Dipartimento di Bioscienze, Università degli Studi di Milano, 20133, Milano, Italy.
Amyloidosis Research and Treatment Center, Fondazione IRCCS Policlinico San Matteo, and Department of Molecular Medicine, University of Pavia, 27100, Pavia, Italy.
Sci Rep. 2017 Dec 1;7(1):16809. doi: 10.1038/s41598-017-16953-7.
Light chain amyloidosis (AL), the most common systemic amyloidosis, is caused by the overproduction and the aggregation of monoclonal immunoglobulin light chains (LC) in target organs. Due to genetic rearrangement and somatic hypermutation, virtually, each AL patient presents a different amyloidogenic LC. Because of such complexity, the fine molecular determinants of LC aggregation propensity and proteotoxicity are, to date, unclear; significantly, their decoding requires investigating large sets of cases. Aiming to achieve generalizable observations, we systematically characterised a pool of thirteen sequence-diverse full length LCs. Eight amyloidogenic LCs were selected as responsible for severe cardiac symptoms in patients; five non-amyloidogenic LCs were isolated from patients affected by multiple myeloma. Our comprehensive approach (consisting of spectroscopic techniques, limited proteolysis, and X-ray crystallography) shows that low fold stability and high protein dynamics correlate with amyloidogenic LCs, while hydrophobicity, structural rearrangements and nature of the LC dimeric association interface (as observed in seven crystal structures here presented) do not appear to play a significant role in defining amyloid propensity. Based on the structural and biophysical data, our results highlight shared properties driving LC amyloid propensity, and these data will be instrumental for the design of synthetic inhibitors of LC aggregation.
轻链淀粉样变性（AL）是最常见的系统性淀粉样变性，由单克隆免疫球蛋白轻链（LC）在靶器官中的过度产生和聚集引起。由于遗传重排和体细胞超突变，实际上每个 AL 患者都存在不同的淀粉样变性 LC。由于这种复杂性，LC 聚集倾向和蛋白毒性的精细分子决定因素尚不清楚；重要的是，它们的解码需要研究大量的病例。为了实现可推广的观察结果，我们系统地描述了一组 13 种序列多样的全长 LC。选择了 8 种淀粉样变性 LC，它们是导致患者严重心脏症状的原因；从多发性骨髓瘤患者中分离出 5 种非淀粉样变性 LC。我们的综合方法（包括光谱技术、有限蛋白水解和 X 射线晶体学）表明，低折叠稳定性和高蛋白质动力学与淀粉样变性 LC 相关，而疏水性、结构重排和 LC 二聚体结合界面的性质（如这里呈现的七个晶体结构中观察到的）似乎在定义淀粉样倾向方面没有起到重要作用。基于结构和生物物理数据，我们的结果突出了驱动 LC 淀粉样倾向的共同特性，这些数据将对 LC 聚集的合成抑制剂的设计具有重要意义。
