排序方式: 共有15条查询结果,搜索用时 15 毫秒
1.
2.
3.
Studying protein ubiquitination is difficult due to the complexity of the E1–E2–E3 ubiquitination cascade. Here we report the discovery that C-terminal ubiquitin thioesters can undergo direct transthiolation with the catalytic cysteine of the model HECT E3 ubiquitin ligase Rsp5 to form a catalytically active Rsp5∼ubiquitin thioester (Rsp5∼Ub). The resulting Rsp5∼Ub undergoes efficient autoubiquitination, ubiquitinates protein substrates, and synthesizes polyubiquitin chains with native Ub isopeptide linkage specificity. Since the developed chemical system bypasses the need for ATP, E1 and E2 enzymes while maintaining the native HECT E3 mechanism, we named it “Bypassing System” (ByS). Importantly, ByS provides direct evidence that E2 enzymes are dispensable for K63 specific isopeptide bond formation between ubiquitin molecules by Rsp5 in vitro. Additionally, six other E3 enzymes including Nedd4-1, Nedd4-2, Itch, and Wwp1 HECT ligases, along with Parkin and HHARI RBR ligases processed Ub thioesters under ByS reaction conditions. These findings provide general mechanistic insights on protein ubiquitination, and offer new strategies for assay development to discover pharmacological modulators of E3 enzymes. 相似文献
4.
Proteasome inhibitors have revolutionized the treatment of multiple myeloma, and validated the therapeutic potential of the ubiquitin proteasome system (UPS). It is believed that in part, proteasome inhibitors elicit their therapeutic effect by inhibiting the degradation of misfolded proteins, which is proteotoxic and causes cell death. In spite of these successes, proteasome inhibitors are not effective against solid tumors, thus necessitating the need to explore alternative approaches. Furthermore, proteasome inhibitors lead to the formation of aggresomes that clear misfolded proteins via the autophagy–lysosome degradation pathway. Importantly, aggresome formation depends on the presence of polyubiquitin tags on misfolded proteins. We therefore hypothesized that inhibitors of ubiquitin conjugation should inhibit both degradation of misfolded proteins, and ubiquitin dependent aggresome formation, thus outlining the path forward toward more effective anticancer therapeutics. To explore the therapeutic potential of targeting the UPS to treat solid cancers, we have developed an inhibitor of ubiquitin conjugation (ABP A3) that targets ubiquitin and Nedd8 E1 enzymes, enzymes that are required to maintain the activity of the entire ubiquitin system. We have shown that ABP A3 inhibits conjugation of ubiquitin to intracellular proteins and prevents the formation of cytoprotective aggresomes in A549 lung cancer cells. Furthermore, ABP A3 induces activation of the unfolded protein response and apoptosis. Thus, similar to proteasome inhibitors MG132, bortezomib, and carfilzomib, ABP A3 can serve as a novel probe to explore the therapeutic potential of the UPS in solid and hematological malignancies. 相似文献
5.
Dergacheva M. B. Statsyuk V. N. Fogel' L. A. Pen'kova N. V. 《Russian Journal of Applied Chemistry》2003,76(6):917-922
Cyclic voltammetry was applied to study the effect of addition of 2,2'-dipyridyl on joint electroreduction of Te(IV) and Cd(II) from sulfuric acid solutions on glassy carbon and titanium electrodes. The optimal potentials of electrodeposition of CdTe films were determined and the structure of these films was studied by means of X-ray phase analysis. 相似文献
6.
B3LYP/6-311+G(d,p) and MP2/6-31G(d,p) methods are used to study the electronic structure of a 1,2,4-triazine molecule. Quantitative characteristics of the reactivity
are obtained in the form of atomic charges and Fukui coefficients. Thermodynamic characteristics are determined for the protonation
reaction and addition of the hydride anion to a 1,2,4-triazine molecule. 相似文献
7.
8.
9.
10.
An ammonia-chloride electrolyte containing 2,2′-bipyridine for preparing CdTe deposits on a glassy carbon electrode with a particle size of 3–5 nm was developed. The joint electroreduction of Cd(II) and Te(IV) ions was studied by voltammetry. 相似文献