Structural basis for the protective effect of the human prion protein carrying the dominant-negative E219K polymorphism
Structural basis for the protective effect of the human prion protein carrying the dominant-negative E219K polymorphism
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DOI：
10.1042/bj20111940
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发表时间：
2012-09-01
影响因子：
4.1
通讯作者：
Legname, Giuseppe
中科院分区：
文献类型：
--
作者：
Biljan, Ivana;Giachin, Gabriele;Legname, Giuseppe
人类最常见的朊病毒疾病是sCJD（散发性克雅氏病）。人类朊蛋白（HuPrP）中天然存在的E219K多态性被认为可以预防sCJD。为了深入了解其保护作用的结构基础，我们确定了携带E219K多态性的重组HuPrP（残基90-231）的核磁共振结构。HuPrP（E219K）蛋白的结构由一个无序的n端尾部（残基90-124）和一个结构良好的c端片段（残基125-231）组成，其中包含三个α -螺旋和两条短的反平行β链。在相同的实验条件下，对野生型和病理突变的HuPrPs的NMR结构进行比较发现，尽管蛋白质的整体结构保持完整，但用赖氨酸残基取代Glu（219）会导致显著的局部结构变化。本研究的结构发现表明，E219K多态性的保护作用是由于表面电荷分布的改变，以及位于朊病毒转化关键的表位内的微妙结构重排。
The most common form of prion disease in humans is sCJD (sporadic Creutzfeldt-Jakob disease). The naturally occurring E219K polymorphism in the HuPrP (human prion protein) is considered to protect against sCJD. To gain insight into the structural basis of its protective influence we have determined the NMR structure of recombinant HuPrP (residues 90-231) carrying the E219K polymorphism. The structure of the HuPrP(E219K) protein consists of a disordered N-terminal tail (residues 90-124) and a well-structured C-terminal segment (residues 125-231) containing three alpha-helices and two short antiparallel beta-strands. Comparison of NMR structures of the wild-type and HuPrPs with pathological mutations under identical experimental conditions revealed that, although the global architecture of the protein remains intact, replacement of Glu(219) with a lysine residue introduces significant local structural changes. The structural findings of the present study suggest that the protective influence of the E219K polymorphism is due to the alteration of surface charge distribution, in addition to subtle structural rearrangements localized within the epitopes critical for prion conversion.