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Synaptotagmin

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https://www.readbyqxmd.com/read/28813412/the-primed-snare-complexin-synaptotagmin-complex-for-neuronal-exocytosis
#1
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 16, 2017: Nature
https://www.readbyqxmd.com/read/28776026/reconstitution-of-calcium-mediated-exocytosis-of-dense-core-vesicles
#2
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
#3
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
#4
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
#5
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
https://www.readbyqxmd.com/read/28746398/tomosyn-associates-with-secretory-vesicles-in-neurons-through-its-n-and-c-terminal-domains
#6
Cornelia J Geerts, Roberta Mancini, Ning Chen, Frank T W Koopmans, Ka Wan Li, August B Smit, Jan R T van Weering, Matthijs Verhage, Alexander J A Groffen
The secretory pathway in neurons requires efficient targeting of cargos and regulatory proteins to their release sites. Tomosyn contributes to synapse function by regulating synaptic vesicle (SV) and dense-core vesicle (DCV) secretion. While there is large support for the presynaptic accumulation of tomosyn in fixed preparations, alternative subcellular locations have been suggested. Here we studied the dynamic distribution of tomosyn-1 (Stxbp5) and tomosyn-2 (Stxbp5l) in mouse hippocampal neurons and observed a mixed diffuse and punctate localization pattern of both isoforms...
2017: PloS One
https://www.readbyqxmd.com/read/28738878/tlr4-response-mediates-ethanol-induced-neurodevelopment-alterations-in-a-model-of-fetal-alcohol-spectrum-disorders
#7
María Pascual, Jorge Montesinos, Sandra Montagud-Romero, Jerónimo Forteza, Marta Rodríguez-Arias, José Miñarro, Consuelo Guerri
BACKGROUND: Inflammation during brain development participates in the pathogenesis of early brain injury and cognitive dysfunctions. Prenatal ethanol exposure affects the developing brain and causes neural impairment, cognitive and behavioral effects, collectively known as fetal alcohol spectrum disorders (FASD). Our previous studies demonstrate that ethanol activates the innate immune response and TLR4 receptor and causes neuroinflammation, brain damage, and cognitive defects in the developmental brain stage of adolescents...
July 24, 2017: Journal of Neuroinflammation
https://www.readbyqxmd.com/read/28716806/different-strokes-for-different-synaptotagmins
#8
Caitlin Sedwick
JGP study shows how synaptotagmins 1 and 7 affect chromaffin cell granule fusion.
July 17, 2017: Journal of General Physiology
https://www.readbyqxmd.com/read/28713915/concurrent-administration-of-thyroxine-and-donepezil-induces-plastic-changes-in-the-prefrontal-cortex-of-adult-hypothyroid-rats
#9
Fen Wang, Zhangbi Wu, Xiaoxue Zha, Yaojun Cai, Bo Wu, Xuemei Jia, Defa Zhu
The aim of the present study was to observe the effects of the concurrent administration of thyroxine (T4) and an acetylcholinesterase (AChE) inhibitor, donepezil (DON), on the hypothyroidism‑induced ultrastructural changes of the prefrontal cortex (PFC) in adult rats. The acetylcholine (ACh) content and AChE activity was assessed, as well as the expressions of synaptotagmin‑1 (syt‑1) and SNAP‑25 were analyzed in the rats. Adding 0.05% propylthiouracil to rats' drinking water induced a hypothyroid rat model...
September 2017: Molecular Medicine Reports
https://www.readbyqxmd.com/read/28696301/otoferlin-is-a-multivalent-calcium-sensitive-scaffold-linking-snares-and-calcium-channels
#10
Nicole Hams, Murugesh Padmanarayana, Weihong Qiu, Colin P Johnson
Sensory hair cells rely on otoferlin as the calcium sensor for exocytosis and encoding of sound preferentially over the neuronal calcium sensor synaptotagmin. Although it is established that synaptotagmin cannot rescue the otoferlin KO phenotype, the large size and low solubility of otoferlin have prohibited direct biochemical comparisons that could establish functional differences between these two proteins. To address this challenge, we have developed a single-molecule colocalization binding titration assay (smCoBRA) that can quantitatively characterize full-length otoferlin from mammalian cell lysate...
July 25, 2017: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/28687607/synaptotagmin-isoforms-confer-distinct-activation-kinetics-and-dynamics-to-chromaffin-cell-granules
#11
Tejeshwar C Rao, Zuleirys Santana Rodriguez, Mazdak M Bradberry, Alexandra H Ranski, Peter J Dahl, Michael W Schmidtke, Paul M Jenkins, Daniel Axelrod, Edwin R Chapman, David R Giovannucci, Arun Anantharam
Adrenomedullary chromaffin cells respond to sympathetic nervous system activation by secreting a cocktail of potent neuropeptides and hormones into the circulation. The distinct phases of the chromaffin cell secretory response have been attributed to the progressive fusion of distinct populations of dense core granules with different activation kinetics. However, it has been difficult to define what distinguishes these populations at the molecular level. Functional segregation of granule pools may depend on selective sorting of synaptotagmin-1 (Syt-1) and synaptotagmin-7 (Syt-7), which our previous work showed are rarely cosorted to the same granule...
