Amyloid fiber formation and membrane disruption are separate processes localized in two distinct regions of IAPP, the type-2-diabetes-related peptide
Amyloid fiber formation and membrane disruption are separate processes localized in two distinct regions of IAPP, the type-2-diabetes-related peptide
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DOI：
10.1021/ja710484d
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发表时间：
2008-05-21
影响因子：
15
通讯作者：
Ramamoorthy, Ayyalusamy
中科院分区：
文献类型：
--
作者：
Brender, Jeffrey R.;Lee, Edgar L.;Ramamoorthy, Ayyalusamy
胰岛淀粉样多肽（IAPP）的聚集与II型糖尿病的发生有关。由于IAPP是一种高度淀粉样蛋白生成肽，因此有人认为IAPP淀粉样纤维的形成会导致细胞膜的破坏，并导致II型糖尿病期间p细胞的死亡。先前的研究表明，主要负责IAPP肽与膜相互作用的是n端1-19区，而不是淀粉样蛋白的20-29区。本研究提出的脂质体渗漏实验证实，全长NAPP的病理性膜破坏活性也与hIAPP共享（1-19）。hIAPP（1-19）片段在低浓度肽下诱导膜破坏的程度与全长肽几乎相同。在较高的肽浓度下，hlAPP（1-19）片段比全长肽诱导更大程度的膜破坏。与全长肽相似，hIAPP（1-19）在溶液中呈随机线圈状构象，与脂质膜结合后呈a-螺旋状构象。然而，与全长肽不同，hIAPP（1-19）片段在与POPG囊泡孵育时不会形成淀粉样蛋白纤维。这些结果表明，在IAPP中，膜破坏可以独立于淀粉样蛋白的形成而发生，并且负责淀粉样蛋白形成和膜破坏的序列位于肽的不同区域。
Aggregation of Islet Amyloid Polypeptide (IAPP) has been implicated in the development of type II diabetes. Because IAPP is a highly amyloidogenic peptide, it has been suggested that the formation of IAPP amyloid fibers causes disruption of the cellular membrane and is responsible for the death of P-cells during type II diabetes. Previous studies have shown that the N-terminal 1-19 region, rather than the amyloidogenic 20-29 region, is primarily responsible for the interaction of the IAPP peptide with membranes. Liposome leakage experiments presented in this study confirm that the pathological membrane disrupting activity of the full-length NAPP is also shared by hIAPP(1-19). The hIAPP(1-19) fragment at a low concentration of peptide induces membrane disruption to a near identical extent as the full-length peptide. At higher peptide concentrations, the hlAPP(1-19) fragment induces a greater extent of membrane disruption than the full-length peptide. Similar to the full-length peptide, hIAPP(1-19) exhibits a random coil conformation in solution and adopts an a-helical conformation upon binding to lipid membranes. However, unlike the full-length peptide, the hIAPP(1-19) fragment did not form amyloid fibers when incubated with POPG vesicles. These results indicate that membrane disruption can occur independently from amyloid formation in IAPP, and the sequences responsible for amyloid formation and membrane disruption are located in different regions of the peptide.