Department of Molecular Pathobiochemistry, Graduate School of Medicine, Gifu University, Gifu, Japan.
United Graduate School of Drug Discovery and Medical Information Sciences, Gifu University, Gifu, Japan.
FASEB J. 2018 Jul;32(7):3641-3652. doi: 10.1096/fj.201701183RR. Epub 2018 Feb 1.
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 Φ-value analysis indicated that the helix 2 region (residues 168-196) acquires an amyloid-like β-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.
淀粉样纤维是与多种人类疾病发病机制相关的丝状蛋白聚集物。这种聚集物的形成通常遵循核依赖性动力学，其中淀粉样蛋白的组装和结构转化为低聚物聚集物（核）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人朊病毒蛋白（PrP）C 端 107 个残基 14-44 的缺失突变体，来获得有关 PrP 低聚物核的结构见解，并研究这些突变体在淀粉样形成中的动力学和热力学性质。使用Φ值分析的概念对实验数据进行分析表明，在成核过程中，螺旋 2 区（残基 168-196）获得类似淀粉样的β-折叠，而其他区域在核中保持相对无序的结构。这一发现表明，螺旋 2 区是组装淀粉样纤维的成核部位。-本田，R.，桑田 K. 证据表明 PrP 螺旋 2 在淀粉样纤维成核中起核心作用。
