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51.
Tyrosine phosphorylation of Munc18‐1 inhibits synaptic transmission by preventing SNARE assembly
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Marieke Meijer Bernhard Dörr Hanna CA Lammertse Chrysanthi Blithikioti Jan RT van Weering Ruud FG Toonen Thomas H Söllner Matthijs Verhage 《The EMBO journal》2018,37(2):300-320
Tyrosine kinases are important regulators of synaptic strength. Here, we describe a key component of the synaptic vesicle release machinery, Munc18‐1, as a phosphorylation target for neuronal Src family kinases (SFKs). Phosphomimetic Y473D mutation of a SFK phosphorylation site previously identified by brain phospho‐proteomics abolished the stimulatory effect of Munc18‐1 on SNARE complex formation (“SNARE‐templating”) and membrane fusion in vitro. Furthermore, priming but not docking of synaptic vesicles was disrupted in hippocampal munc18‐1‐null neurons expressing Munc18‐1Y473D. Synaptic transmission was temporarily restored by high‐frequency stimulation, as well as by a Munc18‐1 mutation that results in helix 12 extension, a critical conformational step in vesicle priming. On the other hand, expression of non‐phosphorylatable Munc18‐1 supported normal synaptic transmission. We propose that SFK‐dependent Munc18‐1 phosphorylation may constitute a potent, previously unknown mechanism to shut down synaptic transmission, via direct occlusion of a Synaptobrevin/VAMP2 binding groove and subsequent hindrance of conformational changes in domain 3a responsible for vesicle priming. This would strongly interfere with the essential post‐docking SNARE‐templating role of Munc18‐1, resulting in a largely abolished pool of releasable synaptic vesicles. 相似文献
52.
铁皮石斛的离体开花 总被引:9,自引:0,他引:9
铁皮石斛(Dendrobium candidum),为一种野生兰科植物,在栽培条件下,从种子萌发到开花通常需要3~4a.研究了多种植物激素和多胺对该种石斛组织培养中花芽形成的影响,结果表明在培养基中加入合适浓度的亚精胺(spermidine)或BA(6-苄基腺嘌呤),或同时加入NAA(萘乙酸)和BA均可诱导原球茎或由之形成的无根小苗在3~6个月开花,频率在31.6%~45.8%.当将原球茎在加有ABA(脱落酸)的培养基上预培养后再移到加有BA的培养基上,花芽形成的频率可提高到平均达82.8%(个别实验中可达100%),这种诱导提早开花的现象也与实验材料的发育阶段(原球茎、无根小苗、已生根的小苗)有关,通常发生在根的形成受到完全或部分抑制的情况中. 相似文献
53.
54.
Efficiencies of different genes and different tree-building methods in recovering a known vertebrate phylogeny 总被引:24,自引:6,他引:18
The relative efficiencies of different protein-coding genes of the
mitochondrial genome and different tree-building methods in recovering a
known vertebrate phylogeny (two whale species, cow, rat, mouse, opossum,
chicken, frog, and three bony fish species) was evaluated. The
tree-building methods examined were the neighbor joining (NJ), minimum
evolution (ME), maximum parsimony (MP), and maximum likelihood (ML), and
both nucleotide sequences and deduced amino acid sequences were analyzed.
Generally speaking, amino acid sequences were better than nucleotide
sequences in obtaining the true tree (topology) or trees close to the true
tree. However, when only first and second codon positions data were used,
nucleotide sequences produced reasonably good trees. Among the 13 genes
examined, Nd5 produced the true tree in all tree-building methods or
algorithms for both amino acid and nucleotide sequence data. Genes Cytb and
Nd4 also produced the correct tree in most tree-building algorithms when
amino acid sequence data were used. By contrast, Co2, Nd1, and Nd41 showed
a poor performance. In general, large genes produced better results, and
when the entire set of genes was used, all tree-building methods generated
the true tree. In each tree-building method, several distance measures or
algorithms were used, but all these distance measures or algorithms
produced essentially the same results. The ME method, in which many
different topologies are examined, was no better than the NJ method, which
generates a single final tree. Similarly, an ML method, in which many
topologies are examined, was no better than the ML star decomposition
algorithm that generates a single final tree. In ML the best substitution
model chosen by using the Akaike information criterion produced no better
results than simpler substitution models. These results question the
utility of the currently used optimization principles in phylogenetic
construction. Relatively simple methods such as the NJ and ML star
decomposition algorithms seem to produce as good results as those obtained
by more sophisticated methods. The efficiencies of the NJ, ME, MP, and ML
methods in obtaining the correct tree were nearly the same when amino acid
sequence data were used. The most important factor in constructing reliable
phylogenetic trees seems to be the number of amino acids or nucleotides
used.
相似文献
55.
56.
