United Graduate School of Drug Discovery and Medical Information Sciences, Gifu University, Tokai National Higher Education and Research System, Gifu, Japan.
Institute for Glyco-core Research, Tokai National Higher Education and Research System, Gifu, Japan.
Prion. 2021 Dec;15(1):37-43. doi: 10.1080/19336896.2021.1910176.
Intermolecular interaction between hPrP and αS was investigated using high-speed atomic force microscopy, dynamic light scattering, and nuclear magnetic resonance. We found that hPrP spontaneously gathered and naturally formed oligomers. Upon addition of monomer αS with a disordered conformation, poly-dispersive property of hPrP was lost, and hetero-dimer formation started quite coherently, and further oligomerization was not observed. Solution structure of hPrP-αS dimer was firstly characterized using hetero-nuclear NMR spectroscopy. In this hetero-dimeric complex, C-terminal helical region of hPrP was in the molten-globule like state, while specific sites including hot spot and C-terminal region of αS selectively interacted with hPrP. Thus αS may suppress amyloidogenesis of hPrP by trapping the hPrP intermediate by the formation of a stable hetero-dimer with hPrP. hPrP, human prion protein of amino acid residues of 23-231; PrP, cellular form of prion protein; PrP, scrapie form of prion protein, HS-AFM; high speed atomic force microscopy; αS, α-synuclein; DLS, dynamic light scattering.
使用高速原子力显微镜、动态光散射和核磁共振研究了 hPrP 与 αS 之间的分子间相互作用。我们发现 hPrP 会自发聚集并自然形成寡聚物。当加入具有无序构象的单体 αS 时，hPrP 的多分散性丧失，异二聚体的形成开始相当一致，并且没有观察到进一步的寡聚化。使用异核 NMR 光谱首次对 hPrP-αS 二聚体的溶液结构进行了表征。在这个异二聚体复合物中，hPrP 的 C 端螺旋区处于无定形的类似熔化状态，而包括热点和 αS 的 C 端区域在内的特定部位与 hPrP 选择性相互作用。因此，αS 可能通过与 hPrP 形成稳定的异二聚体来捕获 hPrP 中间体，从而抑制 hPrP 的淀粉样变。hPrP，人类朊病毒蛋白 23-231 个氨基酸残基；PrP，朊病毒蛋白的细胞形式；PrP，朊病毒蛋白的瘙痒形式，HS-AFM；高速原子力显微镜；αS，α-突触核蛋白；DLS，动态光散射。
