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171.
We have reported previously that autophagy is responsible for amyloid precursor protein-C-terminal fragment (APP-CTF) degradation and therefore Aβ clearance. To elucidate the underlying mechanism, using LC3 affinity purification and mass spectrometry analysis, immunoprecipitation (IP), as well as live imaging analysis, we identified and demonstrated that the adaptor-related protein complex 2 (AP2) and PICALM (phosphatidylinositol binding clathrin assembly protein) are in a complex with LC3 and APP-CTF. Taken together, this new set of data suggests that the AP2-PICALM complex functions as an autophagic cargo receptor for the recognition and shipment of APP-CTF from the endocytic pathway to the LC3-dependent autophagic degradation pathway. Interestingly this AP2-LC3 connection seems to be involved in chemically-induced APP-CTF clearance as we observed using the small compound SMER28. The effect observed following SMER28 was significantly reduced after silencing AP2. While more work is required to elucidate the detailed molecular mechanisms involved, our actual data suggest that there is some level of specificity in the steps mentioned above. 相似文献
173.
E. Jortzik M. Farhadi R. Ahmadi K. Tóth J. Lohr B.M. Helmke S. Kehr A. Unterberg I. Ott R. Gust V. Deborde E. Davioud-Charvet R. Réau K. Becker C. Herold-Mende 《Biochimica et Biophysica Acta - Proteins and Proteomics》2014,1844(8):1415-1426
Glioblastoma, an aggressive brain tumor, has a poor prognosis and a high risk of recurrence. An improved chemotherapeutic approach is required to complement radiation therapy. Gold(I) complexes bearing phosphole ligands are promising agents in the treatment of cancer and disturb the redox balance and proliferation of cancer cells by inhibiting disulfide reductases. Here, we report on the antitumor properties of the gold(I) complex 1-phenyl-bis(2-pyridyl)phosphole gold chloride thio-β-d-glucose tetraacetate (GoPI-sugar), which exhibits antiproliferative effects on human (NCH82, NCH89) and rat (C6) glioma cell lines. Compared to carmustine (BCNU), an established nitrosourea compound for the treatment of glioblastomas that inhibits the proliferation of these glioma cell lines with an IC50 of 430 μM, GoPI-sugar is more effective by two orders of magnitude. Moreover, GoPI-sugar inhibits malignant glioma growth in vivo in a C6 glioma rat model and significantly reduces tumor volume while being well tolerated. Both the gold(I) chloro- and thiosugar-substituted phospholes interact with DNA albeit more weakly for the latter. Furthermore, GoPI-sugar irreversibly and potently inhibits thioredoxin reductase (IC50 4.3 nM) and human glutathione reductase (IC50 88.5 nM). However, treatment with GoPI-sugar did not significantly alter redox parameters in the brain tissue of treated animals. This might be due to compensatory upregulation of redox-related enzymes but might also indicate that the antiproliferative effects of GoPI-sugar in vivo are rather based on DNA interaction and inhibition of topoisomerase I than on the disturbance of redox equilibrium. Since GoPI-sugar is highly effective against glioblastomas and well tolerated, it represents a most promising lead for drug development. This article is part of a Special Issue entitled: Thiol-Based Redox Processes. 相似文献
174.
