Baram Michal, Gilead Sharon, Gazit Ehud, Miller Yifat
Department of Chemistry , Ben-Gurion University of the Negev , Be'er Sheva 84105 , Israel . Email:
The Ilse Katz Institute for Nanoscale Science & Technology , Ben-Gurion University of the Negev , Be'er Sheva 84105 , Israel.
Chem Sci. 2018 Apr 16;9(18):4244-4252. doi: 10.1039/c8sc00481a. eCollection 2018 May 14.
Insulin is a key regulatory polypeptide that is secreted from pancreatic β-cells and has several important effects on the synthesis of lipids, regulation of enzymatic activities, blood glucose levels and the prevention of hyperglycemia. Insulin was demonstrated to self-assemble into ordered amyloid fibrils upon repeated injections, although the possible biological significance of the supramolecular structures is enigmatic. Amylin is also an amyloidogenic polypeptide that is secreted from pancreatic β-cells and plays an important role in glycemic regulation preventing post-prandial spikes in blood glucose levels. These two amyloidogenic proteins are secreted together from the pancreas and have the ability to interact and produce insulin-amylin aggregates. So far, the molecular architecture of insulin-amylin complexes at the atomic resolution has been unknown. The current work identifies for the first time the specific π-π interactions between Y16 in insulin and F19 in amylin that contribute to the stability of the insulin-amylin complex, by using experimental and molecular modeling techniques. We performed additional experiments that verify the functional activity of insulin in amylin aggregation. Our findings illustrate for the first time the specific interactions between insulin and amylin aggregates at the atomic resolution and provide a new mechanistic perspective on the effect of insulin on amylin aggregation and may pave the way towards pharmacological intervention in this process.
胰岛素是一种关键的调节多肽，由胰腺β细胞分泌，对脂质合成、酶活性调节、血糖水平及预防高血糖具有多种重要作用。尽管超分子结构的潜在生物学意义尚不明确，但胰岛素在反复注射后会自组装成有序的淀粉样纤维。胰淀素也是一种由胰腺β细胞分泌的淀粉样生成多肽，在血糖调节中发挥重要作用，可防止餐后血糖水平飙升。这两种淀粉样生成蛋白从胰腺共同分泌，且能够相互作用并形成胰岛素 - 胰淀素聚集体。到目前为止，胰岛素 - 胰淀素复合物在原子分辨率下的分子结构尚不清楚。当前的研究工作首次通过实验和分子建模技术，确定了胰岛素中Y16与胰淀素中F19之间特定的π - π相互作用，这种相互作用有助于胰岛素 - 胰淀素复合物的稳定性。我们还进行了额外的实验，验证了胰岛素在胰淀素聚集过程中的功能活性。我们的研究结果首次在原子分辨率下阐明了胰岛素与胰淀素聚集体之间的特定相互作用，为胰岛素对胰淀素聚集的影响提供了新的机制视角，并可能为该过程的药物干预铺平道路。
