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Synaptotagmin

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https://www.readbyqxmd.com/read/28923929/exceptionally-tight-membrane-binding-may-explain-the-key-role-of-the-synaptotagmin-7-c2a-domain-in-asynchronous-neurotransmitter-release
#1
Rashmi Voleti, Diana R Tomchick, Thomas C Südhof, Josep Rizo
Synaptotagmins (Syts) act as Ca(2+) sensors in neurotransmitter release by virtue of Ca(2+)-binding to their two C2 domains, but their mechanisms of action remain unclear. Puzzlingly, Ca(2+)-binding to the C2B domain appears to dominate Syt1 function in synchronous release, whereas Ca(2+)-binding to the C2A domain mediates Syt7 function in asynchronous release. Here we show that crystal structures of the Syt7 C2A domain and C2AB region, and analyses of intrinsic Ca(2+)-binding to the Syt7 C2 domains using isothermal titration calorimetry, did not reveal major differences that could explain functional differentiation between Syt7 and Syt1...
September 18, 2017: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/28919777/synaptotagmin-7-is-overexpressed-in-hepatocellular-carcinoma-and-regulates-hepatocellular-carcinoma-cell-proliferation-via-chk1-p53-signaling
#2
Hao Jin, Geliang Xu, Qiang Zhang, Qing Pang, Meifang Fang
BACKGROUND: Synaptotagmin-7 (Syt-7) is a member of the synaptotagmin (Syt) family, which plays an important role in many physiological and pathological processes. However, to the best of our knowledge, there is no study describing its function in tumors, particularly in hepatocellular carcinoma (HCC). Therefore, in this study, we examined the role of Syt-7 in HCC and attempted to elucidate its underlying mechanism. MATERIALS AND METHODS: We examined the expression levels of Syt-7 in HCC cell lines and normal hepatocytes by real-time quantitative polymerase chain reaction analysis...
2017: OncoTargets and Therapy
https://www.readbyqxmd.com/read/28906046/the-unique-n-terminal-zinc-finger-of-synaptotagmin-like-protein-4-reveals-fyve-structure
#3
Kazuhide Miyamoto, Arisa Nakatani, Kazuki Saito
Synaptotagmin-like protein 4 (Slp4), expressed in human platelets, is associated with dense granule release. Slp4 is comprised of the N-terminal zinc finger, Slp homology domain, and C2 domains. We synthesized a compact construct (the Slp4N peptide) corresponding to the Slp4 N-terminal zinc finger. Herein, we have determined the solution structure of the Slp4N peptide by NMR. Furthermore, experimental, chemical modification of Cys residues revealed that the Slp4N peptide binds two zinc atoms to mediate proper folding...
September 14, 2017: Protein Science: a Publication of the Protein Society
https://www.readbyqxmd.com/read/28898517/characterization-of-the-functional-activity-of-botulinum-neurotoxin-subtype-b6
#4
Tomoko Kohda, Keiji Nakamura, Koji Hosomi, Yasushi Torii, Shunji Kozaki, Masafumi Mukamoto
Clostridium botulinum produces the highly potent neurotoxin, botulinum neurotoxin (BoNT), which is classified into seven serotypes, A-G, and the subtype classification is confirmed by the diversity of the amino acid sequence among the serotypes. The BoNT from the Osaka05 strain is associated with type B infant botulism and has been divided into BoNT/B subtype B6 (BoNT/B6) by phylogenetic analysis and the antigenicity of its C-terminal heavy chain (HC) domain. However, the molecular basis for its properties, including the potency, is poorly understood...
September 12, 2017: Microbiology and Immunology
https://www.readbyqxmd.com/read/28895532/a-synaptotagmin-suppressor-screen-indicates-snare-binding-controls-the-timing-and-ca-2-cooperativity-of-vesicle-fusion
#5
Zhuo Guan, Maria Bykhovskaia, Ramon A Jorquera, Roger Bryan Sutton, Yulia Akbergenova, J Troy Littleton
The synaptic vesicle Ca(2+) sensor Synaptotagmin binds Ca(2+) through its two C2 domains to trigger membrane interactions. Beyond membrane insertion by the C2 domains, other requirements for Synaptotagmin activity are still being elucidated. To identify key residues within Synaptotagmin required for vesicle cycling, we took advantage of observations that mutations in the C2B domain Ca(2+)-binding pocket dominantly disrupt release from invertebrates to humans. We performed an intragenic screen for suppressors of lethality induced by expression of Synaptotagmin C2B Ca(2+)-binding mutants in Drosophila...
