Applied Physics, University of Tübingen, Tübingen, Baden-Würtemberg, Germany.
University of Surrey Ion Beam Centre, Guildford, United Kingdom.
Biophys J. 2021 Mar 2;120(5):886-898. doi: 10.1016/j.bpj.2020.11.2280. Epub 2021 Feb 3.
Protein aggregation is a widespread process leading to deleterious consequences in the organism, with amyloid aggregates being important not only in biology but also for drug design and biomaterial production. Insulin is a protein largely used in diabetes treatment, and its amyloid aggregation is at the basis of the so-called insulin-derived amyloidosis. Here, we uncover the major role of zinc in both insulin dynamics and aggregation kinetics at low pH, in which the formation of different amyloid superstructures (fibrils and spherulites) can be thermally induced. Amyloid aggregation is accompanied by zinc release and the suppression of water-sustained insulin dynamics, as shown by particle-induced x-ray emission and x-ray absorption spectroscopy and by neutron spectroscopy, respectively. Our study shows that zinc binding stabilizes the native form of insulin by facilitating hydration of this hydrophobic protein and suggests that introducing new binding sites for zinc can improve insulin stability and tune its aggregation propensity.
蛋白质聚集是一种广泛存在的过程，会对生物体造成有害影响，其中淀粉样蛋白聚集不仅在生物学中很重要，而且对于药物设计和生物材料生产也很重要。胰岛素是一种在糖尿病治疗中广泛使用的蛋白质，其淀粉样蛋白聚集是所谓的胰岛素衍生淀粉样变性的基础。在这里，我们揭示了锌在低 pH 值下胰岛素动力学和聚集动力学中的主要作用，在这种情况下，可以通过热诱导形成不同的淀粉样超结构（纤维和球晶）。淀粉样蛋白聚集伴随着锌的释放和对水维持的胰岛素动力学的抑制，这一点分别通过粒子诱导 X 射线发射和 X 射线吸收光谱以及中子光谱得到证实。我们的研究表明，锌结合通过促进这种疏水性蛋白质的水合作用稳定胰岛素的天然形式，并表明引入新的锌结合位点可以提高胰岛素的稳定性并调节其聚集倾向。
