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1.
Compartmentation of glutamate metabolism in brain. Evidence for the existence of two different tricarboxylic acid cycles in brain 总被引:18,自引:9,他引:9
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1. (14)C from [1-(14)C]glucose injected intraperitoneally into mice is incorporated into glutamate, aspartate and glutamine in the brain to a much greater extent than (14)C from [2-(14)C]glucose. This difference for [1-(14)C]glucose and [2-(14)C]glucose increases with time. The amount of (14)C in C-1 of glutamate increases steadily with time with both precursors. It is suggested that a large part of the glutamate and aspartate pools in brain are in close contact with intermediates of a fast-turning tricarboxylic acid cycle. 2. (14)C from [1-(14)C]acetate and [2-(14)C]acetate is incorporated to a much larger extent into glutamine than into glutamate. An examination of the time-course of (14)C incorporated into glutamine and glutamate reveals that glutamine is not formed from the glutamate pool, labelled extensively by glucose, but from a small glutamate pool. This small glutamate pool is not derived from an intermediate of a fast-turning tricarboxylic acid cycle. 3. It is proposed that two different tricarboxylic acid cycles exist in brain. 相似文献
2.
Identification of the site of phosphorylation of the chemotaxis response regulator protein, CheY 总被引:30,自引:0,他引:30
D A Sanders B L Gillece-Castro A M Stock A L Burlingame D E Koshland 《The Journal of biological chemistry》1989,264(36):21770-21778
The protein (Escherichia coli CheY) that controls the direction of flagellar rotation during bacterial chemotaxis has been shown to be phosphorylated on the aspartate 57 residue. The residue phosphorylated is present within a conserved sequence in every member of a family of bacterial regulatory proteins. The phosphorylation is transient, with a much shorter half-life than that expected of a simple acyl phosphate intermediate, indicating that the sequence and conformation of the protein is designed to achieve a rapid hydrolysis. The CheY-phosphate linkage can be reductively cleaved by sodium borohydride. High-performance tandem mass-spectrometric analysis of proteolytic peptides derived from [3H]borohydride-reduced phosphorylated CheY protein was used to identify the position of phosphorylation. Mutants with altered aspartate 57 exhibited no chemotaxis. When aspartate 13, another conserved residue, was changed, greatly reduced chemotaxis was observed, suggesting an important role for aspartate 13. The rate-determining step of chemotactic signaling is governed by the kinetics of formation and hydrolysis of the CheY protein phosphoaspartate bond. The CheY protein apparently functions as a protein phosphatase that possesses a transient covalent intermediate. Transient phosphorylation of an aspartate residue is an effective mechanism for producing a biochemical signal with a short concentration-independent half-life. The duration of the signal can be controlled by small structural elements within the phosphorylated protein. 相似文献
3.
Autoantibody to the nucleosome subunit (H2A-H2B)-DNA is an early and ubiquitous feature of lupus-like conditions 总被引:2,自引:0,他引:2
Chromatin, a huge polymer of nucleosomes, has been implicated as an important target of autoantibodies in idiopathic and drug-induced lupus for decades, but the antigenicity of chromatin has only recently been dissected. IgG reactivity with the (H2A-H2B)-DNA complex, a subunit of the nucleosome, is present in the majority of patients with systemic lupus erythematosus, in >90% of patients with lupus induced by procainamide and in individual patients with lupus induced by a variety of other drugs, but is not seen in people taking these medications who are clinically asymptomatic. Anti-[(H2A-H2B)-DNA] accounted for the bulk of the anti-chromatin activity in drug-induced lupus. The earliest detectable autoantibody in lupus-prone mice recognized similar epitopes in the (H2A-H2B)-DNA subnucleosome complex; as the immune response progressed, native DNA and other constituents of chromatin became antigenic. The importance of chromatin-reactive T cells in the anti-[(H2A-H2B)-DNA] response is suggested by the presence of somatic mutations in antibody VH and VL regions, their perdominant IgG isotype and the similarity in kinetics of their production to that of conventional T cell dependent antigens. Together with the serologic data from human lupus-like disease, these results are consistent with chromatin being a common stimulant for both B and T cells. While chromatin-reactive antibodies are closely associated with systemic disease and have recently been implicated in glomerulonephritis in SLE, the absence of renal disease in drug-induced lupus indicates that additional abnormalities are required to manifest the serious pathogenic potential of anti-[(H2A-H2B)-DNA] antibodies.Abbreviations APC
antigen present cells
- DIL
drug-induced lupus
- ELISA
enzyme-linked immunosorbent assay
- GBM
glomerular basement membrane
- [(H2A-H2B)-DNA]
an intermolecular complex consisting of DNA and a dimer of histones H2A and H2B
- nDNA
native (double-stranded) DNA
- SLE
systemic lupus erythematosus 相似文献
4.
