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81.
82.
Yasunori Yamamoto Sumiko Mochida Takao Kurooka Toshiaki Sakisaka 《The Journal of biological chemistry》2009,284(18):12480-12490
Neurotransmitter release from presynaptic nerve terminals is regulated by
SNARE complex-mediated synaptic vesicle fusion. Tomosyn, a negative regulator
of neurotransmitter release, which is composed of N-terminal WD40 repeats, a
tail domain, and a C-terminal VAMP-like domain, is known to inhibit SNARE
complex formation by sequestering target SNAREs (t-SNAREs) upon interaction of
its C-terminal VAMP-like domain with t-SNAREs. However, it remains unclear how
the inhibitory activity of tomosyn is regulated. Here we show that the tail
domain functions as a regulator of the inhibitory activity of tomosyn through
intramolecular interactions. The binding of the tail domain to the C-terminal
VAMP-like domain interfered with the interaction of the C-terminal VAMP-like
domain with t-SNAREs, and thereby repressed the inhibitory activity of tomosyn
on the SNARE complex formation. The repressed inhibitory activity of tomosyn
was restored by the binding of the tail domain to the N-terminal WD40 repeats.
These results indicate that the probable conformational change of tomosyn
mediated by the intramolecular interactions of the tail domain controls its
inhibitory activity on the SNARE complex formation, leading to a regulated
inhibition of neurotransmitter release.Synaptic vesicles are transported to the presynaptic plasma membrane where
Ca2+ channels are located. Depolarization induces Ca2+
influx into the cytosol of nerve terminals through the Ca2+
channels, and this Ca2+ influx initiates the fusion of the vesicles
with the plasma membrane, finally leading to exocytosis of neurotransmitters
(1). Soluble
N-ethylmaleimide-sensitive fusion protein attachment protein
(SNAP)2
receptors (SNAREs) are essential for synaptic vesicle exocytosis
(2-5).
Synaptic vesicles are endowed with vesicle-associated membrane protein 2
(VAMP-2) as a vesicular SNARE, whereas the presynaptic plasma membrane is
endowed with syntaxin-1 and SNAP-25 as target SNAREs. VAMP-2 interacts with
SNAP-25 and syntaxin-1 to form a stable SNARE complex
(6-9).
The formation of the SNARE complex then brings synaptic vesicles and the
plasma membrane into close apposition, and provides the energy that drives the
mixing of the two lipid bilayers
(3-5,
9).Tomosyn is a syntaxin-1-binding protein that we originally identified
(10). Tomosyn contains
N-terminal WD40 repeats, a tail domain, and a C-terminal domain homologous to
VAMP-2. The C-terminal VAMP-like domain (VLD) of tomosyn acts as a SNARE
domain that competes with VAMP-2. Indeed, a structural study of the VLD
revealed that the VLD, syntaxin-1, and SNAP-25 assemble into a SNARE
complex-like structure (referred to as tomosyn complex hereafter)
(11). Tomosyn inhibits SNARE
complex formation by sequestering t-SNAREs through the tomosyn complex
formation, and thereby inhibits SNARE-dependent neurotransmitter release. The
large N-terminal region of tomosyn shares similarity to the
Drosophila tumor suppressor lethal giant larvae (Lgl), the mammalian
homologues M-Lgl1 and M-Lgl2, and yeast proteins Sro7p and Sro77p
(12,
13). Consistent with the
function of tomosyn, Lgl family members play an important role in polarized
exocytosis by regulating SNARE function on the plasma membrane in yeast and
epithelial cells (12,
13). However, only tomosyn,
Sro7, and Sro77 have the tail domains and the VLDs, suggesting that their
structural regulation is evolutionally conserved. Recently, the crystal
structure of Sro7 was solved and revealed that the tail domain of Sro7 binds
its WD40 repeats (14). Sec9, a
yeast counterpart of SNAP-25, also binds the WD40 repeats of Sro7. This
binding inhibits the SNARE complex formation and exocytosis by sequestering
Sec9. In addition, binding of the tail domain to the WD40 repeats causes a
conformational change of Sro7 and prevents the interaction of the WD40 repeats
with Sec9, leading to regulation of the inhibitory activity of Sro7 on the
SNARE complex formation (14).
