Atypical effect of salts on the thermodynamic stability of human prion protein
Atypical effect of salts on the thermodynamic stability of human prion protein
复制标题
DOI：
10.1074/jbc.m302130200
复制
发表时间：
2003-06-20
影响因子：
4.8
通讯作者：
Surewicz, WK
中科院分区：
文献类型：
--
作者：
Apetri, AC;Surewicz, WK
朊病毒疾病与细胞朊病毒蛋白 PrPC 转化为错误折叠的寡聚形式 PrPSc 相关。先前的研究表明，盐可以促进重组朊病毒蛋白构象转变为 PrPSc 样形式。为了深入了解这种效应的机制，我们研究了多种盐（硫酸钠、氟化钠、乙酸钠和氯化钠）对重组人朊病毒蛋白热力学稳定性的影响。尿素的化学展开研究表明，在低浓度（低于 50 mM）时，所有测试的盐都会显着降低蛋白质的热力学稳定性。在全长朊病毒蛋白以及 N 截短片段 huPrP90-231 和 huPrP122-231 中都观察到了这种对盐的极不寻常的反应。在较高的盐浓度下，不稳定效应逐渐逆转，盐的行为根据它们在霍夫迈斯特系列中的排名而变化。目前的数据表明静电相互作用在朊病毒蛋白的稳定性中发挥着异常重要的作用。盐的异常作用可能是由于极其亲水的螺旋 1 中离子诱导的盐桥（Asp(144)-Arg(148) 和/或 Asp(147)-Arg(151)）不稳定所致。与之前的建议相反，这种作用并不是由于离子与朊病毒蛋白富含甘氨酸的柔性 N 末端区域的相互作用所致。这项研究的结果表明，细胞环境中存在的离子种类可能通过调节天然 PrPC 亚型的热力学稳定性来控制 PrPC 到 PrPSc 的转化。
Prion diseases are associated with the conversion of cellular prion protein, PrPC, into a misfolded oligomeric form, PrPSc. Previous studies indicate that salts promote conformational conversion of the recombinant prion protein into a PrPSc-like form. To gain insight into the mechanism of this effect, here we have studied the influence of a number of salts ( sodium sulfate, sodium fluoride, sodium acetate, and sodium chloride) on the thermodynamic stability of the recombinant human prion protein. Chemical unfolding studies in urea show that at low concentrations ( below similar to50 mM), all salts tested significantly reduced the thermodynamic stability of the protein. This highly unusual response to salts was observed for both the full-length prion protein as well as the N-truncated fragments huPrP90-231 and huPrP122-231. At higher salt concentrations, the destabilizing effect was gradually reversed, and salts behaved according to their ranking in the Hofmeister series. The present data indicate that electrostatic interactions play an unusually important role in the stability of the prion protein. The abnormal effect of salts is likely because of the ion-induced destabilization of salt bridges (Asp(144)-Arg(148) and/or Asp(147)-Arg(151)) in the extremely hydrophilic helix 1. Contrary to previous suggestions, this effect is not due to the interaction of ions with the glycine-rich flexible N-terminal region of the prion protein. The results of this study suggest that ionic species present in the cellular environment may control the PrPC to PrPSc conversion by modulating the thermodynamic stability of the native PrPC isoform.