PDF(Pubmed)
Abstract：
Human islet amyloid polypeptide (hIAPP) forms amyloid deposits that contribute to β-cell death in pancreatic islets and are considered a hallmark of Type II diabetes Mellitus (T2DM). Evidence suggests that the early oligomers of hIAPP formed during the aggregation process are the primary pathological agent in islet amyloid induced β-cell death. The self-assembly mechanism of hIAPP, however, remains elusive, largely due to limitations in conventional biophysical techniques for probing the distribution or capturing detailed structures of the early, structurally dynamic oligomers. The advent of Ion-mobility Mass Spectrometry (IM-MS) has enabled the characterisation of hIAPP early oligomers in the gas phase, paving the way towards a deeper understanding of the oligomerisation mechanism and the correlation of structural information with the cytotoxicity of the oligomers. The sensitivity and the rapid structural characterisation provided by IM-MS also show promise in screening hIAPP inhibitors, categorising their modes of inhibition through \"spectral fingerprints\". This review delves into the application of IM-MS to the dissection of the complex steps of hIAPP oligomerisation, examining the inhibitory influence of metal ions, and exploring the characterisation of hetero-oligomerisation with different hIAPP variants. We highlight the potential of IM-MS as a tool for the high-throughput screening of hIAPP inhibitors, and for providing insights into their modes of action. Finally, we discuss advances afforded by recent advancements in tandem IM-MS and the combination of gas phase spectroscopy with IM-MS, which promise to deliver a more sensitive and higher-resolution structural portrait of hIAPP oligomers. Such information may help facilitate a new era of targeted therapeutic strategies for islet amyloidosis in T2DM.
摘要：
人胰岛淀粉样多肽（hIAPP）形成淀粉样沉积物，导致胰岛β细胞死亡，被认为是II型糖尿病（T2DM）的标志。证据表明，在聚集过程中形成的hIAPP的早期寡聚体是胰岛淀粉样蛋白诱导的β细胞死亡的主要病理因素。HIAPP的自组装机制，然而,仍然难以捉摸，很大程度上是由于传统生物物理技术的局限性，用于探测早期的分布或捕获详细的结构，结构动态低聚物。离子迁移质谱（IM-MS）的出现使气相中hIAPP早期低聚物的表征成为可能，为更深入了解寡聚化机制以及结构信息与寡聚体细胞毒性的相关性铺平了道路。IM-MS提供的灵敏度和快速结构表征在筛选hIAPP抑制剂方面也显示出希望，通过“光谱指纹”对其抑制模式进行分类。本文综述了IM-MS在解剖hIAPP寡聚化复杂步骤中的应用，检查金属离子的抑制作用，并探索不同hIAPP变体的异源寡聚化表征。我们强调IM-MS作为高通量筛选hIAPP抑制剂的工具的潜力，并为他们的行动模式提供见解。最后,我们讨论了串联IM-MS的最新进展以及气相光谱法与IM-MS的结合所带来的进展，这有望提供更灵敏和更高分辨率的hIAPP寡聚体结构肖像。这些信息可能有助于促进T2DM中胰岛淀粉样变性的靶向治疗策略的新时代。
