Molecular architecture of human prion protein amyloid:: A parallel, in-register β-structure
Molecular architecture of human prion protein amyloid:: A parallel, in-register β-structure
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DOI：
10.1073/pnas.0706522104
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发表时间：
2007-11-27
影响因子：
11.1
通讯作者：
Surewicz, Witold K.
中科院分区：
文献类型：
--
作者：
Cobb, Nathan J.;Soennichsen, Frank D.;Surewicz, Witold K.
传染性海绵状脑病（tse）是一组致命的神经退行性疾病，与通常的单体和α -螺旋朊蛋白PrPC向富含β -片的PrPSc的构象转换有关。后一种构象被认为构成传染性TSE病原体的主要成分。与PrPC单体的高分辨率数据相比，致病性PrPSc或合成PrPSc样聚集体的结构仍然难以捉摸。在这里，我们使用了位点定向自旋标记和EPR光谱来探测重组PrP淀粉样蛋白的分子结构，这是一种错误折叠的形式，最近报道在过度表达n端截断形式的PrPC的小鼠中诱导传染性疾病。我们的数据表明，与早期的主要理论模型相反，PrPC的构象转换涉及c端α -螺旋区域的主要再折叠。淀粉样蛋白的核心映射到c端残基，从大约160-220，这些残基形成单分子层，以平行的，在寄存器内对齐的β链堆叠在一起。这一结构洞察对于理解朊病毒传播的分子基础以及遗传性朊病毒疾病具有重要意义，其中大多数与发现发生重折叠到β结构的区域的点突变有关。
Transmissible spongiform encephalopathies (TSEs) represent a group of fatal neurodegenerative diseases that are associated with conformational conversion of the normally monomeric and alpha-helical prion protein, PrPC, to the beta-sheet-rich PrPSc. This latter conformer is believed to constitute the main component of the infectious TSE agent. In contrast to high-resolution data for the PrPC monomer, structures of the pathogenic PrPSc or synthetic PrPSc-like aggregates remain elusive. Here we have used site-directed spin labeling and EPR spectroscopy to probe the molecular architecture of the recombinant PrP amyloid, a misfolded form recently reported to induce transmissible disease in mice over-expressing an N-terminally truncated form of PrPC. Our data show that, in contrast to earlier, largely theoretical models, the conformational conversion of PrPC involves major refolding of the C-terminal alpha-helical region. The core of the amyloid maps to C-terminal residues from approximate to 160-220, and these residues form single-molecule layers that stack on top of one another with parallel, in-register alignment of beta-strands. This structural insight has important implications for understanding the molecular basis of prion propagation, as well as hereditary prion diseases, most of which are associated with point mutations in the region found to undergo a refolding to beta-structure.