September 12, 2017: ELife
https://www.readbyqxmd.com/read/28887593/v-snare-function-in-chromaffin-cells
#6
REVIEW
Madhurima Dhara, Ralf Mohrmann, Dieter Bruns
Vesicle fusion is elementary for intracellular trafficking and release of signal molecules, thus providing the basis for diverse forms of intercellular communication like hormonal regulation or synaptic transmission. A detailed characterization of the mechanisms underlying exocytosis is key to understand how the nervous system integrates information and generates appropriate responses to stimuli. The machinery for vesicular release employs common molecular players in different model systems including neuronal and neuroendocrine cells, in particular members of the SNARE (soluble N-ethylmaleimide-sensitive factor attachment protein receptors) protein family, Sec1/Munc18-like proteins, and other accessory factors...
September 8, 2017: Pflügers Archiv: European Journal of Physiology
https://www.readbyqxmd.com/read/28887184/chronic-fluoxetine-administration-enhances-synaptic-plasticity-and-increases-functional-dynamics-in-hippocampal-ca3-ca1-synapses
#7
Popova Dina, Eero Castren, Tomi Taira
Recent studies demonstrate that chronic administration of the widely used antidepressant fluoxetine (FLX) promotes neurogenesis, synaptogenesis and synaptic plasticity in the adult hippocampus, cortex and amygdala. However, the mechanisms underlying these effects and how are they related to the clinical antidepressant efficacy are still poorly understood. We show here that chronic FLX administration decreases hippocampus-associated neophobia in naïve mice. In parallel, electrophysiological recordings in hippocampal CA3-CA1 circuitry revealed that the FLX treatment resulted in increased short- and long-term plasticity likely attributed to changes in presynaptic function...
September 5, 2017: Neuropharmacology
https://www.readbyqxmd.com/read/28882990/extended-synaptotagmin-localizes-to-presynaptic-er-and-promotes-neurotransmission-and-synaptic-growth-in-drosophila
#8
Koto Kikuma, Xiling Li, Daniel Kim, David Sutter, Dion K Dickman
The endoplasmic reticulum (ER) is an extensive organelle in neurons with important roles at synapses including the regulation of cytosolic Ca(2+), neurotransmission, lipid metabolism, and membrane trafficking. Despite intriguing evidence for these crucial functions, how presynaptic ER influences synaptic physiology remains enigmatic. To gain insight into this question, we have generated and characterized mutations in the single Extended Synaptotagmin (Esyt) ortholog in Drosophila melanogaster Esyts are evolutionarily conserved ER proteins with Ca(2+)-sensing domains that have recently been shown to orchestrate membrane tethering and lipid exchange between the ER and plasma membrane...
September 7, 2017: Genetics
https://www.readbyqxmd.com/read/28860966/a-stimulation-function-of-synaptotagmin-1-in-ternary-snare-complex-formation-dependent-on-munc18-and-munc13
#9
Yun Li, Shen Wang, Tianzhi Li, Le Zhu, Yuanyuan Xu, Cong Ma
The Ca(2+) sensor synaptotagmin-1 (Syt1) plays an essential function in synaptic exocytosis. Recently, Syt1 has been implicated in synaptic vesicle priming, a maturation step prior to Ca(2+)-triggered membrane fusion that is believed to involve formation of the ternary SNARE complex and require priming proteins Munc18-1 and Munc13-1. However, the mechanisms of Syt1 in synaptic vesicle priming are still unclear. In this study, we found that Syt1 stimulates the transition from the Munc18-1/syntaxin-1 complex to the ternary SNARE complex catalyzed by Munc13-1...
2017: Frontiers in Molecular Neuroscience
https://www.readbyqxmd.com/read/28858288/simultaneous-lipid-and-content-mixing-assays-for-in-vitro-reconstitution-studies-of-synaptic-vesicle-fusion
#10
Xiaoxia Liu, Alpay Burak Seven, Junjie Xu, Victoria Esser, Lijing Su, Cong Ma, Josep Rizo
This protocol describes reconstitution assays to study how the neurotransmitter release machinery triggers Ca(2+)-dependent synaptic vesicle fusion. The assays monitor fusion between proteoliposomes containing the synaptic vesicle SNARE synaptobrevin (with or without the Ca(2+) sensor synaptotagmin-1) and proteoliposomes initially containing the plasma membrane SNAREs syntaxin-1 and soluble NSF attachment protein (SNAP)-25. Lipid mixing (from fluorescence de-quenching of Marina-Blue-labeled lipids) and content mixing (from development of fluorescence resonance energy transfer (FRET) between phycoerythrin-biotin (PhycoE-Biotin) and Cy5-streptavidin trapped in the two proteoliposome populations) are measured simultaneously to ensure that true, nonleaky membrane fusion is monitored...
