Valdés-García Gilberto, Millán-Pacheco César, Pastor Nina
Centro de Investigación en Dinámica Celular-IICBA, Universidad Autónoma del Estado de Morelos, Cuernavaca, Morelos, México.
Facultad de Farmacia; Universidad Autónoma del Estado de Morelos, Cuernavaca, Morelos, México.
Biopolymers. 2017 Aug;107(8). doi: 10.1002/bip.23027.
Extracellular deposition as amyloids of immunoglobulin light chains causes light chain amyloidosis. Among the light chain families, lambda 6a is one of the most frequent in light chain amyloidosis patients. Its germline protein, 6aJL2, and point mutants, R24G and P7S, are good models to study fibrillogenesis, because their stability and fibril formation characteristics have been described. Both mutations make the germline protein unstable and speed up its ability to aggregate. To date, there is no molecular mechanism that explains how these differences in amyloidogenesis can arise from a single mutation. To look into the structural and dynamical differences in the native state of these proteins, we carried out molecular dynamics simulations at room temperature. Despite the structural similarity of the germline protein and the mutants, we found differences in their dynamical signatures that explain the mutants' increased tendency to form amyloids. The contact network alterations caused by the mutations, though different, converge in affecting two anti-aggregation motifs present in light chain variable domains, suggesting a different starting point for aggregation in lambda chains compared to kappa chains.
免疫球蛋白轻链以淀粉样蛋白形式在细胞外沉积会导致轻链淀粉样变性。在轻链家族中，λ6a是轻链淀粉样变性患者中最常见的一种。其种系蛋白6aJL2以及点突变体R24G和P7S是研究纤维形成的良好模型，因为它们的稳定性和纤维形成特性已被描述。这两种突变都会使种系蛋白不稳定，并加快其聚集能力。迄今为止，尚无分子机制能解释淀粉样变性中的这些差异是如何由单个突变产生的。为了探究这些蛋白质天然状态下的结构和动力学差异，我们在室温下进行了分子动力学模拟。尽管种系蛋白和突变体在结构上相似，但我们发现它们的动力学特征存在差异，这解释了突变体形成淀粉样蛋白的倾向增加。突变引起的接触网络改变虽各不相同，但都集中影响轻链可变域中存在的两个抗聚集基序，这表明与κ链相比，λ链的聚集起始点不同。
