Meinhardt Jessica, Tartaglia Gian Gaetano, Pawar Amol, Christopeit Tony, Hortschansky Peter, Schroeckh Volker, Dobson Christopher M, Vendruscolo Michele, Fändrich Marcus
Leibniz-Institut für Altersforschung, Fritz-Lipmann-Institut, D-07745 Jena, Germany.
Protein Sci. 2007 Jun;16(6):1214-22. doi: 10.1110/ps.062734207.
Increasing evidence indicates that polypeptide aggregation often involves a nucleation and a growth phase, although the relationship between the factors that determine these two phases has not yet been fully clarified. We present here an analysis of several mutations at different sites of the Abeta(1-40) peptide, including those associated with early onset forms of the Alzheimer's disease, which reveals that the effects of specific amino acid substitutions in the sequence of this peptide are strongly modulated by their structural context. Nevertheless, mutations at different positions perturb in a correlated manner the free energies of aggregation as well as the lag times and growth rates. We show that these observations can be rationalized in terms of the intrinsic propensities for aggregation of the Abeta(1-40) sequence, thus suggesting that, in the case of this peptide, the determinants of the thermodynamics and of the nucleation and growth of the aggregates have a similar physicochemical basis.
越来越多的证据表明，多肽聚集通常涉及成核和生长阶段，尽管决定这两个阶段的因素之间的关系尚未完全阐明。我们在此对β淀粉样蛋白（1-40）肽不同位点的几个突变进行了分析，包括那些与早发性阿尔茨海默病相关的突变，结果显示该肽序列中特定氨基酸取代的影响受到其结构背景的强烈调节。然而，不同位置的突变以相关方式扰动聚集的自由能以及滞后时间和生长速率。我们表明，这些观察结果可以根据β淀粉样蛋白（1-40）序列的内在聚集倾向来合理化，从而表明，对于这种肽而言，聚集体的热力学、成核和生长的决定因素具有相似的物理化学基础。
