Peim Alexander, Hortschansky Peter, Christopeit Tony, Schroeckh Volker, Richter Walter, Fändrich Marcus
Leibniz-Institut für Altersforschung, Jena, Germany.
Protein Sci. 2006 Jul;15(7):1801-5. doi: 10.1110/ps.062116206. Epub 2006 Jun 2.
Amyloid formation is a nucleation-dependent process that is accelerated dramatically in vivo and in vitro upon addition of appropriate fibril seeds. A potent species barrier can be effective in this reaction if donor and recipient come from different biological species. This species barrier is thought to reflect differences in the amino acid sequence between seed and target polypeptide. Here we present an in vitro mutagenic cross-seeding analysis of Alzheimer's Abeta(1-40) peptide in which we mapped out the effect of systematically varied amino acid replacements on the propensity of seed-dependent amyloid fibril formation. We find that the susceptibility of different peptides toward cross-seeding relates to the intrinsic aggregation propensity of the respective polypeptide chain and, therefore, to properties such as beta-sheet propensity and hydrophobicity. These data imply that the seed-dependent formation of amyloid-like fibrils is affected by the intrinsic properties of the polypeptide chain in a manner that is similar to what has been described previously for aggregation reactions in general. Hence, the nucleus acts in this case as a catalyst that promotes the fibrillation of different polypeptide chains according to their intrinsic structural predilection.
淀粉样蛋白的形成是一个依赖成核的过程，在体内和体外，添加合适的纤维种子后，该过程会显著加速。如果供体和受体来自不同的生物物种，强大的物种屏障可能会在这个反应中起作用。这种物种屏障被认为反映了种子多肽和目标多肽之间氨基酸序列的差异。在这里，我们展示了对阿尔茨海默病β-淀粉样蛋白（1-40）肽的体外诱变交叉接种分析，其中我们描绘了系统变化的氨基酸替换对种子依赖性淀粉样纤维形成倾向的影响。我们发现，不同肽对交叉接种的敏感性与各自多肽链的内在聚集倾向有关，因此与诸如β-折叠倾向和疏水性等性质有关。这些数据表明，种子依赖性的类淀粉样纤维形成受到多肽链内在性质的影响，其方式与之前一般描述的聚集反应类似。因此，在这种情况下，核作为一种催化剂，根据不同多肽链的内在结构偏好促进其纤维化。
