houy, Jakob B Sørensen
The molecular mechanisms for calcium-triggered membrane fusion have long been sought for, and detailed models now exist that account for at least some of the functions of the many proteins involved in the process. Key players in the fusion reaction are a group of proteins that, upon binding to calcium, trigger the merger of cargo-filled vesicles with the plasma membrane. Low-affinity, fast-kinetics calcium sensors of the synaptotagmin family - especially synaptotagmin-1 and synaptotagmin-2 - are the main calcium sensors for fast exocytosis triggering in many cell types...
December 2016: Journal of Neurochemistry
https://www.readbyqxmd.com/read/27731796/advances-in-x-ray-free-electron-laser-xfel-diffraction-data-processing-applied-to-the-crystal-structure-of-the-synaptotagmin-1-snare-complex
#17
Artem Y Lyubimov, Monarin Uervirojnangkoorn, Oliver B Zeldin, Qiangjun Zhou, Minglei Zhao, Aaron S Brewster, Tara Michels-Clark, James M Holton, Nicholas K Sauter, William I Weis, Axel T Brunger
X-ray free electron lasers (XFELs) reduce the effects of radiation damage on macromolecular diffraction data and thereby extend the limiting resolution. Previously, we adapted classical post-refinement techniques to XFEL diffraction data to produce accurate diffraction data sets from a limited number of diffraction images (Uervirojnangkoorn et al., 2015), and went on to use these techniques to obtain a complete data set from crystals of the synaptotagmin-1 / SNARE complex and to determine the structure at 3...
October 12, 2016: ELife
https://www.readbyqxmd.com/read/27723113/synaptic-vesicle-pool-specific-modification-of-neurotransmitter-release-by-intravesicular-free-radical-generation
#18
Olusoji A T Afuwape, Catherine R Wasser, Thomas Schikorski, Ege T Kavalali
KEY POINTS: Synaptic transmission is mediated by the release of neurotransmitters from synaptic vesicles in response to stimulation or through the spontaneous fusion of a synaptic vesicle with the presynaptic plasma membrane. There is growing evidence that synaptic vesicles undergoing spontaneous fusion versus those fusing in response to stimuli are functionally distinct. In this study, we acutely probe the effects of intravesicular free radical generation on synaptic vesicles that fuse spontaneously or in response to stimuli...
October 10, 2016: Journal of Physiology
https://www.readbyqxmd.com/read/27716408/the-pre-synaptic-vesicle-protein-synaptotagmin-is-a-novel-biomarker-for-alzheimer-s-disease
#19
Annika Öhrfelt, Ann Brinkmalm, Julien Dumurgier, Gunnar Brinkmalm, Oskar Hansson, Henrik Zetterberg, Elodie Bouaziz-Amar, Jacques Hugon, Claire Paquet, Kaj Blennow
BACKGROUND: Synaptic degeneration is a central pathogenic event in Alzheimer's disease that occurs early during the course of disease and correlates with cognitive symptoms. The pre-synaptic vesicle protein synaptotagmin-1 appears to be essential for the maintenance of an intact synaptic transmission and cognitive function. Synaptotagmin-1 in cerebrospinal fluid is a candidate Alzheimer biomarker for synaptic dysfunction that also may correlate with cognitive decline. METHODS: In this study, a novel mass spectrometry-based assay for measurement of cerebrospinal fluid synaptotagmin-1 was developed, and was evaluated in two independent sample sets of patients and controls...
October 3, 2016: Alzheimer's Research & Therapy
https://www.readbyqxmd.com/read/27701149/mst1-dependent-vesicle-trafficking-regulates-neutrophil-transmigration-through-the-vascular-basement-membrane
#20
Angela R M Kurz, Monika Pruenster, Ina Rohwedder, Mahalakshmi Ramadass, Kerstin Schäfer, Ute Harrison, Gabriel Gouveia, Claudia Nussbaum, Roland Immler, Johannes R Wiessner, Andreas Margraf, Dae-Sik Lim, Barbara Walzog, Steffen Dietzel, Markus Moser, Christoph Klein, Dietmar Vestweber, Rainer Haas, Sergio D Catz, Markus Sperandio
Neutrophils need to penetrate the perivascular basement membrane for successful extravasation into inflamed tissue, but this process is incompletely understood. Recent findings have associated mammalian sterile 20-like kinase 1 (MST1) loss of function with a human primary immunodeficiency disorder, suggesting that MST1 may be involved in immune cell migration. Here, we have shown that MST1 is a critical regulator of neutrophil extravasation during inflammation. Mst1-deficient (Mst1-/-) neutrophils were unable to migrate into inflamed murine cremaster muscle venules, instead persisting between the endothelium and the basement membrane...
November 1, 2016: Journal of Clinical Investigation
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