Normal cellular prion protein with a methionine at position 129 has a more exposed helix 1 and is more prone to aggregate.
Normal cellular prion protein with a methionine at position 129 has a more exposed helix 1 and is more prone to aggregate.
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DOI：
10.1016/j.bbrc.2008.01.172
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发表时间：
2008-04
影响因子：
3.1
通讯作者：
Nancy Pham;Shaoman Yin;Shuiliang Yu;Poki Wong;Shin‐Chung Kang;Chaoyang Li;M. Sy
中科院分区：
文献类型：
--
作者：
Nancy Pham;Shaoman Yin;Shuiliang Yu;Poki Wong;Shin‐Chung Kang;Chaoyang Li;M. Sy
人类朊病毒基因 PRNP 有两种等位基因形式，在密码子 129 处编码蛋氨酸或缬氨酸。这种多态性强烈影响朊病毒疾病的发病机制。然而，其根本机制仍不清楚。我们使用一组对整个蛋白质表位具有特异性的单克隆抗体，比较了野生型人朊病毒蛋白 (rPrPC) 与第 129 位缬氨酸或甲硫氨酸之间的构象。我们发现与 rPrPC(129V) 相比，rPrPC(129M) 具有更多暴露的螺旋 1 区域。螺旋 1 在聚集过程中很重要。因此，rPrPC(129M)以比rPrPC(129V)更快的速率聚集并且形成更多的聚集体。此外，通过使用具有五个额外八肽重复插入的致病性突变的rPrP（rPrP（129M）/10OR）作为“种子”，我们表明rPrP（129M）/10OR比rPrPC（129V）更有效地促进rPrPC（129M）的聚集。这些发现提供了残基 129 对人类朊病毒疾病影响的可能机制。
The human prion gene, PRNP, has two allelic forms that encode either a methionine or valine at codon 129. This polymorphism strongly influences the pathogenesis of prion disease. However, the underlying mechanism remains unclear. We compared the conformation between wild-type human prion protein (rPrPC) with either a valine or methionine at position 129, using a panel of monoclonal antibodies that are specific for epitopes along the entire protein. We found that rPrPC(129M)has a more exposed helix 1 region compared to rPrPC(129V). Helix 1 is important in the aggregation process. Accordingly, rPrPC(129M)aggregates at a faster rate and forms more aggregate than rPrPC(129V). In addition, by using a rPrP with a pathogenic mutation of five additional octapeptide repeat insertions, rPrP(129M)/10OR, as “seeds”, we showed that rPrP(129M)/10ORpromotes the aggregation of rPrPC(129M)more efficiently than rPrPC(129V). These findings provide a possible mechanism underlying the influence of residue 129 on human prion disease.