Moracci Laura, Crotti Sara, Traldi Pietro, Agostini Marco, Cosma Chiara, Lapolla Annunziata
Department of Surgical, Oncological and Gastroenterological Sciences, University of Padova, Padova, Italy.
Fondazione Istituto di Ricerca Pediatrica Città della Speranza, Padova, Italy.
Mass Spectrom Rev. 2023 May;42(3):984-1007. doi: 10.1002/mas.21732. Epub 2021 Sep 24.
Amylin (islet amyloid polypeptide [IAPP]) is a neuroendocrine hormone synthesized with insulin in the beta cells of pancreatic islets. The two hormones act in different ways: in fact insulin triggers glucose uptake in muscle and liver cells, removing glucose from the bloodstream and making it available for energy use and storage, while amylin regulates glucose homeostasis. Aside these positive physiological aspects, human amyloid polypeptide (hIAPP) readily forms amyloid in vitro. Amyloids are aggregates of proteins and in the human body amyloids are considered responsible of the development of various diseases. These aspects have been widely described and discussed in literature and to give a view of the highly complexity of this biochemical behavior the different physical, chemical, biological and medical aspects are shortly described in this review. It is strongly affected by the presence on metal ions, responsible for or inhibiting the formation of fibrils. Mass spectrometry resulted (and still results) to be a particularly powerful tool to obtain valid and effective experimental data to describe the hIAPP behavior. Aside classical approaches devoted to investigation on metal ion-hIAPP structures, which reflects on the identification of metal-protein interaction site(s) and of possible metal-induced conformational changes of the protein, interesting results have been obtained by ion mobility mass spectrometry, giving, on the basis of collisional cross-section data, information on both the oligomerization processes and the conformation changes. Laser ablation electrospray ionization-ion mobility spectrometry-mass spectrometry (LAESI-IMS-MS), allowed to obtain information on the binding stoichiometry, complex dissociation constant, and the oxidation state of the copper for the amylin-copper interaction. Alternatively to inorganic ions, small organic molecules have been tested by ESI-IMS-MS as inhibitor of amyloid assembly. Also in this case the obtained data demonstrate the validity of the ESI-IMS-MS approach as a high-throughput screen for inhibitors of amyloid assembly, providing valid information concerning the identity of the interacting species, the nature of binding and the effect of the ligand on protein aggregation. Effects of Cu and Zn ions in the degradation of human and murine IAPP by insulin-degrading enzyme were studied by liquid chromatography/mass spectrometry (LC/MS). The literature data show that mass spectrometry is a highly valid and effective tool in the study of the amylin behavior, so to individuate medical strategies to avoid the undesired formation of amyloids in in vivo conditions.
胰淀素（胰岛淀粉样多肽[IAPP]）是一种与胰岛素一起在胰岛β细胞中合成的神经内分泌激素。这两种激素的作用方式不同：实际上，胰岛素触发肌肉和肝细胞对葡萄糖的摄取，将葡萄糖从血液中清除，使其可用于能量利用和储存，而胰淀素则调节葡萄糖稳态。除了这些积极的生理方面，人淀粉样多肽（hIAPP）在体外很容易形成淀粉样蛋白。淀粉样蛋白是蛋白质的聚集体，在人体中，淀粉样蛋白被认为是各种疾病发展的原因。这些方面在文献中已有广泛描述和讨论，为了展现这种生化行为的高度复杂性，本综述简要描述了不同的物理、化学、生物和医学方面。它受到金属离子存在的强烈影响，金属离子会导致或抑制原纤维的形成。质谱法一直是获取有效实验数据以描述hIAPP行为的特别强大的工具。除了致力于研究金属离子-hIAPP结构的经典方法（这反映在金属-蛋白质相互作用位点的识别以及蛋白质可能的金属诱导构象变化上），离子淌度质谱法也取得了有趣的结果，基于碰撞截面数据，它能提供有关寡聚化过程和构象变化的信息。激光烧蚀电喷雾电离-离子淌度光谱-质谱法（LAESI-IMS-MS）能够获取有关胰淀素-铜相互作用的结合化学计量、络合物解离常数以及铜的氧化态的信息。作为无机离子的替代物，小分子有机化合物已通过电喷雾电离-离子淌度质谱法（ESI-IMS-MS）作为淀粉样蛋白组装抑制剂进行了测试。在这种情况下，所获得的数据也证明了ESI-IMS-MS方法作为淀粉样蛋白组装抑制剂高通量筛选方法的有效性，它提供了有关相互作用物种的身份、结合性质以及配体对蛋白质聚集影响的有效信息。通过液相色谱/质谱法（LC/MS）研究了铜离子和锌离子对胰岛素降解酶降解人和小鼠IAPP的影响。文献数据表明，质谱法在研究胰淀素行为方面是一种非常有效且可靠的工具，有助于确定在体内条件下避免淀粉样蛋白意外形成的医学策略。
