Potential Allosteric Modulators of the Proteasome Activity
Potential Allosteric Modulators of the Proteasome Activity
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DOI：
10.1002/bip.21381
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发表时间：
2010-05-01
期刊：
影响因子：
2.9
通讯作者：
Kasprzykowski, F.
中科院分区：
文献类型：
--
作者：
Jankowska, E.;Gaczynska, M.;Kasprzykowski, F.
蛋白酶体由管状蛋白水解核心颗粒及其附着的调节模块组成，是泛素-蛋白酶体代谢途径所必需的多功能酶复合物。由于其对细胞生理学调节的巨大参与，蛋白酶体是公认的抗癌药物靶点和治疗炎症或退行性疾病的潜在靶点。迄今为止，核心颗粒的竞争性抑制剂作为药物得到了最多的考虑。我们假设非竞争性作用的小分子化合物将为精确调节蛋白酶体的作用提供极好的手段。在这项研究中，我们根据已知与核心蛋白酶体相互作用的两种蛋白质的序列评估了五种短肽：HIV-1 Tat 和 PA28/REG 激活剂。我们进行了圆二色性 (CD)、傅里叶变换红外光谱 (FTIR) 和核磁共振 (NMR) 分析，并辅以 MD 模拟，并测试了肽对核心颗粒活性位点性能和调节模块功能的影响。我们发现含有 PP2 的 Tat 肽是核心的非竞争性抑制剂，干扰 PA28 αβ 激活剂的作用。此外，在低浓度下，易于转动的 Tat2 能够激活潜在核心。随机卷曲结构的 PA28 衍生肽对核心活性仅表现出微弱或不可检测的直接影响，然而，与 PA28 αβ 的活性增强作用表现出积极的合作。 (C) 2010 Wiley periodicals, Inc. 生物聚合物 93: 481-495, 2010。
Proteasome, consisting of a tube-shaped proteolytic core particle and attached to it regulatory modules, is a multifunctional enzymatic complex essential for the ubiquitin-proteasome metabolic pathway. Due to its immense involvement in regulation of cellular physiology, the proteasome is an acknowledged anticancer drug target and potential target to treat inflammatory or degenerative diseases. So far, competitive inhibitors of the core particle gain most consideration as drugs. We postulate that noncompetitively-acting small-molecule compounds would provide excellent means to precisely regulate actions of the proteasome. In this study, we evaluated five short peptides based on sequences of two proteins known to interact with the core proteasome: HIV-1 Tat and PA28/REG activator. We performed Circular Dichroism (CD), Fourier Transformed Infrared Spectroscopy (FTIR), and Nuclear Magnetic Resonance (NMR) analysis, supplemented by MD simulations, and tested influence of the peptides on performance of the core particle active sites and functioning of regulatory modules. We found that PP2-containing Tat peptides are noncompetitive inhibitors of the core, interfering with the actions of PA28 alpha beta activator. In addition, at low concentrations the turn-prone Tat2 is able to activate the latent core. The random coil-structured PA28-derived peptides display only weak or nondetectable direct effects on the core activities, exhibiting, however, a positive cooperation with activity-enhancing actions of PA28 alpha beta. (C) 2010 Wiley Periodicals, Inc. Biopolymers 93: 481-495, 2010.