Anupama Reddy Joseph D. Growney Nick S. Wilson Caroline M. Emery Jennifer A. Johnson Rebecca Ward Kelli A. Monaco Joshua Korn John E. Monahan Mark D. Stump Felipa A. Mapa Christopher J. Wilson Janine Steiger Jebediah Ledell Richard J. Rickles Vic E. Myer Seth A. Ettenberg Robert Schlegel William R. Sellers Heather A. Huet Joseph Lehár 《PloS one》2016,11(1)
57.
The effects of injections of either bombesin (BBS) or cholecystokinin octapeptide (CCK-8) on patterns of food intake of macronutrients were examined in adult male rats, and compared to the effects following saline injections. The animals were food deprived for 18 hours and then offered one of three isocaloric dietary components (protein, carbohydrate or fat). During the first 30 minutes following injections of BBS, protein intake was decreased. Suppression of carbohydrate intake, significant between 30 and 60 minutes, was sustained up to two hours following injections. During the first 30 minutes following injections of CCK, animals reduced their intake of each macronutrient. Reductions in the consumption of fat and protein were sustained up to one and six hours, respectively. The availability of particular macronutrients is proposed as a possible factor accounting for differences among studies with respect to self-selection profiles and duration effects. 相似文献
58.
Immunological identity of heparin-dependent plasma and urinary protein C inhibitor and plasminogen activator inhibitor-3 总被引:7,自引:0,他引:7
M J Heeb F Espa?a M Geiger D Collen D C Stump J H Griffin 《The Journal of biological chemistry》1987,262(33):15813-15816
Purified plasma and urinary protein C inhibitors (PCI) formed heparin-dependent complexes with activated protein C (APC) which were detected by immunoblotting after nondenaturing gel electrophoresis. Bands representing APC.PCI complexes were also seen on immunoblots after incubation of plasma with APC and heparin. The same immunoblot pattern of complexes was detected by three different methods: method A, monoclonal antibody to plasminogen activator inhibitor-3 (PAI-3, urinary urokinase inhibitor) + 125I-labeled anti-mouse IgG; method B, polyclonal antibodies to PCI + 125I-labeled purified plasma PCI; and method C, monoclonal antibody to protein C + 125I-protein C. Plasma depleted of PAI-3 by immunoadsorption with insolubilized monoclonal antibody to PAI-3 showed no detectable antigen or complexes with APC as visualized by methods A or B. This PAI-3-depleted plasma had less than 10% of the heparin-dependent inhibitory activity of normal plasma toward APC. Purified plasma PCI was fully reactive in an enzyme-linked immunoabsorbent assay for PAI-3, and plasma and urinary PCI inhibited urokinase activity in a heparin-dependent manner. These data indicate that heparin-dependent plasma and urinary PCI and PAI-3 are immunologically and functionally very similar if not identical. This observation identifies a new interrelation between the protein C anticoagulant and the fibrinolytic systems. In addition, plasma contains a heparin-independent inhibitor of APC which is not immunologically related to plasma PCI or to PAI-3. 相似文献
59.
Purification and characterization of a novel low molecular weight form of single-chain urokinase-type plasminogen activator 总被引:5,自引:0,他引:5
A low Mr form (Mr 32,000) of single-chain urokinase-type plasminogen activator (scu-PA) was isolated from conditioned culture medium of a human lung adenocarcinoma cell line, CALU-3 (ATCC, HTB-55). The purified material (scu-PA-32k) consists of a single polypeptide chain and is immunologically similar to Mr 33,000 urokinase. Its NH2-terminal sequence is identical to that beginning at Leu-144 of Mr 54,000 urokinase. Whereas low Mr urokinase is derived from mature Mr 54,000 scu-PA by limited hydrolysis by plasmin first of the Lys-158-Ile-159 peptide bond and then of the Lys-136-Lys-137, scu-PA-32k is generated by specific hydrolysis of the Glu-143-Leu-144 peptide bond by an unidentified protease. scu-PA-32k resembles its Mr 54,000 scu-PA counterpart by its very low activity on chromogenic substrates for urokinase, by plasminogen-dependent fibrinolytic activity on fibrin plates, and by the lack of specific binding to fibrin. It activates plasminogen directly with high affinity, Km = 0.9 microM, but low turnover number, kcat = 0.0028 s-1. It is converted to fully active two-chain urokinase by plasmin with Km = 12 microM and kcat = 0.3 s-1. Like Mr 54,000 scu-PA, it causes significant lysis of a 125I-labeled fibrin clot in human plasma with relatively less fibrinogen breakdown as compared to urokinase. scu-PA-32k, which also has conserved fibrin specificity, represents a molecular variant which may be more suitable for large scale production as a fibrin-specific thrombolytic agent by recombinant DNA technology. 相似文献
60.