However, the solved structure of Sro7 lacks its VLD. Therefore, involvement of
the activity of the VLD in the conformational change of Sro7 remains
elusive.Genetic studies in Caenorhabditis elegans showed that TOM-1, an
ortholog of vertebrate tomosyn, inhibits the priming of synaptic vesicles, and
that this priming is modulated by the balance between TOM-1 and UNC-13
(15,
16). Tomosyn was also shown to
be involved in inhibition of the exocytosis of dense core granules in adrenal
chromaffin cells and PC12 cells
(17,
18). Thus, evidence is
accumulating that tomosyn acts as a negative regulator for formation of the
SNARE complex, thereby inhibiting various vesicle fusion events. However, the
precise molecular mechanism regulating the inhibitory action of tomosyn has
yet to be elucidated.In the present study, we show that the tail domain of tomosyn binds both
the WD40 repeats and the VLD and functions as a regulator for the inhibitory
activity of tomosyn on the SNARE complex formation. Our results indicate that
the probable conformational change of tomosyn mediated by the intramolecular
interactions of the tail domain serves for controlling the inhibitory activity
of the VLD. 相似文献
83.
Differential adaptation of high- and low-chill dormant peaches in winter through aquaporin gene expression and soluble sugar content 总被引:2,自引:0,他引:2
Suravoot Yooyongwech Sumiko Sugaya Yoshihiko Sekozawa Hiroshi Gemma 《Plant cell reports》2009,28(11):1709-1715
Plants have their own mechanisms for overcoming various stresses. In cold regions, plants are subject to stress and must enter
an inherent dormancy, through several complex mechanisms, if they are to continue to exist. In winter, regulation of tonoplast
and plasma membrane aquaporin genes differed in the bud cushions of the high-chill peach (Prunus persica L. Batsch) cv. Kansuke Hakuto and the low-chill peach cv. Coral. In December and January, when the temperature was lowest
(around 2°C), the increased expression of Pp-γTIP1 and Pp-PIP1 seen in the bud cushions of Kansuke Hakuto may have been related to the concomitant high-soluble sugar content of the cushions
of this cultivar. This relationship may have made the cells highly stable and relatively unaffected by low-temperature stress
owing to the presence of “glasses” that prevented ice nucleation. However, a simpler form of cold protection regulation seemed
to occur in Coral, in which there was no winter increase in Pp-γTIP1 and Pp-PIP1 mRNA and a slow decline in total soluble sugar content in December and January. These results suggested that Pp-γTIP1 and Pp-PIP1, respectively, play important roles in intra- and intercellular membrane transport, enhancing cold resistance in the bud
cushions of high-chill cultivars. In addition, Pp-δTIP1 and Pp-PIP2 mRNA increased at the end of endodormancy in both cultivars. This change may be induced by endodormancy-release signals and
the resumption of bud activity in both cultivars. 相似文献
84.
Noriyuki Iwabuchi Noritoshi Takahashi Jin-Zhong Xiao Sumiko Yonezawa Tomoko Yaeshima Keiji Iwatsuki & Satoshi Hachimura 《FEMS immunology and medical microbiology》2009,55(3):324-334
In human trials, Bifidobacterium longum BB536 alleviates subjective symptoms of Japanese cedar pollinosis, an IgE-mediated type I allergy caused by exposure to Japanese cedar, and significantly suppresses the increase of plasma thymus- and activation-regulated chemokine (TARC) associated with pollen dispersion. In the present study, we investigated the suppressive effects of BB536 on the production of T helper type 2 (Th2)-attracting chemokines, such as TARC and macrophage-derived chemokine (MDC), together with the mechanisms of their production. Murine splenocytes were cultured with heat-killed BB536, and the levels of Th2-attracting chemokines in the supernatants were measured. TARC and MDC were produced in cultures without stimulation, and the production was significantly suppressed by BB536. These chemokines were produced by antigen-presenting cells (APCs) of splenocytes stimulated with an anti-CD40 antibody. Furthermore, TARC production was induced with granulocyte macrophage colony-stimulating factor that was produced by T cells and dendritic cells. BB536 suppressed MDC production induced with the anti-CD40 antibody by APCs from the spleen, mesenteric lymph nodes (MLNs) and Peyer's patches, and it suppressed TARC production by APCs from the spleen and MLNs. These results indicate that BB536 suppresses the production of Th2-attracting chemokines induced by the T cell–APC interaction, suggesting a novel mechanism for alleviating symptoms of allergic disorders by probiotics. 相似文献
85.
