共查询到20条相似文献，搜索用时 10 毫秒
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R. J. Oliver J. L. Brigman F. Bolognani A. M. Allan J. L. Neisewander N. I. Perrone‐Bizzozero 《Genes, Brain & Behavior》2018,17(4)
The neuronal RNA‐binding protein HuD is involved in synaptic plasticity and learning and memory mechanisms. These effects are thought to be due to HuD‐mediated stabilization and translation of target mRNAs associated with plasticity. To investigate the potential role of HuD in drug addiction, we first used bioinformatics prediction algorithms together with microarray analyses to search for specific genes and functional networks upregulated within the forebrain of HuD overexpressing mice (HuDOE). When this set was further limited to genes in the knowledgebase of addiction‐related genes database (KARG) that contains predicted HuD‐binding sites in their 3′ untranslated regions (3′UTRs), we found that HuD regulates networks that have been associated with addiction‐like behavior. These genes included Bdnf and Camk2a, 2 previously validated HuD targets. Since addiction is hypothesized to be a disorder stemming from altered gene expression causing aberrant plasticity, we sought to test the role of HuD in cocaine conditioned placed preference (CPP), a model of addiction‐related behaviors. HuD mRNA and protein were upregulated by CPP within the nucleus accumbens of wild‐type C57BL/6J mice. These changes were associated with increased expression of Bdnf and Camk2a mRNA and protein. To test this further, we trained HuDOE and wild‐type mice in CPP and found that HuDOE mice showed increased cocaine CPP compared with controls. This was also associated with elevated expression of HuD target mRNAs and proteins, CaMKIIα and BDNF. These findings suggest HuD involvement in addiction‐related behaviors such as cocaine conditioning and seeking, through increased plasticity‐related gene expression. 相似文献
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Robert J. Kelm Jr Gurpreet S. Lamba Jamie E. Levis Chris E. Holmes 《Journal of cellular biochemistry》2018,119(2):2073-2083
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Tri Duc Ngo Bum Han Ryu Hansol Ju Eun Jin Jang Kyeong Kyu Kim T. Doohun Kim 《Acta Crystallographica. Section D, Structural Biology》2014,70(9):2455-2466
Interest in penicillin‐binding proteins and β‐lactamases (the PBP‐βL family) is increasing owing to their biological and clinical significance. In this study, the crystal structure of Est‐Y29, a metagenomic homologue of the PBP‐βL family, was determined at 1.7 Å resolution. In addition, complex structures of Est‐Y29 with 4‐nitrophenyl phosphate (4NP) and with diethyl phosphonate (DEP) at 2.0 Å resolution were also elucidated. Structural analyses showed that Est‐Y29 is composed of two domains: a β‐lactamase fold and an insertion domain. A deep hydrophobic patch between these domains defines a wide active site, and a nucleophilic serine (Ser58) residue is located in a groove defined primarily by hydrophobic residues between the two domains. In addition, three hydrophobic motifs, which make up the substrate‐binding site, allow this enzyme to hydrolyze a wide variety of hydrophobic compounds, including fish and olive oils. Furthermore, cross‐linked Est‐Y29 aggregates (CLEA‐Est‐Y29) significantly increase the stability of the enzyme as well as its potential for extensive reuse in various deactivating conditions. The structural features of Est‐Y29, together with biochemical and biophysical studies, could provide a molecular basis for understanding the properties and regulatory mechanisms of the PBP‐βL family and their potential for use in industrial biocatalysts. 相似文献
