The amino-terminal PrP domain is crucial to modulate prion misfolding and aggregation
The amino-terminal PrP domain is crucial to modulate prion misfolding and aggregation
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DOI：
10.1529/biophysj.105.067603
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发表时间：
2005-10-01
影响因子：
3.4
通讯作者：
Silva, JL
中科院分区：
文献类型：
--
作者：
Cordeiro, Y;Kraineva, J;Silva, JL
朊病毒疾病的主要假设是细胞蛋白（PrPC）可以被改变成错误折叠的富含β -薄片的异构体（PrPSc），这种异构体发生聚集并引发传染性海绵状脑病的发病。本文研究了氨基末端缺失突变rPrP（Delta 51 - 90）和rPrP(Delta 32)（- 121）对重组鼠PrP的稳定性和包装性能的影响。缺乏rPrP的区域（Delta 51 - 90）在生理上参与铜结合，而另一个结构缺乏更多的氨基末端残基（从32到121）。rPrP（Delta 51 - 90）和rPrP（Delta 32 - 121）的压力稳定性随着N-域长度的减小而显著降低，该过程不可逆，而野生型的rPrP是完全可逆的。傅里叶变换红外光谱观察到，减压到大气压力触发突变体的立即聚集，而野生型则是缓慢的聚集过程。温度诱导的转变导致所有rPrP聚集，但rPrP氨基末端缺失突变体的展开温度较低。氨基末端缺失突变体对压力的敏感性较高可以通过水合作用和空腔分布的变化来解释。综上所述，我们的研究结果表明，氨基末端区域在朊病毒错误折叠和聚集的发展中起着关键作用。
The main hypothesis for prion diseases is that the cellular protein ( PrPC) can be altered into a misfolded, beta- sheet-rich isoform ( PrPSc), which undergoes aggregation and triggers the onset of transmissible spongiform encephalopathies. Here, we investigate the effects of amino- terminal deletion mutations, rPrP(Delta 51 - 90) and rPrP(Delta 32) (- 121), on the stability and the packing properties of recombinant murine PrP. The region lacking in rPrP(Delta 51 - 90) is involved physiologically in copper binding and the other construct lacks more amino- terminal residues ( from 32 to 121). The pressure stability is dramatically reduced with decreasing N- domain length and the process is not reversible for rPrP(Delta 51 - 90) and rPrP(Delta 32 - 121), whereas it is completely reversible for the wild- type form. Decompression to atmospheric pressure triggers immediate aggregation for the mutants in contrast to a slow aggregation process for the wild- type, as observed by Fourier- transform infrared spectroscopy. The temperature- induced transition leads to aggregation of all rPrPs, but the unfolding temperature is lower for the rPrP amino- terminal deletion mutants. The higher susceptibility to pressure of the amino- terminal deletion mutants can be explained by a change in hydration and cavity distribution. Taken together, our results show that the amino- terminal region has a pivotal role on the development of prion misfolding and aggregation.