Cu(II) induces small-size aggregates with amyloid characteristics in two alleles of recombinant ovine prion proteins.
Cu(II) induces small-size aggregates with amyloid characteristics in two alleles of recombinant ovine prion proteins.
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DOI：
10.1016/j.bbapap.2006.04.013
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发表时间：
2006-07
期刊：
影响因子：
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通讯作者：
K. Tsiroulnikov;H. Rezaei;M. Dalgalarrondo;J. Chobert;J. Grosclaude;T. Haertlé
中科院分区：
文献类型：
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作者：
K. Tsiroulnikov;H. Rezaei;M. Dalgalarrondo;J. Chobert;J. Grosclaude;T. Haertlé
传染性海绵状脑病的症状之一是与正常细胞朊蛋白PrP转化为淀粉样蛋白亚型抵抗蛋白水解裂解有关。本研究表明，与铜离子的相互作用将单体重组羊瘙痒症易感PrP-VRQ和羊瘙痒症抗性PrP-ARR变体转化为具有淀粉样蛋白特征的蛋白酶抗性可溶性寡聚体-显性β折叠二级结构和与硫代黄素S的相互作用。与此相反，锌离子的结合导致相同的抗蛋白水解不会引起两种PrP多态性变体的α-螺旋单体结构的转化。PrP N-末端的切割使这种聚集体的可溶形式不稳定，并且与金属阳离子络合的N-截短的PrPrec沉淀。与Zn络合的N-截短的PrPrec比与Cu络合的N-截短的PrPrec沉淀得快得多。根据关于小PrP寡聚体在PrPC-PrPSc转化中的关键作用的假设，与Cu络合的PrP的可溶性寡聚体的形成可以构成TSE传播中的附加元素。相同的金属螯合行为的两个研究多态性PrPrec的变体赋予不同的易感性羊瘙痒症可能表明他们不同的能力，形成原纤维。这也可能意味着，除了PrP-VRQ和PrP-ARR之间的理化差异以及PrP转化差异之外，其他因素也是导致TSE发作的原因。
One of symptoms of transmissible spongiform encephalopathies is associated with the transformation of normal cellular prion protein, PrP, in its amyloid isoform resistant to proteolytic cleavage. The present study shows that interaction with copper ions converts both monomeric recombinant scrapie-susceptible PrP-VRQ and scrapie-resistant PrP-ARR variants into protease-resistant soluble oligomers with amyloid characteristics — dominant β-sheet secondary structure and interaction with thioflavine S. In contrast, binding of zinc ions resulting in the same resistance to proteolysis does not provoke transformation of α-helical monomeric structure of both PrP polymorphic variants. Cleavage of PrP N-terminus destabilises soluble form of such aggregates, and N-truncated PrPrec complexed with metal cations precipitate. N-truncated PrPrec complexed with Zn precipitated much faster than N-truncated PrPrec complexed with Cu. According to the hypothesis about the key role of small PrP oligomers in PrPC-PrPSctransformation, formation of soluble oligomers of PrP complexed with Cu can constitute an additional element in TSE propagation. Identical metal-chelating behaviour of two studied polymorphic PrPrec variants conferring different susceptibilities of sheep to scrapie could indicate their different capabilities to form fibrils. This could imply also that other factors than physico-chemical differences between PrP-VRQ and PrP-ARR and the differences in PrP transformation are responsible for the onset of TSE.