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From humble beginnings of a contaminated petri dish, β‐lactam antibiotics have distinguished themselves among some of the most powerful drugs in human history. The devastating effects of antibiotic resistance have nevertheless led to an “arms race” with disquieting prospects. The emergence of multidrug resistant bacteria threatens an ever‐dwindling antibiotic arsenal, calling for new discovery, rediscovery, and innovation in β‐lactam research. Here the current state of β‐lactam antibiotics from a structural perspective was reviewed. 相似文献
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《Peptide Science》2017,108(3)
The conformational characteristics of protected homo‐oligomeric Boc‐[β3(R)Val]n‐OMe, n = 1, 2, 3, 4, 6, 9, and 12 have been investigated in organic solvents using nuclear magnetic resonance (NMR), Fourier transform infrared (FTIR) absorption spectroscopy and circular dichroism (CD) methods. The detailed 1H NMR analysis of Boc‐[β3(R)Val]12‐OMe reveals that the peptide aggregates extensively in CDCl3, but is disaggregated in 20%, (v/v) dimethyl sulfoxide (DMSO) in CDCl3 and in CD3OH. Limited assignment of the N‐terminus NH groups, together with solvent dependence of NH chemical shifts and temperature coefficients provides evidence for 14‐helix conformation in the 12‐residue peptide. FTIR analysis in CHCl3 establishes that the onset of folding and aggregation, as evidenced by NH stretching bands at 3375 cm−1 (intramolecular) and 3285 cm−1 (intermolecular), begins at the level of the tetrapeptide. The observed CD bands, 214 nm (negative) and 198 nm (positive), support 14‐helix formation in the 9 and 12 residue sequences. The folding and aggregation tendencies of homo‐oligomeric α‐, β‐, and γ‐ residues is compared in the model peptides Boc‐[ωVal]n‐NHMe, ω = α, β, and γ and n = 1, 2, and 3. Analysis of the FTIR spectra in CHCl3, establish that the tendency to aggregate at the di and tripeptide level follows the order β > α∼γ, while the tendency to fold follows the order γ > β > α. 相似文献
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Masaaki Aoki Mariko Iwamoto‐Sugai Ikuko Sugiura Chizuko Sasaki Tsukasa Hasegawa Chieko Okumura Shigetoshi Sugio Toshiyuki Kohno Takao Matsuzaki 《Acta Crystallographica. Section D, Structural Biology》2000,56(11):1464-1465
Human tau‐protein kinase I (TPK‐I; also known as glycogen synthase kinase‐3β, GSK‐3β) is a serine/threonine protein kinase. Full‐length TPK‐I/GSK‐3β was expressed in Escherichia coli as a fusion protein with a 6×His tag at the C‐terminus and was crystallized using the hanging‐drop vapour‐diffusion method. Prismatic crystals of dimensions 0.4 × 0.2 × 0.1 mm were obtained using 12–15%(w/v) polyethylene glycol 6000 as a precipitant at 278 K. The crystals belong to the orthorhombic space group P212121, with unit‐cell parameters a = 82.9, b = 86.1, c = 178.1 Å measured at 100 K, diffract to 2.3 Å resolution and seem to contain two enzyme molecules per asymmetric unit. 相似文献
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RG13 is a 72 kDa engineered allosteric enzyme comprised of a fusion between maltose binding protein (MBP) and TEM1 β‐lactamase (BLA) for which maltose is a positive effector of BLA activity. We have used NMR spectroscopy to acquire [15N, 1H]‐TROSY‐HSQC spectra of RG13 in the presence and absence of maltose. The RG13 chemical shift data was compared to the published chemical shift data of MBP and BLA. The spectra are consistent with the expectation that the individual domain structures of RG13 are substantially conserved from MBP and BLA. Differences in the spectra are consistent with the fusion geometry of MBP and BLA and the maltose‐dependent differences in the kinetics of RG13 enzyme activity. In particular, the spectra provide evidence for a maltose‐dependent conformational change of a key active site glutamate involved in deacylation of the enzyme‐substrate intermediate. Proteins 2010. © 2009 Wiley‐Liss, Inc. 相似文献
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Ariyama Y Shimizu H Satoh T Tsuchiya T Okada S Oyadomari S Mori M Mori M 《Obesity (Silver Spring, Md.)》2007,15(7):1647-1656