Joseph H. Sellin Roland DeSoignie Susan Burlingame 《The Journal of membrane biology》1993,136(2):147-158
Short-chain fatty acids (SCFAs) are the predominant luminal anion in the mammalian colon. Although they are rapidly absorbed
in vivo, little is known about the mechanisms of transepithelial transport in vitro. Previous studies have suggested that
SCFA transport may be linked to Na absorption or an anion exchange mechanism. We compared the transport of propionate under
short-circuit conditions in rabbit proximal and distal colon to determine whether there were segmental differences, how SCFAs
may be linked to either Na absorption or anion transport, and whether SCFAs, as weak electrolytes, may be affected by transepithelial
pH gradients. In distal colon, propionate transport was not significantly altered by stimulation of electrogenic Na absorption,
epinephrine or Cl removal. However, a modest transepithelial pH gradient (luminal 6.8/serosal 7.4) stimulated propionate absorption.
In proximal colon, propionate transport was significantly altered by manuevers that either stimulated (lowered [Na] in the
bathing media) or inhibited (theophylline) apical Na−H exchange. Neither Cl removal, nor the anion exchange inhibitor DIDS,
nor a transepithelial bicarbonate gradient, altered propionate transport. A transepithelial pH gradient inhibited propionate
secretion, but not in a manner entirely consistent with the effect of pH on the distribution of a weak electrolyte. These
results suggest that there is significant segmental heterogeneity in colonic SCFA transport; that transepithelial propionate
fluxes are altered by changes in pH or electroneutral Na absorption (Na−H exchange), but not by chloride removal, bicarbonate
gradients or electrogenic Na absorption. Regulation of SCFA transport may be an important factor in the physiology of colonic
fluid balance. 相似文献
5.
Identification of glycoinositol phospholipid linked and truncated forms of the scrapie prion protein 总被引:9,自引:0,他引:9
Analysis of carboxy-terminal peptides derived from endoproteinase Lys-C digests of the scrapie isoform of the hamster prion protein revealed that the majority of the molecules are glycoinositol phospholipid linked through ethanolamine attached at serin-231. However, approximately 15% of PrPSc had a carboxy-terminal peptide that ends at glycine-228. It is intriguing that this glycine is part of the PrP sequence Gly-Arg-Arg, which is an established target sequence for the proteolysis and release of bioactive peptides from larger precursors. The mechanism of formation, as well as the role of the truncated carboxy terminus in the dissemination and neuropathology of scrapie, remains to be determined. 相似文献
6.
7.
Yi Liu Michael J. Trnka Shenheng Guan Doyoung Kwon Do-Hyung Kim J.-J. Chen Peter A. Greer A. L. Burlingame Maria Almira Correia 《Molecular & cellular proteomics : MCP》2020,19(12):1968-1986
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- •Liver Mallory-Denk-Body inducers elicited an IκBα-loss and NF-κB-activation.
- •IκBα-loss was due to its sequestration into insoluble cytoplasmic aggregates.
- •Four proteomic approaches identified 10 IκBα-interacting/aggregating proteins.
- •Nup153/RanBP2-aggregation prevented IκBα nuclear entry for ending NF-κB-activation.
8.
