Division of Molecular Neurobiology, The Institute for Enzyme Research (KOSOKEN), Tokushima University, 3-18-15 Kuramoto, Tokushima 770-8503, Japan.
Int J Mol Sci. 2020 Aug 28;21(17):6233. doi: 10.3390/ijms21176233.
The normal cellular isoform of prion protein, designated PrP, is constitutively converted to the abnormally folded, amyloidogenic isoform, PrP, in prion diseases, which include Creutzfeldt-Jakob disease in humans and scrapie and bovine spongiform encephalopathy in animals. PrP is a membrane glycoprotein consisting of the non-structural -terminal domain and the globular C-terminal domain. During conversion of PrP to PrP, its 2/3 C-terminal region undergoes marked structural changes, forming a protease-resistant structure. In contrast, the N-terminal region remains protease-sensitive in PrP. Reverse genetic studies using reconstituted PrP-knockout mice with various mutant PrP molecules have revealed that the N-terminal domain has an important role in the normal function of PrP and the conversion of PrP to PrP. The N-terminal domain includes various characteristic regions, such as the positively charged residue-rich polybasic region, the octapeptide repeat (OR) region consisting of five repeats of an octapeptide sequence, and the post-OR region with another positively charged residue-rich polybasic region followed by a stretch of hydrophobic residues. We discuss the normal functions of PrP, the conversion of PrP to PrP, and the neurotoxicity of PrP by focusing on the roles of the N-terminal regions in these topics.
正常细胞朊病毒蛋白的同种型，称为 PrP，在朊病毒病中会被连续地转化为异常折叠的、淀粉样的同种型 PrP，朊病毒病包括人类的克雅氏病和羊瘙痒病以及动物的牛海绵状脑病。PrP 是一种膜糖蛋白，由无结构的 N 端结构域和球形的 C 端结构域组成。在 PrP 向 PrP 转化的过程中，其 2/3 的 C 端区域会发生显著的结构变化，形成一种抗蛋白酶的结构。相比之下，PrP 中的 N 端区域仍然对蛋白酶敏感。使用具有各种突变 PrP 分子的重组 PrP 敲除小鼠的反向遗传学研究表明，N 端结构域在 PrP 的正常功能和 PrP 向 PrP 的转化中具有重要作用。N 端结构域包含各种特征区域，如富含正电荷的多碱性区域、由五个八肽序列重复组成的八肽重复（OR）区域，以及紧随其后的带正电荷的富含多碱性区域和一段疏水性残基的 OR 后区域。我们将通过关注 N 端区域在这些主题中的作用，讨论 PrP 的正常功能、PrP 向 PrP 的转化以及 PrP 的神经毒性。
