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https://www.readbyqxmd.com/read/29231734/t-snare-transmembrane-domain-clustering-modulates-lipid-organization-and-membrane-curvature
#1
Satyan Sharma, Manfred Lindau
The t-SNARE complex plays a central role in neuronal fusion. Its components, syntaxin-1 and SNAP25 are largely present in individual clusters and partially co-localize at the presumptive fusion site. How these protein clusters modify local lipid composition and membrane morphology is largely unknown. In this work, using coarse-grained molecular dynamics, the transmembrane domains (TMDs) of t-SNARE complexes are shown to form aggregates leading to formation of lipid nano-domains, which are enriched in cholesterol, phosphatidylinositol 4,5-bisphosphate and gangliosidic lipids...
December 12, 2017: Journal of the American Chemical Society
https://www.readbyqxmd.com/read/29230398/insulin-signaling-deficiency-produces-immobility-in-caenorhabditis-elegans-that-models-diminished-motivation-states-in-man-and-responds-to-antidepressants
#2
Julie Dagenhardt, Angeline Trinh, Halen Sumner, Jeffrey Scott, Eric Aamodt, Donard S Dwyer
Defects in insulin signaling have been reported in schizophrenia and major depressive disorder, which also share certain negative symptoms such as avolition, anhedonia, and apathy. These symptoms reflect diminished motivational states, which have been modeled in rodents as increased immobility in the forced swimming test. We have discovered that loss-of-function mutations in the insulin receptor (daf-2) and syntaxin (unc-64) genes in Caenorhabditis elegans, brief food deprivation, and exposure to DMSO produce immobility and avolition in non-dauer adults...
November 2017: Molecular Neuropsychiatry
https://www.readbyqxmd.com/read/29230050/synaptic-weight-set-by-munc13-1-supramolecular-assemblies
#3
Hirokazu Sakamoto, Tetsuroh Ariyoshi, Naoya Kimpara, Kohtaroh Sugao, Isamu Taiko, Kenji Takikawa, Daisuke Asanuma, Shigeyuki Namiki, Kenzo Hirose
The weight of synaptic connections, which is controlled not only postsynaptically but also presynaptically, is a key determinant in neuronal network dynamics. The mechanisms controlling synaptic weight, especially on the presynaptic side, remain elusive. Using single-synapse imaging of the neurotransmitter glutamate combined with super-resolution imaging of presynaptic proteins, we identify a presynaptic mechanism for setting weight in central glutamatergic synapses. In the presynaptic terminal, Munc13-1 molecules form multiple and discrete supramolecular self-assemblies that serve as independent vesicular release sites by recruiting syntaxin-1, a soluble N-ethylmaleimide-sensitive-factor attachment receptor (SNARE) protein essential for synaptic vesicle exocytosis...
December 11, 2017: Nature Neuroscience
https://www.readbyqxmd.com/read/29218485/apical-membrane-alterations-in-non-intestinal-organs-in-microvillus-inclusion-disease
#4
Cameron Schlegel, Victoria G Weis, Byron C Knowles, Lynne A Lapierre, Martin G Martin, Paul Dickman, James R Goldenring, Mitchell D Shub
OBJECTIVES: Microvillus inclusion disease (MVID) is a severe form of neonatal diarrhea, caused mainly by mutations in MYO5B. Inactivating mutations in MYO5B causes depolarization of enterocytes in the small intestine, which gives rise to chronic, unremitting secretory diarrhea. While the pathology of the small intestine in MVID patients is well described, little is known about extraintestinal effects of MYO5B mutation. METHODS: We examined stomach, liver, pancreas, colon, and kidney in Navajo MVID patients, who share a single homozygous MYO5B-P660L (1979C>T p...
December 7, 2017: Digestive Diseases and Sciences
https://www.readbyqxmd.com/read/29180572/the-atpase-activity-of-asna1-trc40-is-required-for-pancreatic-progenitor-cell-survival
#5
Stefan Norlin, Vishal Parekh, Helena Edlund
Asna1, also known as TRC40, is implicated in delivery of tail anchored (TA) proteins into the ER, in vesicle-mediated transport, and in chaperoning unfolded proteins during oxidative stress/ATP depletion. We recently showed that Asna1 inactivation in β-cells resulted in impaired retrograde transport, ER stress and diabetes in mice. Here we show that Asna1 inactivation in pancreatic progenitor cells leads to redistribution of the Golgi TA SNAREs Syntaxin-5 and Syntaxin-6, Golgi fragmentation, and accumulation of cytosolic p62+ puncta...