86.
Yamamoto Y Mochida S Miyazaki N Kawai K Fujikura K Kurooka T Iwasaki K Sakisaka T 《The Journal of biological chemistry》2010,285(52):40943-40955
Neurotransmitter release is triggered by Ca(2+) binding to a low affinity Ca(2+) sensor, mostly synaptotagmin-1, which catalyzes SNARE-mediated synaptic vesicle fusion. Tomosyn negatively regulates Ca(2+)-dependent neurotransmitter release by sequestering target SNAREs through the C-terminal VAMP-like domain. In addition to the C terminus, the N-terminal WD40 repeats of tomosyn also have potent inhibitory activity toward Ca(2+)-dependent neurotransmitter release, although the molecular mechanism underlying this effect remains elusive. Here, we show that through its N-terminal WD40 repeats tomosyn directly binds to synaptotagmin-1 in a Ca(2+)-dependent manner. The N-terminal WD40 repeats impaired the activities of synaptotagmin-1 to promote SNARE complex-mediated membrane fusion and to bend the lipid bilayers. Decreased acetylcholine release from N-terminal WD40 repeat-microinjected superior cervical ganglion neurons was relieved by microinjection of the cytoplasmic domain of synaptotagmin-1. These results indicate that, upon direct binding, the N-terminal WD40 repeats negatively regulate the synaptotagmin-1-mediated step of Ca(2+)-dependent neurotransmitter release. Furthermore, we show that synaptotagmin-1 binding enhances the target SNARE-sequestering activity of tomosyn. These results suggest that the interplay between tomosyn and synaptotagmin-1 underlies inhibitory control of Ca(2+)-dependent neurotransmitter release. 相似文献
87.
Sumiko Minobe Shingo Fukui Rumiko Saiki Tadashi Kajita Suchitra Changtragoon Nor Aini Ab Shukor A. Latiff B. R. Ramesh Osamu Koizumi Tsuneyuki Yamazaki 《Conservation Genetics》2010,11(1):301-310
To evaluate the genetic diversity of a mangrove species and clarify the genetic structure of its populations, we studied nucleotide
polymorphism in two DNA regions of Bruguiera gymnorhiza collected from the southern islands of Japan, Thailand, Malaysia, Indonesia, Micronesia, and India. The two DNA sequences
were the chloroplast (cp) intergenic spacer between trnL and trnF genes (ca. 300 bp), and a part (ca. 550 bp) of the nuclear gene coding for glyceraldehyde-3-phosphate dehydrogenase (GapCp). Little polymorphism was found within each of the three geographical regions, Pacific Ocean, Bay of Bengal and Arabian Sea.
Throughout the vast regions east of the Malay peninsula including Indonesia, Thailand, Micronesia and the southern islands
of Japan (Pacific Ocean), essentially only one haplotype (apart from variation in number of a T repeat) was present. A second
haplotype was present on the western coast of Malay Peninsula and the eastern coast of India (Bay of Bengal). On the southwest
of Malay Peninsula both of these haplotypes were present. Finally a third haplotype was found only on the western coast of
India (Arabian Sea). When taken over all geographic populations, total nucleotide variation within the species was large (μ = 0.006, average of the two genes). Our results are consistent with the hypothesis that this low genetic diversity within
any local population and differentiation between the different oceans or regions are caused by very low gene flow between
each of the different oceans coupled with frequent fluctuation of population sizes due to the change in sea level. The significance
of these results is discussed from evolutionary point of the mangrove forests. 相似文献
88.
High-performance liquid chromatography with on-line electrospray ionization mass spectrometry (ESI-LC/MS) was investigated for the analysis of carbohydrate heterogeneity using RNase B as a model glycoprotein. Oligosaccharides released from RNase B with endoglycosidase H were reduced and separated on a graphitized carbon column (GCC). GCC-HPLC/MS in the positive-ion mode was successful in the identification of one Man5GlcNAc, three Man6GlcNAc, three Man7GlcNAc, three Man8GlcNAc, one Man9GlcNAc, and an oligosaccharide having six hexose units (Hex) and two N-acetylhexosamine units (HexNAc). The branch structures of the three Man7GlcNAc isomers were determined by liquid chromatography with tandem mass spectrometry (LC/MS/MS). LC/MS/MS analysis was shown to be useful for the detection and identification of a trace amount of Hex6HexNAc2 alditol as a hybrid-type oligosaccharide. Its structure was confirmed by the combination of LC/MS with enzymatic digestion using beta-galactosidase and N-acetyl-beta-glucosaminidase. The relative quantities of high-mannose-type oligosaccharides in RNase B detected by ESI-LC/MS are in reasonable agreement with those by UV, high-pH anion-exchange chromatography with pulsed amperometric detection, fluorophore-assisted carbohydrate electrophoresis. Our results indicate that LC/MS and LC/MS/MS can be utilized to elucidate the distribution of oligosaccharides and their structures, which differ in molecular weight, sugar sequence, and branch structure. 相似文献
89.
