Myers Ryan, Cembran Alessandro, Fernandez-Funez Pedro
Department of Biomedical Sciences, University of Minnesota Medical School, Duluth, MN, United States.
Department of Chemistry and Biochemistry, University of Minnesota Duluth, Duluth, MN, United States.
Front Cell Neurosci. 2020 Aug 18;14:254. doi: 10.3389/fncel.2020.00254. eCollection 2020.
Prion diseases are a group of neurodegenerative diseases endemic in humans and several ruminants caused by the misfolding of native prion protein (PrP) into pathological conformations. Experimental work and the mad-cow epidemic of the 1980s exposed a wide spectrum of animal susceptibility to prion diseases, including a few highly resistant animals: horses, rabbits, pigs, and dogs/canids. The variable susceptibility to disease offers a unique opportunity to uncover the mechanisms governing PrP misfolding, neurotoxicity, and transmission. Previous work indicates that PrP-intrinsic differences (sequence) are the main contributors to disease susceptibility. Several residues have been cited as critical for encoding PrP conformational stability in prion-resistant animals, including D/E159 in dog, S167 in horse, and S174 in rabbit and pig PrP (all according to human numbering). These amino acids alter PrP properties in a variety of assays, but we still do not clearly understand the structural correlates of PrP toxicity. Additional insight can be extracted from comparative structural studies, followed by molecular dynamics simulations of selected mutations, and testing in manipulable animal models. Our working hypothesis is that protective amino acids generate more compact and stable structures in a C-terminal subdomain of the PrP globular domain. We will explore this idea in this review and identify subdomains within the globular domain that may hold the key to unravel how conformational stability and disease susceptibility are encoded in PrP.
朊病毒病是一组在人类和几种反刍动物中流行的神经退行性疾病，由天然朊病毒蛋白（PrP）错误折叠成病理构象引起。实验工作以及20世纪80年代的疯牛病疫情揭示了多种动物对朊病毒病的易感性，包括一些高度抗性的动物：马、兔子、猪和狗/犬科动物。对疾病的不同易感性为揭示控制PrP错误折叠、神经毒性和传播的机制提供了独特的机会。先前的研究表明，PrP内在差异（序列）是疾病易感性的主要因素。几个残基被认为对编码抗朊病毒动物中PrP的构象稳定性至关重要，包括狗中的D/E159、马中的S167以及兔子和猪PrP中的S174（均根据人类编号）。这些氨基酸在各种实验中改变了PrP的特性，但我们仍然不清楚PrP毒性的结构相关性。可以从比较结构研究中获取更多见解，随后对选定突变进行分子动力学模拟，并在可操作的动物模型中进行测试。我们的工作假设是，保护性氨基酸在PrP球状结构域的C末端亚结构域中产生更紧凑和稳定的结构。我们将在本综述中探讨这一观点，并确定球状结构域内的亚结构域，这些亚结构域可能是解开PrP中构象稳定性和疾病易感性如何编码的关键。