November 27, 2017: Development
https://www.readbyqxmd.com/read/29175153/novel-distinctive-roles-of-docking-proteins-in-short-term-synaptic-plasticity-of-frog-neuromuscular-transmission-revealed-by-botulinum-neurotoxins
#6
Yasuhiro Imafuku, Koh-Ichi Enomoto, Hiroko Kataoka, Isao Ito, Takashi Maeno
Short-term synaptic plasticity (SSP) is a basic mechanism for temporal processing of neural information in synaptic transmission. Facilitation, the fastest component of SSP, has been extensively investigated with regard to Ca2+ signalling and other relevant substances. However, systematic analyses on the slower components of SSP, originated by Magleby and Zengel, have remained stagnant for decades, as few chemicals directly modifying these slower components have been identified. In combination with refined experimental protocols designed to study the stimulation frequency-dependence of SSP and botulinum neurotoxins A and C (BoNT-A and BoNT-C), we investigated SSP of frog neuromuscular transmission to clarify the roles of synaptosomal-associated protein of 25 kDa (SNAP-25) and syntaxin, SNARE proteins exclusively participating in vesicular events including docking, priming and exocytosis...
November 23, 2017: Neuroscience
https://www.readbyqxmd.com/read/29139159/syntaxin1b-contributes-to-regulation-of-the-dopaminergic-system-through-gaba-transmission-in-the-cns
#7
Tomonori Fujiwara, Takefumi Kofuji, Tatsuya Mishima, Kimio Akagawa
In neuronal plasma membrane, two syntaxin isoforms, HPC-1/syntaxin1A (STX1A) and syntaxin1B (STX1B), are predominantly expressed as soluble N-ethylmaleimide-sensitive fusion attachment protein receptors, also known as t-SNAREs. We previously reported that glutamatergic and GABAergic synaptic transmission is impaired in Stx1b null mutant (Stx1b(-/-) ) mice, but is almost normal in Stx1a null mutant (Stx1a(-/-) ) mice. These observations suggested that STX1A and STX1B have distinct functions in fast synaptic transmission in the central nervous system (CNS)...
November 15, 2017: European Journal of Neuroscience
https://www.readbyqxmd.com/read/29133430/the-dual-function-of-the-polybasic-juxtamembrane-region-of-syntaxin-1a-in-clamping-spontaneous-release-and-stimulating-ca-2-triggered-release-in-neuroendocrine-cells
#8
Dafna Singer-Lahat, Noa Barak-Broner, Anton Sheinin, Dafna Greitzer-Antes, Izhak Michaelevski, Ilana Lotan
The exact function of the polybasic juxtamembrane region (5RK) of the plasma membrane neuronal SNARE, syntaxin 1A (Syx), in vesicle exocytosis, although widely studied, is currently not clear. Here, we addressed the role of 5RK in Ca(2+)-triggered release, using our Syx-based intramolecular FRET probe, which previously allowed us to resolve a depolarization-induced Ca(+2)- dependent close-to-open transition (CDO) of Syx that occurs concomitant with evoked release, both in PC12 cells and hippocampal neurons and was abolished upon charge neutralization of 5RK...
November 13, 2017: Journal of Neuroscience: the Official Journal of the Society for Neuroscience
https://www.readbyqxmd.com/read/29122960/mir-335-overexpression-impairs-insulin-secretion-through-defective-priming-of-insulin-vesicles
#9
Vishal A Salunkhe, Jones K Ofori, Nikhil R Gandasi, Sofia A Salö, Sofia Hansson, Markus E Andersson, Anna Wendt, Sebastian Barg, Jonathan L S Esguerra, Lena Eliasson
MicroRNAs contribute to the maintenance of optimal cellular functions by fine-tuning protein expression levels. In the pancreatic β-cells, imbalances in the exocytotic machinery components lead to impaired insulin secretion and type 2 diabetes (T2D). We hypothesize that dysregulated miRNA expression exacerbates β-cell dysfunction, and have earlier shown that islets from the diabetic GK-rat model have increased expression of miRNAs, including miR-335-5p (miR-335). Here, we aim to determine the specific role of miR-335 during development of T2D, and the influence of this miRNA on glucose-stimulated insulin secretion and Ca(2+)-dependent exocytosis...
November 2017: Physiological Reports
https://www.readbyqxmd.com/read/29113160/germline-cytotoxic-lymphocytes-defective-mutations-in-chinese-patients-with-lymphoma
#10
Xue Chen, Yang Zhang, Fang Wang, Mangju Wang, Wen Teng, Yuehui Lin, Xiangping Han, Fangyuan Jin, Yuanli Xu, Panxiang Cao, Jiancheng Fang, Ping Zhu, Chunrong Tong, Hongxing Liu
Certain patients with lymphoma may harbor mutations in perforin 1 (PRF1), unc-13 homolog D (UNC13D), syntaxin 11 (STX11), STXBP2 (syntaxin binding protein 2) or SH2 domain containing 1A (SH2D1A), which causes functional defects of cytotoxic lymphocytes. Data regarding the association between genetic defects and the development of lymphoma in Chinese patients are limited to date. In the present study, 90 patients with lymphoma were analyzed for UNC13D, PRF1, STXBP2, STX11, SH2D1A and X-linked inhibitor of apoptosis...