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Pu Wang Pei‐Pei Guan Jing‐Wen Guo Long‐Long Cao Guo‐Biao Xu Xin Yu Yue Wang Zhan‐You Wang 《Aging cell》2016,15(5):861-871
Cyclooxygenase‐2 (COX‐2) has been recently identified to be involved in the pathogenesis of Alzheimer's disease (AD). Yet, the role of an important COX‐2 metabolic product, prostaglandin (PG) I2, in the pathogenesis of AD remains unknown. Using human‐ and mouse‐derived neuronal cells as well as amyloid precursor protein/presenilin 1 (APP/PS1) transgenic mice as model systems, we elucidated the mechanism of anterior pharynx‐defective (APH)‐1α and pharynx‐defective‐1β induction. In particular, we found that PGI2 production increased during the course of AD development. Then, PGI2 accumulation in neuronal cells activates PKA/CREB and JNK/c‐Jun signaling pathways by phosphorylation, which results in APH‐1α/1β expression. As PGI2 is an important metabolic by‐product of COX‐2, its suppression by NS398 treatment decreases the expression of APH‐1α/1β in neuronal cells and APP/PS1 mice. More importantly, β‐amyloid protein (Aβ) oligomers in the cerebrospinal fluid (CSF) of APP/PS1 mice are critical for stimulating the expression of APH‐1α/1β, which was blocked by NS398 incubation. Finally, the induction of APH‐1α/1β was confirmed in the brains of patients with AD. Thus, these findings not only provide novel insights into the mechanism of PGI2‐induced AD progression but also are instrumental for improving clinical therapies to combat AD. 相似文献
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Balu Chakravarthy Michel Ménard Leslie Brown Melissa Hewitt Trevor Atkinson James Whitfield 《Journal of neurochemistry》2013,126(3):415-424
We have recently reported that a ~19‐kDa polypeptide, rPK‐4, is a protein kinase Cs inhibitor that is 89% homologous to the 1171–1323 amino acid region of the 228‐kDa human pericentriolar material‐1 (PCM‐1) protein (Chakravarthy et al. 2012). We have now discovered that rPK‐4 binds oligomeric amyloid‐β peptide (Aβ)1‐42 with high affinity. Most importantly, a PCM‐1‐selective antibody co‐precipitated Aβ and amyloid β precursor protein (AβPP) from cerebral cortices and hippocampi from AD (Alzheimer's disease) transgenic mice that produce human AβPP and Aβ1‐42, suggesting that PCM‐1 may interact with amyloid precursor protein/Aβ in vivo. We have identified rPK‐4′s Aβ‐binding domain using a set of overlapping synthetic peptides. We have found with ELISA, dot‐blot, and polyacrylamide gel electrophoresis techniques that a ~ 5 kDa synthetic peptide, amyloid binding peptide (ABP)‐p4‐5 binds Aβ1‐42 at nM levels. Most importantly, ABP‐p4‐5, like rPK‐4, appears to preferentially bind Aβ1‐42 oligomers, believed to be the toxic AD‐drivers. As expected from these observations, ABP‐p4‐5 prevented Aβ1‐42 from killing human SH‐SY5Y neuroblastoma cells via apoptosis. These findings indicate that ABP‐p4‐5 is a possible candidate therapeutic for AD. 相似文献
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Ann L Cornish Caroline E Sutton Joanne O'Donnell Louise H Cengia Andrew W Roberts Ian P Wicks Kingston H G Mills Ben A Croker 《EMBO reports》2010,11(8):640-646
Reports describing the effect of interferon‐γ (IFNγ) on interleukin‐1β (IL‐1β) production are conflicting. We resolve this controversy by showing that IFNγ potentiates IL‐1β release from human cells, but transiently inhibits the production of IL‐1β from mouse cells. Release from this inhibition is dependent on suppressor of cytokine signalling 1. IL‐1β and Th17 cells are pathogenic in mouse models for autoimmune disease, which use Mycobacterium tuberculosis (MTB), in which IFNγ and IFNβ are anti‐inflammatory. We observed that these cytokines suppress IL‐1β production in response to MTB, resulting in a reduced number of IL‐17‐producing cells. In human cells, IFNγ increased IL‐1β production, and this might explain why IFNγ is detrimental for multiple sclerosis. In mice, IFNγ decreased IL‐1β and subsequently IL‐17, indicating that the adaptive immune response can provide a systemic, but transient, signal to limit inflammation. 相似文献