July 7, 2017: Journal of General Physiology
https://www.readbyqxmd.com/read/28686803/the-calcium-sensor-synaptotagmin-1-is-expressed-and-regulated-in-hippocampal-postsynaptic-spines
#12
Suleman Hussain, Daniel Lawer Egbenya, Yi-Chen Lai, Zita J Dosa, Jakob B Sørensen, Anne Anderson, Svend Davanger
Synaptotagmin 1 is a presynaptic calcium sensor, regulating SNARE-mediated vesicle exocytosis of transmitter. Increasing evidence indicate roles of SNARE proteins in postsynaptic glutamate receptor trafficking. However, a possible postsynaptic expression of synaptotagmin 1 has not been demonstrated previously. Here, we used postembedding immunogold electron microscopy to determine the subsynaptic localization of synaptotagmin 1 in rat hippocampal CA1 Schaffer collateral synapses. We report for the first time that synaptotagmin 1 is present in rat hippocampal postsynaptic spines, both on cytoplasmic vesicles and at the postsynaptic density (PSD)...
July 7, 2017: Hippocampus
https://www.readbyqxmd.com/read/28686317/synaptotagmin-11-inhibits-cytokine-secretion-and-phagocytosis-in-microglia
#13
Cuilian Du, Yalong Wang, Feifan Zhang, Shuxin Yan, Yuan Guan, Xiaoli Gong, Ting Zhang, Xiuyu Cui, Xiaomin Wang, Claire Xi Zhang
Cytokine secretion and phagocytosis are key functions of activated microglia. However, the molecular mechanisms underlying their regulation in microglia remain largely unknown. Here, we report that synaptotagmin-11 (Syt11), a non-Ca(2+) -binding Syt implicated in Parkinson disease and schizophrenia, inhibits cytokine secretion and phagocytosis in microglia. We found Syt11 expression in microglia in brain slices and primary microglia. Interestingly, Syt11-knockdown (KD) increased cytokine secretion and NO release in primary microglia both in the absence and presence of lipopolysaccharide...
July 7, 2017: Glia
https://www.readbyqxmd.com/read/28683263/igf1-dependent-synaptic-plasticity-of-mitral-cells-in-olfactory-memory-during-social-learning
#14
Zhihui Liu, Zijun Chen, Congping Shang, Fei Yan, Yingchao Shi, Jiajing Zhang, Baole Qu, Hailin Han, Yanying Wang, Dapeng Li, Thomas C Südhof, Peng Cao
During social transmission of food preference (STFP), mice form long-term memory of food odors presented by a social partner. How does the brain associate a social context with odor signals to promote memory encoding? Here we show that odor exposure during STFP, but not unconditioned odor exposure, induces glomerulus-specific long-term potentiation (LTP) of synaptic strength selectively at the GABAergic component of dendrodendritic synapses of granule and mitral cells in the olfactory bulb. Conditional deletion of synaptotagmin-10, the Ca(2+) sensor for IGF1 secretion from mitral cells, or deletion of IGF1 receptor in the olfactory bulb prevented the socially relevant GABAergic LTP and impaired memory formation after STFP...
July 5, 2017: Neuron
https://www.readbyqxmd.com/read/28674381/engineered-botulinum-neurotoxin-b-with-improved-efficacy-for-targeting-human-receptors
#15
Liang Tao, Lisheng Peng, Ronnie P-A Berntsson, Sai Man Liu, SunHyun Park, Feifan Yu, Christopher Boone, Shilpa Palan, Matthew Beard, Pierre-Etienne Chabrier, Pål Stenmark, Johannes Krupp, Min Dong
Botulinum neurotoxin B is a Food and Drug Administration-approved therapeutic toxin. However, it has lower binding affinity toward the human version of its major receptor, synaptotagmin II (h-Syt II), compared to mouse Syt II, because of a residue difference. Increasing the binding affinity to h-Syt II may improve botulinum neurotoxin B's therapeutic efficacy and reduce adverse effects. Here we utilized the bacterial adenylate cyclase two-hybrid method and carried out a saturation mutagenesis screen in the Syt II-binding pocket of botulinum neurotoxin B...
