Baral Pravas Kumar, Swayampakula Mridula, Aguzzi Adriano, James Michael N G
Department of Biochemistry, Faculty of Medicine and Dentistry, University of Alberta, Edmonton, AB T6G 2H7, Canada.
Department of Pathology, Institute of Neuropathology, University Hospital Zurich, Zurich, Switzerland.
J Struct Biol. 2015 Oct;192(1):37-47. doi: 10.1016/j.jsb.2015.08.014. Epub 2015 Aug 28.
Misfolded prion proteins are the cause of neurodegenerative diseases that affect many mammalian species, including humans. Transmission of the prion diseases poses a considerable public-health risk as a specific prion disease such as bovine spongiform encephalopathy can be transferred to humans and other mammalian species upon contaminant exposure. The underlying mechanism of prion propagation and the species barriers that control cross species transmission has been investigated quite extensively. So far a number of prion strains have been characterized and those have been intimately linked to species-specific infectivity and other pathophysiological manifestations. These strains are encoded by a protein-only agent, and have a high degree of sequence identity across mammalian species. The molecular events that lead to strain differentiation remain elusive. In order to contribute to the understanding of strain differentiation, we have determined the crystal structures of the globular, folded domains of four prion proteins (cow, deer, elk and Syrian hamster) bound to the POM1 antibody fragment Fab. Although the overall structural folds of the mammalian prion proteins remains extremely similar, there are several local structural variations observed in the misfolding-initiator motifs. In additional molecular dynamics simulation studies on these several prion proteins reveal differences in the local fluctuations and imply that these differences have possible roles in the unfolding of the globular domains. These local variations in the structured domains perpetuate diverse patterns of prion misfolding and possibly facilitate the strain selection and adaptation.
错误折叠的朊病毒蛋白是导致包括人类在内的许多哺乳动物神经退行性疾病的原因。朊病毒疾病的传播带来了相当大的公共卫生风险，因为特定的朊病毒疾病，如牛海绵状脑病，在接触污染物时可传染给人类和其他哺乳动物。朊病毒传播的潜在机制以及控制跨物种传播的物种屏障已得到广泛研究。到目前为止，已经鉴定出许多朊病毒毒株，这些毒株与物种特异性感染性和其他病理生理表现密切相关。这些毒株由仅蛋白质的病原体编码，并且在哺乳动物物种中具有高度的序列同一性。导致毒株分化的分子事件仍然难以捉摸。为了有助于理解毒株分化，我们确定了与POM1抗体片段Fab结合的四种朊病毒蛋白（牛、鹿、麋鹿和叙利亚仓鼠）的球状折叠结构域的晶体结构。尽管哺乳动物朊病毒蛋白的整体结构折叠仍然极其相似，但在错误折叠起始基序中观察到了一些局部结构变化。此外，对这几种朊病毒蛋白的分子动力学模拟研究揭示了局部波动的差异，并暗示这些差异可能在球状结构域的展开中起作用。结构域中的这些局部变化使朊病毒错误折叠的模式多样化，并可能促进毒株的选择和适应。