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Vanessa Delfosse Jean‐Emmanuel Hugonnet Wladimir Sougakoff Claudine Mayer 《Acta Crystallographica. Section F, Structural Biology Communications》2005,61(11):1006-1008
The genome of the hyperthermophilic archaeon Pyrococcus abyssi contains a gene (pab0087) encoding a penicillin‐binding protein (PBP) homologue. This sequence consists of 447 residues and shows significant sequence similarity to low‐molecular‐weight PBPs and class C β‐lactamases. The Pab0087 protein was overexpressed, purified and crystallized. Diffraction data from two different crystal forms were collected to 2.7 and 2.0 Å resolution. Both crystals belong to space group C2, with unit‐cell parameters a = 160.59, b = 135.74, c = 113.02 Å, β = 117.36° and a = 166.97, b = 131.25, c = 189.39 Å, β = 113.81°, respectively. The asymmetric unit contains four and eight molecules, respectively, with fourfold non‐crystallographic symmetry. 相似文献
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Vivek Malhotra 《The EMBO journal》2013,32(12):1660-1664
The process by which proteins are secreted without entering the classical endoplasmic reticulum (ER)–Golgi complex pathway, in eukaryotic cells, is conveniently called unconventional protein secretion. Recent studies on one such protein called Acb1 have revealed a number of components involved in its secretion. Interestingly, conditions that promote the secretion of Acb1 trigger the biogenesis of a new compartment called CUPS (Compartment for Unconventional Protein Secretion). CUPS form near the ER exit site but lack ER‐specific proteins. Other proteins that share some of the features common with the secretion of Acb1 are interleukin‐1β and tissue transglutaminase. Here I will review recent advances made in the field and propose a new model for unconventional protein secretion. 相似文献
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The stress response neuropeptide CRF increases amyloid‐β production by regulating γ‐secretase activity 
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下载免费PDF全文 Hyo‐Jin Park Yong Ran Joo In Jung Oliver Holmes Ashleigh R Price Lisa Smithson Carolina Ceballos‐Diaz Chul Han Michael S Wolfe Yehia Daaka Andrey E Ryabinin Seong‐Hun Kim Richard L Hauger Todd E Golde Kevin M Felsenstein 《The EMBO journal》2015,34(12):1674-1686
The biological underpinnings linking stress to Alzheimer's disease (AD) risk are poorly understood. We investigated how corticotrophin releasing factor (CRF), a critical stress response mediator, influences amyloid‐β (Aβ) production. In cells, CRF treatment increases Aβ production and triggers CRF receptor 1 (CRFR1) and γ‐secretase internalization. Co‐immunoprecipitation studies establish that γ‐secretase associates with CRFR1; this is mediated by β‐arrestin binding motifs. Additionally, CRFR1 and γ‐secretase co‐localize in lipid raft fractions, with increased γ‐secretase accumulation upon CRF treatment. CRF treatment also increases γ‐secretase activity in vitro, revealing a second, receptor‐independent mechanism of action. CRF is the first endogenous neuropeptide that can be shown to directly modulate γ‐secretase activity. Unexpectedly, CRFR1 antagonists also increased Aβ. These data collectively link CRF to increased Aβ through γ‐secretase and provide mechanistic insight into how stress may increase AD risk. They also suggest that direct targeting of CRF might be necessary to effectively modulate this pathway for therapeutic benefit in AD, as CRFR1 antagonists increase Aβ and in some cases preferentially increase Aβ42 via complex effects on γ‐secretase. 相似文献
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Cheril Tapia‐Rojas Patricia V. Burgos Nibaldo C. Inestrosa 《Journal of neurochemistry》2016,139(6):1175-1191