September 2017: Nature Protocols
https://www.readbyqxmd.com/read/28857293/sr-2-has-low-efficiency-in-regulating-spontaneous-release-at-the-calyx-of-held-synapses
#11
Shuli Zhang, Xuefeng Wang, Xiaohui Wang, Xuefeng Shen, Jianyuan Sun, Xintian Hu, Peihua Chen
It has been known that Ca(2+) plays an essential role in mediating different modes of neurotransmitter release via different sensing mechanisms. Synaptotagmin 1, 2, 9 were found to act as the Ca(2+) sensors for synchronous release and synaptotagmin 7 and Doc-2 were proposed as the Ca(2+) sensors for asynchronous release. Comparatively, the Ca(2+) sensor for spontaneous release remains a mystery. At the Calyx of Held synapse, the Ca(2+) sensor for spontaneous release was found not identical to the sensor for synchronous release, synaptotagmin2...
August 31, 2017: Synapse
https://www.readbyqxmd.com/read/28852855/how-does-the-stimulus-define-exocytosis-in-adrenal-chromaffin-cells
#12
REVIEW
Fernando D Marengo, Ana M Cárdenas
The extent and type of hormones and active peptides secreted by the chromaffin cells of the adrenal medulla have to be adjusted to physiological requirements. The chromaffin cell secretory activity is controlled by the splanchnic nerve firing frequency, which goes from approximately 0.5 Hz in basal conditions to more than 15 Hz in stress. Thus, these neuroendocrine cells maintain a tonic release of catecholamines under resting conditions, massively discharge intravesicular transmitters in response to stress, or adequately respond to moderate stimuli...
August 29, 2017: Pflügers Archiv: European Journal of Physiology
https://www.readbyqxmd.com/read/28821645/mutant-huntingtin-is-secreted-via-a-late-endosomal-lysosomal-unconventional-secretory-pathway
#13
Katarina Trajkovic, Hyunkyong Jeong, Dimitri Krainc
Huntington's disease (HD) is an autosomal dominant neurodegenerative disorder caused by the expansion of a CAG triplet in the gene encoding for huntingtin. The resulting mutant protein huntingtin (mHtt) with extended polyglutamine (polyQ) sequence at the N-terminus leads to neuronal degeneration both in cell-autonomous and non-cell-autonomous manners. Recent studies identified mHtt in the extracellular environment and suggested that its spreading contributes to toxicity, but the mechanism of mHtt release from the cell of origin remains unknown...
August 16, 2017: Journal of Neuroscience: the Official Journal of the Society for Neuroscience
https://www.readbyqxmd.com/read/28821560/optoacoustic-detection-of-early-therapy-induced-tumor-cell-death-using-a-targeted-imaging-agent
#14
Bangwen Xie, Michal R Tomaszewski, Andre Neves, Susana Ros, De-En Hu, Sarah McGuire, Stefanie Roshy Mullins, David A Tice, Richard C A Sainson, Sarah E Bohndiek, Robert W Wilkinson, Kevin M Brindle
The development of new treatments and their deployment in the clinic may be assisted by imaging methods that allow an early assessment of treatment response in individual patients. The C2A domain of Synaptotagmin-I (C2Am), which binds to the phosphatidylserine (PS) exposed by apoptotic and necrotic cells, has been developed as an imaging probe for detecting cell death. Multispectral optoacoustic tomography (MSOT) is a real-time and clinically applicable imaging modality that was used here with a near infrared (NIR) fluorophore-labeled C2Am to image tumor cell death in mice treated with a TNF-related apoptosis-inducing ligand receptor 2 (TRAILR2) agonist and with 5-fluorouracil (5-FU)...
August 18, 2017: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
https://www.readbyqxmd.com/read/28815523/endoplasmic-reticulum-plasma-membrane-crosstalk-mediated-by-the-extended-synaptotagmins
#15
Yasunori Saheki
The endoplasmic reticulum (ER) possesses multiplicity of functions including protein synthesis, membrane lipid biogenesis, and Ca(2+) storage and has broad localization throughout the cell. While the ER and most other membranous organelles are highly interconnected via vesicular traffic that relies on membrane budding and fusion reactions, the ER forms direct contacts with virtually all other membranous organelles, including the plasma membrane (PM), without membrane fusion. Growing evidence suggests that these contacts play major roles in cellular physiology, including the regulation of Ca(2+) homeostasis and signaling and control of cellular lipid homeostasis...
