Aggregation of prion protein with insertion mutations is proportional to the number of inserts.
Aggregation of prion protein with insertion mutations is proportional to the number of inserts.
复制标题
具有插入突变的朊病毒蛋白的聚集与插入的数量成正比。
DOI：
10.1042/bj20061592
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发表时间：
2007-04
期刊：
影响因子：
--
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中科院分区：
文献类型：
--
作者：
Prion基因PRNP的突变约占。10%-15%的人类普恩病毒疾病。然而，对突变的普恩蛋白(PrP)致病的机制知之甚少。我们比较了野生型人类PrP(C)(重组野生型PrP)和两种插入突变的重组人PrP(C)的生化性质，其中一种具有三个以上的八肽重复，rPrP(8OR)，另一个具有五个八肽重复，rPrP(10OR)。我们发现，插入突变的蛋白质更容易聚集，聚集的程度和动力学与插入的数量成正比。八肽重复区和α-螺旋1区在聚集体的形成中很重要，因为这些区域的表位特异性的单抗抑制了聚集性。我们还发现少量突变蛋白可以促进突变蛋白与野生型rPrP(C)的混合聚集体的形成。因此，rPrP(10OR)在促进rPrP(C)聚集方面也比rPrP(8OR)更有效。这些发现为临床观察到具有插入突变的患者的疾病严重程度与插入的数量成正比提供了生化解释，从而对遗传性人类Pron病的发病机制有一定的意义。
Mutation in the prion gene, PRNP, accounts for approx. 10-15% of human prion diseases. However, little is known about the mechanisms by which a mutant prion protein (PrP) causes disease. We compared the biochemical properties of a wild-type human prion protein, rPrP(C) (recombinant wild-type PrP), which has five octapeptide-repeats, with two recombinant human prion proteins with insertion mutations, one with three more octapeptide repeats, rPrP(8OR), and the other with five more octapeptide repeats, rPrP(10OR). We found that the insertion mutant proteins are more prone to aggregate, and the degree and kinetics of aggregation are proportional to the number of inserts. The octapeptide-repeat and alpha-helix 1 regions are important in aggregate formation, because aggregation is inhibited with monoclonal antibodies that are specific for epitopes in these regions. We also showed that a small amount of mutant protein could enhance the formation of mixed aggregates that are composed of mutant protein and wild-type rPrP(C). Accordingly, rPrP(10OR) is also more efficient in promoting the aggregation of rPrP(C) than rPrP(8OR). These findings provide a biochemical explanation for the clinical observations that the severity of the disease in patients with insertion mutations is proportional to the number of inserts, and thus have implications for the pathogenesis of inherited human prion disease.
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影响因子：
82.9
作者：
Chen, SG;Parchi, P;Gambetti, P
通讯作者：
Gambetti, P
DOI：
10.1016/j.bbapap.2006.04.013
发表时间：
2006-07
期刊：
Biochimica et biophysica acta
影响因子：
--
作者：
K. Tsiroulnikov;H. Rezaei;M. Dalgalarrondo;J. Chobert;J. Grosclaude;T. Haertlé
通讯作者：
K. Tsiroulnikov;H. Rezaei;M. Dalgalarrondo;J. Chobert;J. Grosclaude;T. Haertlé
影响因子：
4.8
作者：
Shaoman Yin;Shuiliang Yu;Chaoyang Li;Poki Wong;Binggong Chang;F. Xiao;Shin‐Chung Kang;Huimin Yan;Gengfu Xiao;J. Grassi;P. Tien;M. Sy
通讯作者：
Shaoman Yin;Shuiliang Yu;Chaoyang Li;Poki Wong;Binggong Chang;F. Xiao;Shin‐Chung Kang;Huimin Yan;Gengfu Xiao;J. Grassi;P. Tien;M. Sy
影响因子：
2.9
作者：
Liemann, S;Glockshuber, R
通讯作者：
Glockshuber, R
影响因子：
64.8
作者：
Silveira, JR;Raymond, GJ;Caughey, B
通讯作者：
Caughey, B