Membrane disruption and early events in the aggregation of the diabetes related peptide IAPP from a molecular perspective.
Membrane disruption and early events in the aggregation of the diabetes related peptide IAPP from a molecular perspective.
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DOI：
10.1021/ar200189b
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发表时间：
2012-03-20
影响因子：
18.3
通讯作者：
Ramamoorthy, Ayyalusamy
中科院分区：
文献类型：
--
作者：
Brender, Jeffrey R.;Salamekh, Samer;Ramamoorthy, Ayyalusamy
蛋白质的聚集在生命系统中受到严格控制，并且在杂交蛋白质的聚集之前，通常会去除错误折叠的蛋白质，但出于某些个体而言，这种降解过程不明确，并且在不折叠的蛋白（淀粉样蛋白沉积物）随着时间的流逝。蛋白质纤维包括淀粉样蛋白沉积物，尽管缺乏明显的序列相似性，但淀粉样蛋白的淀粉样蛋白具有惊人的相似之处，由长，高度有序的不溶性纤维组成。和临床研究，作为淀粉样蛋白的很高比例与常见的退化性疾病有关，包括阿尔茨海默氏症，II型糖尿病和帕金森氏症。
淀粉样蛋白和疾病之间的明显联系归因于蛋白质的淀粉样蛋白，但越来越多的证据表明，毒性是由于淀粉样蛋白纤维组装过程中产生的中间体。通过产生炎症，产生反应性氧和超负荷的蛋白质反应途径，是一种常见的，良好的机制。血浆和细胞器膜的破坏。
在这个说法中，我们检查了早期的分子级事件在淀粉样多肽的聚集中（IAPP，也称为氨基蛋白），并增强了膜的破坏在II型糖尿病患者的淀粉样蛋白沉积物中经常发现的淀粉样蛋白原。涉及从II型糖尿病的早期到后期的因素。 β细胞的破坏。转弯与膜中的渗透深度有关。
尽管在IAPP和其他淀粉样蛋白之间存在许多相似之处，但一个重要的差异似乎是小寡聚在淀粉样蛋白的组装过程中的作用。但是，在IAPP中，小寡聚似乎是短暂的，并且迅速转化为淀粉样蛋白纤维。 IAPP受释放的秘密颗粒中存在的其他辅助因子（例如锌和胰岛素）的控制，该控制机制在某种程度上是在II型糖尿病患者中不平衡的。分子水平的II型糖尿病。
The aggregation of proteins is tightly controlled in living systems, and misfolded proteins are normally removed before aggregation of the misfolded protein can occur. But for reasons not clearly understood, in some individuals this degradation process breaks down, and misfolded proteins accumulate in insoluble protein aggregates (amyloid deposits) over time. Of the many proteins expressed in humans, a small but growing number have been found to form the long, highly ordered β-sheet protein fibers that comprise amyloid deposits. Despite a lack of obvious sequence similarity, the amyloid forms of diverse proteins are strikingly similar, consisting of long, highly ordered insoluble fibers with a characteristic crossed β-sheet pattern. Amyloidogenesis has been the focus of intense basic and clinical research, as a high proportion of amyloidogenic proteins has been linked to common degenerative diseases, including Alzheimer’s, type II diabetes, and Parkinson’s. The apparent link between amyloidogenic proteins and disease was initially attributed to the amyloid form of the protein; however, increasing evidence suggests the toxicity is due to intermediates generated during the assembly of amyloid fibers. These intermediates have been proposed to attack cells in a variety of ways, such as by generating inflammation, creating reactive oxygen species, and overloading the misfolded protein response pathway. One common, well-studied mechanism is the disruption of the plasma and organelle membranes. In this Account, we examine the early molecular-level events in the aggregation of the Islet amyloid polypeptide (IAPP, also called amylin) and its ensuing disruption of membranes. IAPP is a 37-residue peptide secreted in conjunction with insulin; it is highly amyloidogenic and often found in amyloid deposits in type II diabetics. IAPP aggregates are highly toxic to the β-cells that produce insulin, and thus IAPP is believed to be one of the factors involved in the transition from early to later stages of type II diabetes. Using variants of IAPP that are combinations of toxic or non-toxic and amyloidogenic or nonamyloidogenic, we have shown that formation of amyloid fibers is a sufficient but not necessary condition for the disruption of β-cells. Instead, the ability to induce membrane disruption in model membranes appears to be related to the peptide’s ability to stabilize curvature in the membrane, which in turn is related to the depth of penetration in the membrane. Although many similarities exist between IAPP and other amyloidogenic proteins, one important difference appears to be the role of small oligomers in the assembly process of amyloid fibers. In many amyloidogenic proteins, small oligomers form a distinct metastable intermediate that is frequently the most toxic species; however, in IAPP, small oligomers appear to be transient and are rapidly converted to amyloid fibers. Moreover, the aggregation and toxicity of IAPP is controlled by other cofactors present in the secretory granule from which it is released, such as zinc and insulin, in a control mechanism that is somehow unbalanced in type II diabetics. Investigations into this process are likely to give clues to the mysterious origins of type II diabetes on the molecular level.
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影响因子：
3.4
作者：
Nanga, Ravi Prakash Reddy;Brender, Jeffrey R.;Vivekanandan, Subramanian;Ramamoorthy, Ayyalusamy
通讯作者：
Ramamoorthy, Ayyalusamy
影响因子：
5.6
作者：
Hall, D;Hirota, N;Dobson, CM
通讯作者：
Dobson, CM
影响因子：
3.4
作者：
Khemtemourian, Lucie;Engel, Maarten F. M.;Killian, J. Antoinette
通讯作者：
Killian, J. Antoinette
影响因子：
5.6
作者：
McNulty, BC;Young, GB;Pielak, GJ
通讯作者：
Pielak, GJ
影响因子：
15
作者：
Brender, Jeffrey R.;Lee, Edgar L.;Ramamoorthy, Ayyalusamy
通讯作者：
Ramamoorthy, Ayyalusamy