Prion protein NMR structures of elk and of mouse/elk hybrids
Prion protein NMR structures of elk and of mouse/elk hybrids
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DOI：
10.1073/pnas.0409008102
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发表时间：
2005-01-18
影响因子：
11.1
通讯作者：
Wüthrich, K
中科院分区：
文献类型：
--
作者：
Gossert, AD;Bonjour, S;Wüthrich, K
本文描述了重组麋鹿朊蛋白（ePrP）的核磁共振结构，它代表了健康生物体中的细胞异构体（ePrP(c)）。正如高度保守的氨基酸序列所预测的那样，ePrPc具有与其他哺乳动物朊病毒蛋白（PrPs）相同的全局折叠，具有23-124残基灵活无序的“尾巴”和125-226球形结构域，具有三个a-螺旋和短的反平行β -片。然而，与大多数其他哺乳动物prp（特别是人类、牛和小鼠prp）相比，ePrP(c)显示出惊人的局部结构差异。连接β片和α 2-螺旋的残基166-175环是假设的“蛋白质X”表位的一部分，它的定义非常明确，而这个环在其他物种中是无序的。通过对两种小鼠PrP变体mPrP[N174T]和mPrP[S170N，N174T]的核磁共振结构测定，本研究表明，ePrPc中的结构环与这两种局部氨基酸交换有关，因此mPrP[S170N，N174T]完全模仿了ePrPc。这些结果在最近美国和加拿大圈养和自由放养鹿和麋鹿慢性消耗性疾病（CWD）报告的背景下进行了评估，并提出了一种动物模型，以支持CWD的未来研究。
The NMR structure of the recombinant elk prion protein (ePrP), which represents the cellular isoform (ePrP(c)) in the healthy organism, is described here. As anticipated from the highly conserved amino acid sequence, ePrPc has the same global fold as other mammalian prion proteins (PrPs), with a flexibly disordered "tail" of residues 23-124 and a globular domain 125-226 with three a-helices and a short antiparallel beta-sheet. However, ePrP(c) shows a striking local structure variation when compared with most other mammalian PrPs, in particular human, bovine, and mouse PrPc. A loop of residues 166-175, which links the beta-sheet with the alpha2-helix and is part of a hypothetical "protein X" epitope, is outstandingly well defined, whereas this loop is disordered in the other species. Based on NMR structure determinations of two mouse PrP variants, mPrP[N174T] and mPrP[S170N,N174T], this study shows that the structured loop in ePrPc relates to these two local amino acid exchanges, so that mPrP[S170N,N174T] exactly mimics ePrPc. These results are evaluated in the context of recent reports on chronic wasting disease (CWD) in captive and free-ranging deer and elk in the U.S. and Canada, and an animal model is proposed for support of future research on CWD.