November 2017: Oncology Letters
https://www.readbyqxmd.com/read/29101845/motor-cortex-excitability-in-seizure-free-stx1b-mutation-carriers-with-a-history-of-epilepsy-and-febrile-seizures
#11
Maria-Ioanna Stefanou, Debora Desideri, Justus Marquetand, Paolo Belardinelli, Christoph Zrenner, Holger Lerche, Ulf Ziemann
OBJECTIVE: Mutations in STX1B encoding the presynaptic protein syntaxin-1B are associated with febrile seizures with or without epilepsy. It is unclear to what extent these mutations are linked to abnormalities of cortical glutamatergic or GABAergic neurotransmission. We explored this question using single- and paired-pulse transcranial magnetic stimulation (TMS) excitability markers. METHODS: We studied nine currently asymptomatic adult STX1B mutation carriers with history of epilepsy and febrile seizures, who had been seizure-free for at least eight years without antiepileptic drug treatment, and ten healthy age-matched controls...
October 20, 2017: Clinical Neurophysiology: Official Journal of the International Federation of Clinical Neurophysiology
https://www.readbyqxmd.com/read/29076559/genetic-influences-on-cognition-in-progressive-supranuclear-palsy
#12
Adam Gerstenecker, Erik D Roberson, Gerard D Schellenberg, David G Standaert, David R Shprecher, Benzi M Kluger, Irene Litvan
BACKGROUND: Cognitive dysfunction is common in progressive supranuclear palsy, but the influence of genetics on cognition in this disorder has not been well studied. The objective of this study was to investigate the effect of genes previously identified as risk alleles, including microtubule-associated protein tau, myelin-associated oligodendrocyte basic protein, eukaryotic translation initiation factor 2-alpha kinase 3, and syntaxin 6, as well as apolipoprotein E, on cognitive function in progressive supranuclear palsy...
October 27, 2017: Movement Disorders: Official Journal of the Movement Disorder Society
https://www.readbyqxmd.com/read/29073720/malat1-modulates-the-autophagy-of-retinoblastoma-cell-through-mir-124-mediated-stx17-regulation
#13
Jun Huang, Yuting Yang, Fang Fang, Ke Liu
The retinoblastoma is the most common intraocular malignant tumor in infants and children; it is one of the deadliest forms of cancer due to its limited sensitivity to chemotherapy and radiotherapy. In several cancers, chemoresistance is associated with autophagy induction. Non-coding RNAs, including long non-coding RNAs (lncRNA) and microRNAs (miRNAs) have been reported to regulate physiological activities of the cells, including proliferation, apoptosis, migration, as well as autophagy. MALAT1, a well-established lncRNA acts as an oncogene, promotes cancer proliferation and metastasis via the stimulation of autophagy...
October 26, 2017: Journal of Cellular Biochemistry
https://www.readbyqxmd.com/read/29067685/a-possible-link-between-kcnq2-and-stxbp1-related-encephalopathies-stxbp1-reduces-the-inhibitory-impact-of-syntaxin-1a-on-m-current
#14
Jérôme Devaux, Sandra Dhifallah, Michela De Maria, Geoffrey Stuart-Lopez, Hélène Becq, Mathieu Milh, Florence Molinari, Laurent Aniksztejn
OBJECTIVE: Kv7 channels mediate the voltage-gated M-type potassium current. Reduction of M current due to KCNQ2 mutations causes early onset epileptic encephalopathies (EOEEs). Mutations in STXBP1 encoding the syntaxin binding protein 1 can produce a phenotype similar to that of KCNQ2 mutations, suggesting a possible link between STXBP1 and Kv7 channels. These channels are known to be modulated by syntaxin-1A (Syn-1A) that binds to the C-terminal domain of the Kv7.2 subunit and strongly inhibits M current...
October 25, 2017: Epilepsia
https://www.readbyqxmd.com/read/29066608/molecular-mechanisms-of-developmentally-programmed-crinophagy-in-drosophila
#15
Tamás Csizmadia, Péter Lőrincz, Krisztina Hegedűs, Szilvia Széplaki, Péter Lőw, Gábor Juhász
At the onset of metamorphosis, Drosophila salivary gland cells undergo a burst of glue granule secretion to attach the forming pupa to a solid surface. Here, we show that excess granules evading exocytosis are degraded via direct fusion with lysosomes, a secretory granule-specific autophagic process known as crinophagy. We find that the tethering complex HOPS (homotypic fusion and protein sorting); the small GTPases Rab2, Rab7, and its effector, PLEKHM1; and a SNAP receptor complex consisting of Syntaxin 13, Snap29, and Vamp7 are all required for the fusion of secretory granules with lysosomes...
