Wopfner F, Weidenhöfer G, Schneider R, von Brunn A, Gilch S, Schwarz T F, Werner T, Schätzl H M
Genecenter, Department of Virology, Max von Pettenkofer-Institute for Medical Microbiology, Ludwig-Maximilians-University of Munich, Feodor-Lynen-Str. 25, Munich, 81377, Germany.
J Mol Biol. 1999 Jun 25;289(5):1163-78. doi: 10.1006/jmbi.1999.2831.
Prion diseases are fatal neurodegenerative disorders in man and animal associated with conformational conversion of a cellular prion protein (PrPc) into the pathologic isoform (PrPSc). The function of PrPcand the tertiary structure of PrPScare unclear. Various data indicate which parts of PrP might control the species barrier in prion diseases and the binding of putative factors to PrP. To elucidate these features, we analyzed the evolutionary conservation of the prion protein. Here, we add the primary PrP structures of 20 ungulates, three rodents, three carnivores, one maritime mammal, and nine birds. Within mammals and birds we found a high level of amino acid sequence identity, whereas between birds and mammals the overall homology was low. Various structural elements were conserved between mammals and birds. Using the CONRAD space-scale alignment, which predicts conserved and variable blocks, we observed similar patterns in avian and mammalian PrPs, although 130 million years of separate evolution lie in between. Our data support the suggestion that the repeat elements might have expanded differently within the various classes of vertebrates. Of note is the N-terminal part of PrP (amino acid residues 23-90), which harbors insertions and deletions, whereas in the C-terminal portion (91-231) mainly point mutations are found. Strikingly, we found a high level of conservation of sequences that are not part of the structured segment 121-231 of PrPcand of the structural elements therein, e.g. the N-terminal region from amino acid residue 23-90 and the regions located upstream of alpha-helices 1 and 3.
朊病毒疾病是人和动物中致命的神经退行性疾病，与细胞朊蛋白（PrPc）向病理异构体（PrPSc）的构象转变有关。PrPc的功能和PrPSc的三级结构尚不清楚。各种数据表明PrP的哪些部分可能控制朊病毒疾病中的物种屏障以及假定因子与PrP的结合。为了阐明这些特征，我们分析了朊蛋白的进化保守性。在此，我们增加了来自20种有蹄类动物、3种啮齿动物、3种食肉动物、1种海洋哺乳动物和9种鸟类的PrP一级结构。在哺乳动物和鸟类中，我们发现氨基酸序列具有高度同一性，而在鸟类和哺乳动物之间，总体同源性较低。哺乳动物和鸟类之间存在各种保守的结构元件。使用CONRAD空间尺度比对（可预测保守和可变区域），我们观察到鸟类和哺乳动物的PrP具有相似模式，尽管它们之间有1.3亿年的独立进化史。我们的数据支持这样的观点，即重复元件可能在各类脊椎动物中以不同方式扩展。值得注意的是PrP的N端部分（氨基酸残基23 - 90）存在插入和缺失，而在C端部分（91 - 231）主要发现点突变。令人惊讶地是，我们发现PrPc的121 - 231结构化片段及其结构元件之外的序列，例如氨基酸残基23 - 90的N端区域以及α螺旋1和3上游的区域，具有高度保守性。
