Institute for Protein Research, Osaka University, 3-2 Yamadaoka, Suita, Osaka 565-0871, Japan.
J Mol Biol. 2012 Sep 21;422(3):390-402. doi: 10.1016/j.jmb.2012.05.034. Epub 2012 Jun 6.
Amyloid fibrils are proteinous aggregates associated with various diseases, including Alzheimer's disease, type II diabetes, and dialysis-related amyloidosis. It is generally thought that, during the progression of these diseases, a precursor peptide or protein assumes a partially denatured structure, which interacts with the fibril seed to change into the final amyloid form. β2-Microglobulin (β2m), associated with dialysis-related amyloidosis, is known to form amyloid fibrils at low pH via a partially structured state. However, the molecular mechanism by which the conformation of β2m changes from the precursor to the final fibril structure is poorly understood. We performed various NMR experiments to characterize acid-denatured β2m. The analysis of the transverse relaxation rates revealed that acid-denatured β2m undergoes a structural exchange with an extensively unfolded form. The results of transferred cross-saturation experiments indicated that residues with a residual structure in the acid-denatured state are associated with the interaction with the fibril seed. Our experimental data suggest the partially structured state to be "activated" to become extensively unfolded, in which state the hydrophobic residues are exposed and associate with the seed. Our results provide general information about the extension of amyloid fibrils.
淀粉样纤维是与多种疾病相关的蛋白质聚集物，包括阿尔茨海默病、2 型糖尿病和透析相关淀粉样变性。一般认为，在这些疾病的进展过程中，前体肽或蛋白质呈现部分变性结构，与纤维种子相互作用转化为最终的淀粉样形式。β2-微球蛋白（β2m）与透析相关淀粉样变性有关，已知在低 pH 值下通过部分结构状态形成淀粉样纤维。然而，β2m 的构象从前体到最终纤维结构的变化的分子机制还了解甚少。我们进行了各种 NMR 实验来表征酸变性的β2m。横向弛豫率的分析表明，酸变性的β2m 经历与广泛展开形式的结构交换。转移交叉饱和实验的结果表明，在酸变性状态下具有残留结构的残基与纤维种子的相互作用有关。我们的实验数据表明部分结构状态被“激活”以变得广泛展开，在这种状态下，疏水性残基暴露并与种子结合。我们的结果提供了关于淀粉样纤维延伸的一般信息。
