aβ peptide fibrillar architectures controlled by conformational constraints of the monomeraβ肽原纤结构的构象限制单体控制.pdf

Ab Peptide Fibrillar Architectures Controlled by Conformational Constraints of the Monomer ¨ ¨ 1 ¨ 2 1 Kristoffer Brannstrom , Anders Ohman *, Anders Olofsson * ˚ ˚ ˚ ˚ 1 Department of Medical Biochemistry and Biophysics, Umea University, Umea, Sweden, 2 Department of Chemistry, Umea University, Umea, Sweden Abstract Anomalous self-assembly of the Ab peptide into fibrillar amyloid deposits is strongly correlated with the development of Alzheimer’s disease. Ab fibril extension follows a template guided ‘‘dock and lock’’ mechanism where polymerisation is catalysed by the fibrillar ends. Using surface plasmon resonance (SPR) and quenched hydrogen-deuterium exchange NMR (H/D-exchange NMR), we have analysed the fibrillar structure and polymerisation properties of both the highly aggregation prone Ab1–40 Glu22Gly (Ab40Arc) and wild type Ab1–40 (Ab40WT). The solvent protection patterns from H/D exchange experiments suggest very similar structures of the fibrillar forms. However, through cross-seeding experiments monitored by SPR, we found that the monomeric form of Ab40WT is significantly impaired to acquire the fibrillar architecture of Ab40Arc. A detailed characterisation demonstrated that Ab40WT has a restricted ability to dock and isomerise with high binding affinity onto Ab40Arc fibrils. These results have general implications for the process of fibril assembly, where the rate of polymerisation, and consequently the architecture of the formed fibrils, is restricted by conformational constraints of the monomers. Interestingly, we also found that the kinetic rate of fibril