Monomeric α-synuclein (αS) inhibits amyloidogenesis of human prion protein (hPrP) by forming a stable αS-hPrP hetero-dimer.

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. <b>Abbreviations:</b> hPrP, human prion protein of amino acid residues of 23-231; PrP^C, cellular form of prion protein; PrP^Sc, scrapie form of prion protein, HS-AFM; high speed atomic force microscopy; αS, α-synuclein; DLS, dynamic light scattering

本研究采用高速原子力显微镜（high-speed atomic force microscopy, HS-AFM）、动态光散射（dynamic light scattering, DLS）及核磁共振（nuclear magnetic resonance, NMR）技术，对人朊蛋白（human prion protein, hPrP）与α-突触核蛋白（α-synuclein, αS）之间的分子间相互作用展开探究。实验发现，hPrP可自发聚集并自然形成寡聚体；当向体系中加入构象无序的单体αS后，hPrP的多分散性消失，异源二聚体开始稳定形成，且未观察到进一步的寡聚化过程。本研究首次通过异核核磁共振波谱法表征了hPrP-αS异源二聚体的溶液结构。在该异源二聚体复合物中，hPrP的C端螺旋区处于类熔球态，而αS的特定位点（包括热点区域与C端区域）可选择性与hPrP结合。据此推测，αS可通过与hPrP形成稳定异源二聚体捕获hPrP中间产物，从而抑制hPrP的淀粉样蛋白生成过程。<b>缩写说明：</b> hPrP，氨基酸残基23-231位的人朊蛋白；PrP^C，朊蛋白的细胞型；PrP^Sc，朊蛋白的瘙痒病型；HS-AFM，高速原子力显微镜；αS，α-突触核蛋白；DLS，动态光散射