October 24, 2017: Journal of Cell Biology
https://www.readbyqxmd.com/read/29046354/evidence-for-a-conserved-inhibitory-binding-mode-between-the-membrane-fusion-assembly-factors-munc18-and-syntaxin-in-animals
#16
Czuee Morey, C Nickias Kienle, Tobias H Klöpper, Pawel Burkhardt, Dirk Fasshauer
The membrane fusion necessary for vesicle trafficking is driven by the assembly of heterologous SNARE proteins orchestrated by the binding of Sec1/Munc18 (SM) proteins to specific syntaxin SNARE proteins. However, the precise mode of interaction between SM proteins and SNAREs is debated, as contrasting binding modes have been found for different members of the SM protein family, including the three vertebrate Munc18 isoforms. While different binding modes could be necessary given their roles in different secretory processes in different tissues, the structural similarity of the three isoforms makes this divergence perplexing...
October 18, 2017: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/29044293/down-regulation-of-the-munc18b-syntaxin-11-complex-and-%C3%AE-1-tubulin-impairs-secretion-and-spreading-in-neonatal-platelets
#17
Eva Caparrós-Pérez, Raúl Teruel-Montoya, Verónica Palma-Barquero, José M Torregrosa, José E Blanco, Juan L Delgado, María Luisa Lozano, Vicente Vicente, Martha Sola-Visner, José Rivera, Constantino Martínez, Francisca Ferrer-Marín
Neonatal platelets are hyporeactive and show impaired agonist-induced secretion despite no obvious abnormalities in their granules. Here, we examined, for the first time, the ultrastructure of neonatal and adult platelets following agonist activation. Under resting conditions, neonatal and adult platelets appeared ultrastructurally identical. Following agonist stimulation, however, noticeable degranulation occurred in adult platelets, while granules in neonatal platelets remained clearly visible and apparently unable to centralize or fuse...
October 10, 2017: Thrombosis and Haemostasis
https://www.readbyqxmd.com/read/29040524/potentiation-of-excitatory-synaptic-transmission-ameliorates-aggression-in-mice-with-stxbp1-haploinsufficiency
#18
Hiroyuki Miyamoto, Atsushi Shimohata, Manabu Abe, Teruo Abe, Emi Mazaki, Kenji Amano, Toshimitsu Suzuki, Tetsuya Tatsukawa, Shigeyoshi Itohara, Kenji Sakimura, Kazuhiro Yamakawa
Genetic studies point to a major role of de novo mutations in neurodevelopmental disorders of intellectual disability, autism spectrum disorders, and epileptic encephalopathy. The STXBP1 gene encodes the syntaxin-binding protein 1 (Munc18-1) that critically controls synaptic vesicle exocytosis and synaptic transmission. This gene harbors a high frequency of de novo mutations, which may play roles in these neurodevelopmental disorders. However, the system and behavioral-level pathophysiological changes caused by these genetic defects remain poorly understood...
October 11, 2017: Human Molecular Genetics
https://www.readbyqxmd.com/read/28979270/functional-characterization-of-a-syntaxin-involved-in-tomato-solanum-lycopersicum-resistance-against-powdery-mildew
#19
Valentina Bracuto, Michela Appiano, Zheng Zheng, Anne-Marie A Wolters, Zhe Yan, Luigi Ricciardi, Richard G F Visser, Stefano Pavan, Yuling Bai
Specific syntaxins, such as Arabidopsis AtPEN1 and its barley ortholog ROR2, play a major role in plant defense against powdery mildews. Indeed, the impairment of these genes results in increased fungal penetration in both host and non-host interactions. In this study, a genome-wide survey allowed the identification of 21 tomato syntaxins. Two of them, named SlPEN1a and SlPEN1b, are closely related to AtPEN1. RNAi-based silencing of SlPEN1a in a tomato line carrying a loss-of-function mutation of the susceptibility gene SlMLO1 led to compromised resistance toward the tomato powdery mildew fungus Oidium neolycopersici...
2017: Frontiers in Plant Science
https://www.readbyqxmd.com/read/28966893/the-legionella-pneumophila-effector-lpg1137-is-a-homologue-of-mitochondrial-slc25-carrier-proteins-not-of-known-serine-proteases
#20
Marcin Gradowski, Krzysztof Pawłowski
Many bacterial effector proteins that are delivered to host cells during infection are enzymes targeting host cell signalling. Recently, Legionella pneumophila effector Lpg1137 was experimentally characterised as a serine protease that cleaves human syntaxin 17. We present strong bioinformatic evidence that Lpg1137 is a homologue of mitochondrial carrier proteins and is not related to known serine proteases. We also discuss how this finding can be reconciled with the apparently contradictory experimental results...
2017: PeerJ
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