Evidence for a central role of PrP helix 2 in the nucleation of amyloid fibrils
Evidence for a central role of PrP helix 2 in the nucleation of amyloid fibrils
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DOI：
10.1096/fj.201701183rr
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发表时间：
2018-07-01
期刊：
影响因子：
4.8
通讯作者：
Kuwata, Kazuo
中科院分区：
文献类型：
--
作者：
Honda, Ryo;Kuwata, Kazuo
淀粉样原纤维是与多种人类疾病的发病机制相关的丝状蛋白质聚集体。这种聚集体的形成通常遵循成核依赖性动力学，其中淀粉样蛋白生成蛋白向寡聚聚集体（核）的组装和结构转化是整个反应的限速步骤。在这项研究中，我们试图通过制备一系列缺失突变体来获得对人朊病毒蛋白（PrP）寡聚核的结构见解，这些缺失突变体缺失PrP C-末端107个残基中的14-44个，并检查这些突变体在淀粉样蛋白形成中的动力学和热力学。使用φ值分析的概念的实验数据的分析表明，螺旋2区域（残基168-196）获得淀粉样蛋白样片层在成核过程中，而其他区域保留相对无序的结构在核中。这一发现表明，螺旋2区域作为淀粉样纤维组装的成核位点。桑田湾PrP螺旋2在淀粉样纤维成核中的核心作用的证据。
Amyloid fibrils are filamentous protein aggregates associated with the pathogenesis of a wide variety of human diseases. The formation of such aggregates typically follows nucleation-dependent kinetics, wherein the assembly and structural conversion of amyloidogenic proteins into oligomeric aggregates (nuclei) is the rate-limiting step of the overall reaction. In this study, we sought to gain structural insights into the oligomeric nuclei of the human prion protein (PrP) by preparing a series of deletion mutants lacking 14-44 of the C-terminal 107 residues of PrP and examined the kinetics and thermodynamics of these mutants in amyloid formation. An analysis of the experimental data using the concepts of the phi-value analysis indicated that the helix 2 region (residues 168-196) acquires an amyloid-like -sheet during nucleation, whereas the other regions preserves a relatively disordered structure in the nuclei. This finding suggests that the helix 2 region serves as the nucleation site for the assembly of amyloid fibrils.Honda, R., Kuwata, K. Evidence for a central role of PrP helix 2 in the nucleation of amyloid fibrils.