Akbarian Mohsen, Kianpour Maryam, Yousefi Reza, Moosavi-Movahedi Ali Akbar
Protein Chemistry Laboratory (PCL), Department of Biology, College of Sciences, Shiraz University Shiraz Iran.
Institute of Biochemistry and Biophysics (IBB), The University of Tehran Tehran Iran
RSC Adv. 2020 Aug 13;10(50):29885-29899. doi: 10.1039/d0ra05414c. eCollection 2020 Aug 10.
Insulin rapidly fibrillates in the presence of amyloid seeds from different sources. To address its cross-reactivity we chose the seeds of seven model proteins and peptides along with the seeds of insulin itself. Model candidates were selected/designed according to their size, amino acid sequence, and hydrophobicity. We found while some seeds provided catalytic ends for inducing the formation of non-native insulin conformers and increase fibrillation, others attenuated insulin fibrillation kinetics. We also observed competition between the intermediate insulin conformers which formed with urea and amyloid seeds in entering the fibrillogenic pathway. Simultaneous incubation of insulin with urea and amyloid seeds resulted in the formation of nearly similar insulin intermediate conformers which synergistically enhance insulin fibrillation kinetics. Given these results, it is highly likely that, structurally, there is a specific intermediate in different pathways of insulin fibrillation that governs fibrillation kinetics and morphology of the final mature fibril. Overall, this study provides a novel mechanistic insight into insulin fibrillation and gives new information on how seeds of different proteins are capable of altering insulin fibrillation kinetics and morphology. This report, for the first time, tries to answer an important question that why fibrillation of insulin is either accelerated or attenuated in the presence of amyloid fibril seeds from different sources.
在存在来自不同来源的淀粉样蛋白种子的情况下，胰岛素会迅速形成纤维。为了研究其交叉反应性，我们选择了七种模型蛋白质和肽的种子以及胰岛素自身的种子。根据模型候选物的大小、氨基酸序列和疏水性进行选择/设计。我们发现，虽然一些种子为诱导非天然胰岛素构象体的形成并加速纤维化提供了催化末端，但其他种子则减弱了胰岛素的纤维化动力学。我们还观察到，在进入纤维化途径时，由尿素和淀粉样蛋白种子形成的中间胰岛素构象体之间存在竞争。胰岛素与尿素和淀粉样蛋白种子同时孵育会导致形成几乎相似的胰岛素中间构象体，这些构象体协同增强胰岛素的纤维化动力学。鉴于这些结果，很有可能在结构上，胰岛素纤维化的不同途径中存在一种特定的中间体，它控制着最终成熟纤维的纤维化动力学和形态。总体而言，本研究为胰岛素纤维化提供了新的机制见解，并提供了关于不同蛋白质的种子如何能够改变胰岛素纤维化动力学和形态的新信息。本报告首次试图回答一个重要问题，即为什么在存在来自不同来源的淀粉样纤维种子的情况下，胰岛素的纤维化会加速或减弱。