Jonathan C. Trinidad Agnes Thalhammer Alma L. Burlingame Ralf Schoepfer 《Molecular & cellular proteomics : MCP》2013,12(1):29-41
Synapses are highly dynamic structures that mediate cell–cell communication in the central nervous system. Their molecular composition is altered in an activity-dependent fashion, which modulates the efficacy of subsequent synaptic transmission events. Whereas activity-dependent trafficking of individual key synaptic proteins into and out of the synapse has been characterized previously, global activity-dependent changes in the synaptic proteome have not been studied.To test the feasibility of carrying out an unbiased large-scale approach, we investigated alterations in the molecular composition of synaptic spines following mass stimulation of the central nervous system induced by pilocarpine. We observed widespread changes in relative synaptic abundances encompassing essentially all proteins, supporting the view that the molecular composition of the postsynaptic density is tightly regulated. In most cases, we observed that members of gene families displayed coordinate regulation even when they were not known to physically interact.Analysis of correlated synaptic localization revealed a tightly co-regulated cluster of proteins, consisting of mainly glutamate receptors and their adaptors. This cluster constitutes a functional core of the postsynaptic machinery, and changes in its size affect synaptic strength and synaptic size. Our data show that the unbiased investigation of activity-dependent signaling of the postsynaptic density proteome can offer valuable new information on synaptic plasticity.Excitatory synaptic transmission is the primary mode of cell–cell communication in the central nervous system. The efficacy of synaptic transmission is highly regulated, and alterations in the strength of synaptic signaling within networks of neurons provide a mechanism for learning and memory storage, as well as for overall network stability. Modulation of synapse efficacy can occur through alterations in the structure and composition of the postsynaptic spine. The synaptic abundance of several molecules has been shown to be regulated in response to activity (1).The levels of individual proteins at postsynaptic spines are regulated through multiple processes. Active transport mechanisms exist and have been well characterized for AMPA-type glutamate receptors (AMPA-Rs)1 via either insertion into the synapse or tighter association with the postsynaptic density (PSD) following lateral diffusion within the cell membrane (2). In addition to AMPA-Rs, other proteins known to be subject to activity-dependent regulation include calcium calmodulin-dependent protein kinase II alpha and beta, NMDA-type glutamate receptors (NMDA-Rs), and proteosome subunits (3–5). Synaptic protein content is dysregulated in a number of neuropsychiatric and neurodegenerative diseases, including Alzheimer''s disease and fragile X mental retardation (6–8).Most studies reported thus far have focused on a small number of selected molecules in individual experiments using a subset of synapses. Whereas learning and memory rely on the differential response of individual synapses to their specific input patterns, overall network excitability has to be maintained by homeostatic means. This homeostasis is governed by multiple pathways, and very little is known about the principles that regulate synaptic protein content across large numbers of synapses and neurons. The contributions of individual pathways and the interactions among them are largely unknown.In order to explore synaptic dynamics with a global view, we took advantage of a chemically induced mass stimulation protocol to stimulate synapses broadly throughout the central nervous system. We employed mass spectrometry and isotopically encoded isobaric peptide tagging with the iTRAQ reagent to quantify changes in the abundance of 893 proteins (9). We then analyzed changes in the relative abundance of these proteins at 0, 10, 20, and 60 min after the onset of stimulation.We observed evidence of the coordinated activation of synaptic protein groups, thereby identifying functional core complexes within the PSD. We demonstrate that adopting a quantitative systems biology approach provides insight allowing for a new level of analysis of synaptic function. 相似文献
9.
Janine O. Ilagan Robert J. Chalkley A.L. Burlingame Melissa S. Jurica 《RNA (New York, N.Y.)》2013,19(3):400-412
In spliceosomes, dynamic RNA/RNA and RNA/protein interactions position the pre-mRNA substrate for the two chemical steps of splicing. Not all of these interactions have been characterized, in part because it has not been possible to arrest the complex at clearly defined states relative to chemistry. Previously, it was shown in yeast that the DEAD/H-box protein Prp22 requires an extended 3′ exon to promote mRNA release from the spliceosome following second-step chemistry. In line with that observation, we find that shortening the 3′ exon blocks cleaved lariat intron and mRNA release in human splicing extracts, which allowed us to stall human spliceosomes in a new post-catalytic complex (P complex). In comparison to C complex, which is blocked at a point following first-step chemistry, we detect specific differences in RNA substrate interactions near the splice sites. These differences include extended protection across the exon junction and changes in protein crosslinks to specific sites in the 5′ and 3′ exons. Using selective reaction monitoring (SRM) mass spectrometry, we quantitatively compared P and C complex proteins and observed enrichment of SF3b components and loss of the putative RNA-dependent ATPase DHX35. Electron microscopy revealed similar structural features for both complexes. Notably, additional density is present when complexes are chemically fixed, which reconciles our results with previously reported C complex structures. Our ability to compare human spliceosomes before and after second-step chemistry has opened a new window to rearrangements near the active site of spliceosomes, which may play roles in exon ligation and mRNA release. 相似文献
10.