A beta Peptide Fibrillar Architectures Controlled by Conformational Constraints of the Monomer

作者：Brannstrom Kristoffer^*; Ohman Anders; Olofsson Anders

来源：PLos One, 2011, 6(9): e25157.

DOI：10.1371/journal.pone.0025157

Anomalous self-assembly of the A beta peptide into fibrillar amyloid deposits strongly correlated with the development of Alzheimer's disease. A beta 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 A beta 1-40 Glu22Gly (A beta(40Arc)) and wild type A beta 1-40 (A beta(40WT)). 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 A beta(40WT) is significantly impaired to acquire the fibrillar architecture of A beta(40Arc). A detailed characterisation demonstrated that A beta(40WT) has a restricted ability to dock and isomerise with high binding affinity onto A beta(40Arc) 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 formation rather than the thermodynamically lowest energy state determines the overall fibrillar structure.

• 出版日期2011-9-29