Mochida S Yoshimoto T Mimura S Inao M Matsui A Ohno A Koh H Saitoh E Nagoshi S Fujiwara K 《Biochemical and biophysical research communications》2004,317(1):114-120
Osteopontin, a crucial factor for Th1 immune response, is expressed in stellate cells and macrophages activated in injured liver. To clarify the role of osteopontin in inflammatory changes in the liver, we attempted to establish transgenic mice expressing osteopontin in hepatocytes. Mouse osteopontin cDNA, cloned from concanavalin-A-stimulated spleen cells in C57BL/6 mice, was constructed into the vector containing serum amyloid-P component promoter. This construction was microinjected into fertilized eggs of C57BL/6 mice, and 4 lines of the transgenic mice were obtained. Western blotting and immunohistochemistry revealed that osteopontin was expressed in hepatocytes, but not in non-parenchymal cells, in the transgenic mice. The mean osteopontin concentrations in the liver and plasma in the mice were 13 and 2.6 times higher than those in negative littermates. Antinuclear antibody was positive in the plasma in 50% of the transgenic mice. In the transgenic mice later than 12 weeks of age, mononuclear cell infiltration in the liver developed, and these cells were positive for CD8 and HLA-DR. Plasma ALT activity was increased with focal necrosis in hepatic lobules in the transgenic mice later than 24 weeks of age. The transgenic mice expressing osteopontin in hepatocytes may be useful as a model of autoimmune hepatitis. 相似文献
90.
Genetic polymorphims in promoter region of osteopontin gene may be a marker reflecting hepatitis activity in chronic hepatitis C patients 总被引:2,自引:0,他引:2
Mochida S Hashimoto M Matsui A Naito M Inao M Nagoshi S Nagano M Egashira T Mishiro S Fujiwara K 《Biochemical and biophysical research communications》2004,313(4):1079-1085
BACKGROUND AND AIMS: Osteopontin, an extracellular matrix protein with RGD motif, is shown to be a cytokine essential for Th1 immune response initiation. Genetic polymorphisms in the osteopontin gene (OPN) determine the magnitude of immunity against rickettsial infection in mice. Similar polymorphisms, if present also in human beings, might affect hepatitis activity in those infected with HCV. METHODS: Blood was collected from 176 patients with chronic hepatitis C. SNPs in the promoter region of OPN were analyzed in 20 patients by direct sequencing of DNA fragments amplified by PCR and in 156 patients by Invader assay. Ninety-five patients compatible to evaluation criteria were classified into three groups depending on maximal serum ALT levels during the observation periods at least for 2 years as follows; lower than 30IU/L (low-activity group), between 30 and 80IU/L with no hepatoprotective treatment (medium-activity group), and higher than 80IU/L irrespective of hepatoprotective treatment (high-activity group). RESULTS: There were 16, 19, and 60 patients in the low-, medium-, and high-activity groups, respectively. Four SNPs (nt -155, -443, -616, and -1748) were detected in the promoter region of OPN. Among them, the SNP at nt -443 (C or T) was a novel one and showed an association with hepatitis activity in our patients: T/T homozygosity was found in 2 (13%), 8 (42%), and 25 (44%), and C/T heterozygosity in 12 (75%), 8 (42%), and 23 (40%), in the low-, medium-, and high-activity groups, respectively. The other 3 SNPs already known showed linkage disequilibrium with D(') and r(2) greater than 0.937 to each other without correlation to disease activity. CONCLUSIONS. OPN promoter region SNP at nt -433 may be a useful marker reflecting hepatitis activity in chronic hepatitis C patients. 相似文献