July 3, 2017: Nature Communications
https://www.readbyqxmd.com/read/28640879/dual-targeting-of-a-virus-movement-protein-to-er-and-plasma-membrane-subdomains-is-essential-for-plasmodesmata-localization
#16
Kazuya Ishikawa, Masayoshi Hashimoto, Akira Yusa, Hiroaki Koinuma, Yugo Kitazawa, Osamu Netsu, Yasuyuki Yamaji, Shigetou Namba
Plant virus movement proteins (MPs) localize to plasmodesmata (PD) to facilitate virus cell-to-cell movement. Numerous studies have suggested that MPs use a pathway either through the ER or through the plasma membrane (PM). Furthermore, recent studies reported that ER-PM contact sites and PM microdomains, which are subdomains found in the ER and PM, are involved in virus cell-to-cell movement. However, functional relationship of these subdomains in MP traffic to PD has not been described previously. We demonstrate here the intracellular trafficking of fig mosaic virus MP (MPFMV) using live cell imaging, focusing on its ER-directing signal peptide (SPFMV)...
June 2017: PLoS Pathogens
https://www.readbyqxmd.com/read/28600435/rassf4-controls-soce-and-er-pm-junctions-through-regulation-of-pi-4-5-p2
#17
Yu-Ju Chen, Chi-Lun Chang, Wan-Ru Lee, Jen Liou
RAS association domain family 4 (RASSF4) is involved in tumorigenesis and regulation of the Hippo pathway. In this study, we identify new functional roles of RASSF4. First, we discovered that RASSF4 regulates store-operated Ca(2+) entry (SOCE), a fundamental Ca(2+) signaling mechanism, by affecting the translocation of the endoplasmic reticulum (ER) Ca(2+) sensor stromal interaction molecule 1 (STIM1) to ER-plasma membrane (PM) junctions. It was further revealed that RASSF4 regulates the formation of ER-PM junctions and the ER-PM tethering function of extended synaptotagmins E-Syt2 and E-Syt3...
July 3, 2017: Journal of Cell Biology
https://www.readbyqxmd.com/read/28574251/non-native-metal-ion-reveals-the-role-of-electrostatics-in-synaptotagmin-1-membrane-interactions
#18
Sachin Katti, Sarah B Nyenhuis, Bin Her, Atul K Srivastava, Alexander B Taylor, P John Hart, David S Cafiso, Tatyana I Igumenova
C2 domains are independently folded modules that often target their host proteins to anionic membranes in a Ca(2+)-dependent manner. In these cases, membrane association is triggered by Ca(2+) binding to the negatively charged loop region of the C2 domain. Here, we used a non-native metal ion, Cd(2+), in lieu of Ca(2+) to gain insight into the contributions made by long-range Coulombic interactions and direct metal ion-lipid bridging to membrane binding. Using X-ray crystallography, NMR, Förster resonance energy transfer, and vesicle cosedimentation assays, we demonstrate that, although Cd(2+) binds to the loop region of C2A/B domains of synaptotagmin 1 with high affinity, long-range Coulombic interactions are too weak to support membrane binding of individual domains...
June 27, 2017: Biochemistry
https://www.readbyqxmd.com/read/28554774/tubular-lipid-binding-proteins-tulips-growing-everywhere
#19
REVIEW
Louise H Wong, Tim P Levine
Tubular lipid binding proteins (TULIPs) have become a focus of interest in the cell biology of lipid signalling, lipid traffic and membrane contact sites. Each tubular domain has an internal pocket with a hydrophobic lining that can bind a hydrophobic molecule such as a lipid. This allows TULIP proteins to carry lipids through the aqueous phase. TULIP domains were first found in a large family of extracellular proteins related to the bacterial permeability-inducing protein (BPI) and cholesterol ester transfer protein (CETP)...
September 2017: Biochimica et Biophysica Acta
https://www.readbyqxmd.com/read/28550152/er-plasma-membrane-contact-sites-contribute-to-autophagosome-biogenesis-by-regulation-of-local-pi3p-synthesis
#20
Anna Chiara Nascimbeni, Francesca Giordano, Nicolas Dupont, Daniel Grasso, Maria I Vaccaro, Patrice Codogno, Etienne Morel
The double-membrane-bound autophagosome is formed by the closure of a structure called the phagophore, origin of which is still unclear. The endoplasmic reticulum (ER) is clearly implicated in autophagosome biogenesis due to the presence of the omegasome subdomain positive for DFCP1, a phosphatidyl-inositol-3-phosphate (PI3P) binding protein. Contribution of other membrane sources, like the plasma membrane (PM), is still difficult to integrate in a global picture. Here we show that ER-plasma membrane contact sites are mobilized for autophagosome biogenesis, by direct implication of the tethering extended synaptotagmins (E-Syts) proteins...
July 14, 2017: EMBO Journal
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