Structural properties of prion protein protofibrils and fibrils: An experimental assessment of atomic models
Structural properties of prion protein protofibrils and fibrils: An experimental assessment of atomic models
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DOI：
10.1021/bi0612723
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发表时间：
2006-12-26
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.;Silveira, Jay;Daggett, Valerie
在朊蛋白与传染性海绵状脑病有关的几十年后，其毒性异构体的结构及其毒性机制仍然未知。尽管分辨率很低，但通过收集现有的实验数据，可以解开朊病毒之谜的一些谜团。目前，有两种完全不同的朊病毒原纤维模型。一种是基于朊蛋白在淀粉样蛋白形成条件下的分子动力学模拟，称为螺旋模型。另一个模型是通过将一部分朊病毒序列穿过蛋白质数据库中的β -螺旋结构构建的。在这里，我们将这些模型与所有可用的实验信息进行比较和对比，包括电子显微图、对称性、二级结构、寡聚化界面、酶消化、表位暴露和解聚谱。当这两种模型被引入时，这些信息中的大部分都是不可用的。总的来说，我们发现螺旋模型与所有实验结果是一致的。相比之下，一些实验观测结果很难与β -螺旋模型相协调。虽然实验限制是低分辨率的，但在将以前不相关的实验结合在一起时，我们已经对朊病毒聚集体有了更清晰的了解。改进的朊病毒聚集体表征和现有的原子模型都可以用于设计进一步的实验，以更好地阐明朊病毒原纤维的错误折叠途径和结构。
Decades after the prion protein was implicated in transmissible spongiform encephalopathies, the structure of its toxic isoform and its mechanism of toxicity remain unknown. By gathering available experimental data, albeit low resolution, a few pieces of the prion puzzle can be put in place. Currently, there are two fundamentally different models of a prion protofibril. One has its building blocks derived from a molecular dynamics simulation of the prion protein under amyloidogenic conditions, termed the spiral model. The other model was constructed by threading a portion of the prion sequence through a beta-helical structure from the Protein Data Bank. Here we compare and contrast these models with respect to all of the available experimental information, including electron micrographs, symmetries, secondary structure, oligomerization interfaces, enzymatic digestion, epitope exposure, and disaggregation profiles. Much of this information was not available when the two models were introduced. Overall, we find that the spiral model is consistent with all of the experimental results. In contrast, it is difficult to reconcile several of the experimental observables with the beta-helix model. While the experimental constraints are of low resolution, in bringing together the previously disconnected experiments, we have developed a clearer picture of prion aggregates. Both the improved characterization of prion aggregates and the existing atomic models can be used to devise further experiments to better elucidate the misfolding pathway and the structure of prion protofibrils.