Molecular mechanism for low pH triggered misfolding of the human prion protein
Molecular mechanism for low pH triggered misfolding of the human prion protein
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DOI：
10.1021/bi0619066
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发表时间：
2007-03-20
期刊：
影响因子：
2.9
通讯作者：
Daggett, Valerie
中科院分区：
文献类型：
--
作者：
DeMarco, Mari L.;Daggett, Valerie
朊病毒蛋白的构象变化导致传染性海绵状脑病，也称为朊病毒病。在其天然状态下，朊病毒蛋白是无害的（PrPC），但它可以错误折叠成神经毒性和感染性同种型（PrPSc）。朊病毒蛋白的全长细胞形式由残基23-230组成，其中超过一半的序列属于非结构化的N-末端结构域，其余残基形成小的球状结构域。在错误折叠和聚集过程中，结构化和非结构化结构域的一部分被并入聚集体中。在蛋白酶K的有限蛋白水解后，来自脑源性朊病毒原纤维的最丰富的片段是由残基90-230组成的141个残基的片段。在这里，我们描述了在低pH值，触发错误折叠，并在中性pH值作为对照的人朊病毒蛋白的这一片段的模拟。模拟，与实验一致，表明这种生物学和病理学相关的朊病毒结构是稳定的和天然的，在中性pH值。相反，在低pH值的朊病毒蛋白是不稳定的，通过破坏关键的远程盐桥。在一个低pH值的模拟，这种不稳定导致的构象转变为PrPSc样亚型与我们以前的模拟一个较小的结构一致。
Conformational changes in the prion protein cause transmissible spongiform encephalopathies, also referred to as prion diseases. In its native state, the prion protein is innocuous (PrPC), but it can misfold into a neurotoxic and infectious isoform (PrPSc). The full-length cellular form of the prion protein consists of residues 23-230, with over half of the sequence belonging to the unstructured N-terminal domain and the remaining residues forming a small globular domain. During misfolding and aggregation, portions of both the structured and unstructured domains are incorporated into the aggregates. After limited proteolysis by proteinase K, the most abundant fragment from brain-derived prion fibrils is a 141-residue fragment composed of residues 90-230. Here we describe simulations of this fragment of the human prion protein at low pH, which triggers misfolding, and at neutral pH as a control. The simulations, in agreement with experiment, show that this biologically and pathologically relevant prion construct is stable and native-like at neutral pH. In contrast, at low pH the prion protein is destabilized via disruption of critical long-range salt bridges. In one of the low pH simulations this destabilization resulted in a conformational transition to a PrPSc-like isoform consistent with our previous simulations of a smaller construct.