Molecular evolution of the mammalian prion protein
Molecular evolution of the mammalian prion protein
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DOI：
10.1093/molbev/msg014
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发表时间：
2003-01-01
影响因子：
10.7
通讯作者：
de Jong, WW
中科院分区：
文献类型：
--
作者：
van Rheede, T;Smolenaars, MMW;de Jong, WW
朊病毒蛋白（PrP）序列到目前为止，只有六个胎盘哺乳动物的18个订单。对哺乳动物朊病毒进行更广泛的比较可能有助于理解这种蛋白质神秘的功能和致病特性。因此，我们确定PrP编码序列在26种哺乳动物，包括所有胎盘的订单和主要的从属群体。糖基化位点、形成二硫桥的半胱氨酸和疏水跨膜区是完全保守的。此外，负责二级结构元件、前体蛋白的N-和C-末端加工以及糖基-磷脂酰肌醇膜锚附着的序列也很保守。PrP的N-末端区域通常含有5个或6个重复序列P（Q/H）GGG（G/-）WGQ，但在某些物种中观察到具有2个、4个和7个重复序列的等位基因。这表明，连同这些重复序列中氨基酸替换的模式，重复序列的扩展和收缩的规律性发生。组氨酸涉及铜离子结合和脯氨酸参与4-羟基化是缺乏在一些物种中，这质疑他们的重要性，细胞PrP的正常功能。在某些物种中发现的两个或七个重复序列，以及与人类朊病毒疾病相关的氨基酸取代，挑战了这种突变与朊病毒病理学的相关性。从PrP序列推导的基因树与物种树基本一致，表明朊病毒基因在不同胎盘谱系中的进化没有发生重大偏差。在一个物种中，食蚁兽，除了活性基因外，还存在朊病毒假基因。
Prion protein (PrP) sequences are until now available for only six of the 18 orders of placental mammals. A broader comparison of mammalian prions might help to understand the enigmatic functional and pathogenic properties of this protein. We therefore determined PrP coding sequences in 26 mammalian species to include all placental orders and major subordinal groups. Glycosylation sites, cysteines forming a disulfide bridge, and a hydrophobic transmembrane region are perfectly conserved. Also, the sequences responsible for secondary structure elements, for N- and C-terminal processing of the precursor protein, and for attachment of the glycosyl-phosphatidylinositol membrane anchor are well conserved. The N-terminal region of PrP generally contains five or six repeats of the sequence P(Q/H)GGG(G/-)WGQ, but alleles with two, four, and seven repeats were observed in some species. This suggests, together with the pattern of amino acid replacements in these repeats, the regular occurrence of repeat expansion and contraction. Histidines implicated in copper ion binding and a proline involved in 4-hydroxylation are lacking in some species, which questions their importance for normal functioning of cellular PrP. The finding in certain species of two or seven repeats, and of amino acid substitutions that have been related to human prion diseases, challenges the relevance of such mutations for prion pathology. The gene tree deduced from the PrP sequences largely agrees with the species tree, indicating that no major deviations occurred in the evolution of the prion gene in different placental lineages. In one species, the anteater, a prion pseudogene was present in addition to the active gene.