Dissecting the Role of Single Regions of an IAPP Mimic and IAPP in Inhibition of Aβ40 Amyloid Formation and Cytotoxicity
Dissecting the Role of Single Regions of an IAPP Mimic and IAPP in Inhibition of Aβ40 Amyloid Formation and Cytotoxicity
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DOI：
10.1002/cbic.201100192
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发表时间：
2011-06-14
期刊：
影响因子：
3.2
通讯作者：
Kapurniotu, Aphrodite
中科院分区：
文献类型：
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作者：
Andreetto, Erika;Yan, Li-Mei;Kapurniotu, Aphrodite
阿尔茨海默病(AD)和2型糖尿病(T2D)分别与β-淀粉样多肽(Aβ)和胰岛淀粉样多肽(IAPP)的自我关联有关。我们已经证明，IAPP-GI是一种可溶性的IAPP类似物，是非淀粉样变性和无毒性的IAPP的模拟物，它以高亲和力结合Aβ，并阻止其细胞毒性自组装和纤维形成。我们还表明，IAPP和Aβ相互作用形成无纤维和无毒的异质复合体，从而抑制两种多肽的细胞毒性自结合。因此，Aβ-IAPP相互作用可能是AD和T2D之间的分子联系。我们研究了IAPP-GI区和IAPP区在抑制Aβ40自结合和细胞毒作用中的作用。我们发现，IAPP(8-28)中Aβ-IAPP相互作用界面的两个热点区域的存在不足以发挥抑制作用，并且除了IAPP(8-28)外，N-末端区域IAPP(1-7)的存在是绝对必要的。相反，C-末端区域IAPP(30-37)并不是必需的，尽管它与IAPP(1-7)一起存在于IAPP-GI中，与IAPP(1-28)-GI相比，其抑制作用显著增强。我们认为IAPP-GI和IAPP对Aβ40纤维形成和细胞毒性的抑制作用主要是通过Aβ-IAPP相互作用界面的热区和IAPP的N端的相互作用来实现的，而N端和C端的IAPP区域的协同和可能的结构稳定作用加强了这一作用。这些结果确定了Aβ40-IAPP相互作用中淀粉样蛋白抑制功能的重要分子决定因素，并可能有助于设计新型的Aβ40聚集和细胞退化抑制剂。
Alzheimer's disease (AD) and type 2 diabetes (T2D) are linked to the self-association of beta-amyloid peptide (A beta) and islet amyloid polypeptide (IAPP), respectively. We have shown that IAPP-GI, a soluble IAPP analogue and mimic of nonamyloidogenic and nontoxic IAPP, binds A beta with high affinity and blocks its cytotoxic self-assembly and fibrillogenesis. We have also shown that IAPP and A beta interact with each other into nonfibrillar and nontoxic heterocomplexes that suppress cytotoxic self-association by both polypeptides. The A beta-IAPP interaction might thus be a molecular link between AD and T2D. We studied the role of individual IAPP-GI and IAPP regions in their inhibitory function on A beta 40 self-association and cytotoxicity. We found that the presence of the two hot-spot regions of the A beta-IAPP interaction interface in IAPP(8-28) is not sufficient for inhibitory function and that, in addition to IAPP(8-28), the presence of the N-terminal region IAPP(1-7) is absolutely required. By contrast, the C-terminal region, IAPP(30-37), is not required although its presence together with IAPP(1-7) in IAPP-GI results in a marked enhancement of the inhibitory effect as compared to IAPP(1-28)-GI. We suggest that the inhibitory effect of IAPP-GI and IAPP on A beta 40 fibrillogenesis and cell toxicity is mediated primarily by interactions involving the hot regions of the A beta-IAPP interaction interface and the N terminus of IAPP while a concerted and likely structure-stabilizing action of the N- and C-terminal IAPP regions potentiates this effect. These results identify important molecular determinants of the amyloid suppressing function of the A beta 40-IAPP interaction and could contribute to the design of novel inhibitors of A beta 40 aggregation and cell degeneration.