Sabrina Thomas Patrick J. BakkesSander H.J. Smits Lutz Schmitt 《Biochimica et Biophysica Acta - Proteins and Proteomics》2014,1844(9):1500-1510
HlyA from Escherichia coli is a member of the repeats in toxin (RTX) protein family, produced by a wide range of Gram-negative bacteria and secreted by a dedicated Type 1 Secretion System (T1SS). RTX proteins are thought to be secreted in an unfolded conformation and to fold upon secretion by Ca2 + binding. However, the exact mechanism of secretion, ion binding and folding to the correct native state remains largely unknown. In this study we provide an easy protocol for high-level pro-HlyA purification from E. coli. Equilibrium folding studies, using intrinsic tryptophan fluorescence, revealed the well-known fact that Ca2 + is essential for stability as well as correct folding of the whole protein. In the absence of Ca2 +, pro-HlyA adopts a non-native conformation. Such molecules could however be rescued by Ca2 + addition, indicating that these are not dead-end species and that Ca2 + drives pro-HlyA folding. More importantly, pro-HlyA unfolded via a two-state mechanism, whereas folding was a three-state process. The latter is indicative of the presence of a stable folding intermediate. Analysis of deletion and Trp mutants revealed that the first folding transition, at 6–7 M urea, relates to Ca2 + dependent structural changes at the extreme C-terminus of pro-HlyA, sensed exclusively by Trp914. Since all Trp residues of HlyA are located outside the RTX domain, our results demonstrate that Ca2 + induced folding is not restricted to the RTX domain. Taken together, Ca2 + binding to the pro-HlyA RTX domain is required to drive the folding of the entire protein to its native conformation. 相似文献
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176.
杂交水稻及其“三系”线粒体DNA的AP—PCR指纹图谱 总被引:22,自引:1,他引:22
为了研究水稻(Oryza sativa L.)细胞质雄性不育(CMS)与线粒体基因组的关系,应用AP-PCR 分析,用7 个任意单引物对6 种水稻品系线粒体DNA 进行了扩增。水稻线粒体DNA 的AP-PCR 产物可分为三种类型:(1)所有供试品系均能扩增的片段,它们代表了线粒体DNA 在进化上的保守性序列。有4 个引物检测到这类片段。(2)2 个以上水稻品系共同出现而在全部供试材料间存在差异的扩增片段,这类片段是检测水稻线粒体DNA多态性的主要来源。(3)一种细胞质类型所特有的扩增片段,从引物R2 和V5 的扩增产物中发现了这类片段,它们可能与CMS有关联。另外,WA型不育系珍汕97A 与其杂种之间在6 个引物的扩增图谱上均存在不同程度的差异,说明两者的线粒体DNA序列结构可能存在某种差别 相似文献
177.
Genome‐wide dissection of AP2/ERF and HSP90 gene families in five legumes and expression profiles in chickpea and pigeonpea 下载免费PDF全文
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180.
Thomas Schmitt Stefan Lange Stefan Sonnenberger Bodo Dobner Bruno Demé Andreas Langner Reinhard H.H. Neubert 《生物化学与生物物理学报:生物膜》2019,1861(1):306-315
This study used neutron diffraction to investigate a ceramide-[NP] C24/[AP] C24 /[EOS]-br C30/cholesterol/lignoceric acid (0.6: 0.3: 0.1: 0.7: 1) based stratum corneum modelling system. By adding specifically deuterated ceramides-[NP]-D3, [AP]-D3, and [EOS]-br-D3, detailed information on the lamellar and the nanostructure of the system was obtained. For the short periodicity phase a natural-like lamellar repeat distance of 5.47?±?0.02?nm was observed, similar to the [NP]/[AP] base system without the [EOS]-br. Unlike in this system the ceramides here were slightly tilted, hinting towards a slightly less natural arrangement. Due to the deuteration it was possible to observe that the long ceramide chains were overlapping in the lamellar mid-plane. This is considered to be an important feature for the natural stratum corneum. Despite the presence of a ceramide [EOS] analogue – able to form a long phase arrangement – no distinct long periodicity phase was formed, despite a slightly higher than natural ω-acyl ceramide ratio of 10?mol%. The deuterated variant of this ceramide determined that the very long ceramide was integrated into the short periodicity phase, spanning multiple layers instead. The – compared to the base system – unchanged repeat distance highlights the stability of this structure. Furthermore, the localisation of the very long ceramide in the short periodicity phase indicates the possibility of a crosslinking effect and thus a multilayer stabilizing role for the ceramide [EOS]. It can be concluded, that additionally to the mere presence of ceramide-[EOS] more complex conditions have to be met in order to form this long phase. This has to be further investigated in the future. 相似文献