2017: Advances in Experimental Medicine and Biology
https://www.readbyqxmd.com/read/28813412/the-primed-snare-complexin-synaptotagmin-complex-for-neuronal-exocytosis
#16
Qiangjun Zhou, Peng Zhou, Austin L Wang, Dick Wu, Minglei Zhao, Thomas C Südhof, Axel T Brunger
Synaptotagmin, complexin, and neuronal SNARE (soluble N-ethylmaleimide sensitive factor attachment protein receptor) proteins mediate evoked synchronous neurotransmitter release, but the molecular mechanisms mediating the cooperation between these molecules remain unclear. Here we determine crystal structures of the primed pre-fusion SNARE-complexin-synaptotagmin-1 complex. These structures reveal an unexpected tripartite interface between synaptotagmin-1 and both the SNARE complex and complexin. Simultaneously, a second synaptotagmin-1 molecule interacts with the other side of the SNARE complex via the previously identified primary interface...
August 24, 2017: Nature
https://www.readbyqxmd.com/read/28776026/reconstitution-of-calcium-mediated-exocytosis-of-dense-core-vesicles
#17
Alex J B Kreutzberger, Volker Kiessling, Binyong Liang, Patrick Seelheim, Shrutee Jakhanwal, Reinhard Jahn, J David Castle, Lukas K Tamm
Regulated exocytosis is a process by which neurotransmitters, hormones, and secretory proteins are released from the cell in response to elevated levels of calcium. In cells, secretory vesicles are targeted to the plasma membrane, where they dock, undergo priming, and then fuse with the plasma membrane in response to calcium. The specific roles of essential proteins and how calcium regulates progression through these sequential steps are currently incompletely resolved. We have used purified neuroendocrine dense-core vesicles and artificial membranes to reconstruct in vitro the serial events that mimic SNARE (soluble N-ethylmaleimide-sensitive factor attachment protein receptor)-dependent membrane docking and fusion during exocytosis...
July 2017: Science Advances
https://www.readbyqxmd.com/read/28772123/molecular-mechanisms-of-synaptic-vesicle-priming-by-munc13-and-munc18
#18
Ying Lai, Ucheor B Choi, Jeremy Leitz, Hong Jun Rhee, Choongku Lee, Bekir Altas, Minglei Zhao, Richard A Pfuetzner, Austin L Wang, Nils Brose, JeongSeop Rhee, Axel T Brunger
Munc13 catalyzes the transit of syntaxin from a closed complex with Munc18 into the ternary SNARE complex. Here we report a new function of Munc13, independent of Munc18: it promotes the proper syntaxin/synaptobrevin subconfiguration during assembly of the ternary SNARE complex. In cooperation with Munc18, Munc13 additionally ensures the proper syntaxin/SNAP-25 subconfiguration. In a reconstituted fusion assay with SNAREs, complexin, and synaptotagmin, inclusion of both Munc13 and Munc18 quadruples the Ca(2+)-triggered amplitude and achieves Ca(2+) sensitivity at near-physiological concentrations...
August 2, 2017: Neuron
https://www.readbyqxmd.com/read/28769926/serum-neuroinflammatory-disease-induced-central-nervous-system-proteins-predict-clinical-onset-of-experimental-autoimmune-encephalomyelitis
#19
Itay Raphael, Johanna Webb, Francisco Gomez-Rivera, Carol A Chase Huizar, Rishein Gupta, Bernard P Arulanandam, Yufeng Wang, William E Haskins, Thomas G Forsthuber
There is an urgent need in multiple sclerosis (MS) patients to develop biomarkers and laboratory tests to improve early diagnosis, predict clinical relapses, and optimize treatment responses. In healthy individuals, the transport of proteins across the blood-brain barrier (BBB) is tightly regulated, whereas, in MS, central nervous system (CNS) inflammation results in damage to neuronal tissues, disruption of BBB integrity, and potential release of neuroinflammatory disease-induced CNS proteins (NDICPs) into CSF and serum...
2017: Frontiers in Immunology
https://www.readbyqxmd.com/read/28753981/a-membrane-fusion-model-that-exploits-a-%C3%AE-to-%C3%AE-transition-in-the-hydrophobic-domains-of-syntaxin-1a-and-synaptobrevin-2
#20
Cameron B Gundersen
Parallel zippering of the SNARE domains of syntaxin 1A/B, SNAP-25, and VAMP/synaptobrevin 2 is widely regarded as supplying the driving force for exocytotic events at nerve terminals and elsewhere. However, in spite of intensive research, no consensus has been reached concerning the molecular mechanism by which these SNARE proteins catalyze membrane fusion. As an alternative to SNARE-based models, a scenario was developed in which synaptotagmin 1 (or, 2) can serve as a template to guide lipid movements that underlie fast, synchronous exocytosis at nerve terminals...
July 21, 2017: International Journal of Molecular Sciences
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