Influence of amino acid substitutions related to inherited human prion diseases on the thermodynamic stability of the cellular prion protein
Influence of amino acid substitutions related to inherited human prion diseases on the thermodynamic stability of the cellular prion protein
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DOI：
10.1021/bi982714g
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发表时间：
1999-03-16
期刊：
影响因子：
2.9
通讯作者：
Glockshuber, R
中科院分区：
文献类型：
--
作者：
Liemann, S;Glockshuber, R
传染性海绵状脑病 (TSE) 是由一种独特的传染原引起的，这种传染原似乎与 PrPSc 相同，PrPSc 是细胞朊病毒蛋白 PrPC 的一种寡聚、错误折叠亚型。人类 TSE 的所有遗传形式，即家族性克雅氏病、格斯特曼-施特劳斯勒-沙因克综合征和致命性家族性失眠症，都因编码人类 PrP 的基因中的特定点突变或插入而分离。在这里，我们测试了以下假设：这些突变会破坏 PrPC 的稳定性，从而促进其转化为 PrPSc。八个疾病特异性氨基酸替换位于 PrPC 的 C 端结构域 PrP(121-231)，它构成了 PrPC 唯一具有明确三级结构的部分。将所有这些替换引入 PrP(121-231) 中产生的变体具有与野生型 PrP(121-231) 相同的光谱特征并且与全长 PrP(23-231) 相似，这排除了先验交换诱导 PrPSc 样构象的可能性。变体的热力学稳定性与特定疾病表型不相关。其中五个氨基酸替换使 PrP(121-231) 不稳定，但其他变体具有与野生型蛋白质相同的稳定性。这些数据表明，PrPC 的不稳定既不是 PrPSc 形成的一般机制，也不是遗传性人类 TSE 疾病表型的基础。
Transmissible spongiform encephalopathies (TSEs) are caused by a unique infectious agent which appears to be identical with PrPSc, an oligomeric, misfolded isoform of the cellular prion protein, PrPC. All inherited forms of human TSEs, i.e., familial Creutzfeldt-Jakob disease, Gerstmann-Straussler-Scheinker syndrome, and fatal familial insomnia, segregate with specific point mutations or insertions in the gene coding for human PrP. Here we have tested the hypothesis that these mutations destabilize PrPC and thus facilitate its conversion into PrPSc. Eight of the disease-specific amino acid replacements are located in the C-terminal domain of PrPC, PrP(121-231), which constitutes the only part of PrPC with a defined tertiary structure. Introduction of all these replacements into PrP(121-231) yielded variants with the same spectroscopic characteristics as wild-type PrP(121-231) and similar to full-length PrP(23-231), which excludes the possibility that the exchanges a priori induce a PrPSc-like conformation. The thermodynamic stabilities of the variants do not correlate with specific disease phenotypes. Five of the amino acid replacements destabilize PrP(121-231), but the other variants have the same stability as the wild-type protein. These data suggest that destabilization of PrPC is neither a general mechanism underlying the formation of PrPSc nor the basis of disease phenotypes in inherited human TSEs.