Induction of negative curvature as a mechanism of cell toxicity by amyloidogenic peptides: the case of islet amyloid polypeptide.
Induction of negative curvature as a mechanism of cell toxicity by amyloidogenic peptides: the case of islet amyloid polypeptide.
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DOI：
10.1021/ja809002a
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发表时间：
2009-04-01
影响因子：
15
通讯作者：
Ramamoorthy A
中科院分区：
文献类型：
--
作者：
Smith PE;Brender JR;Ramamoorthy A
胰岛素分泌β细胞的死亡是2型糖尿病发病机制中的关键步骤。淀粉样蛋白生成肽胰岛淀粉样蛋白多肽（IAPP，也称为胰淀素）已显示破坏β细胞膜，导致β细胞死亡。尽管有强有力的证据将IAPP与β细胞膜完整性的破坏和细胞死亡联系起来，但对IAPP毒性的机制知之甚少。特别是，IAPP对双层结构的影响在很大程度上还没有得到表征。在这项研究中，我们已经确定了淀粉样蛋白和毒性hIAPP 1 -37肽和无毒和非淀粉样蛋白的rIAPP 1 -37肽对膜的DSC和固态NMR光谱相结合的效果。我们还表征了毒性但大部分非淀粉样蛋白生成的rIAPP 1 -19和hIAPP 1 -19片段。DSC显示，淀粉样蛋白生成（hIAPP 1 -37）和大部分非淀粉样蛋白生成（hIAPP 1 -19和rIAPP 1 -19）毒性版本的肽强烈有利于脂质双层中负曲率的形成，而无毒的全长大鼠IAPP 1 -37肽则不然。这一结果通过固态NMR光谱得到证实，其显示在由高曲率和低曲率区域组成的双胞中，无毒rIAPP 1 -37结合到低曲率区域，而毒性rIAPP 1 -19结合到高曲率区域。类似地，固态NMR光谱显示毒性rIAPP 1 -19肽显著破坏脂质双层结构，而无毒rIAPP 1 -37没有显著影响。这些结果表明IAPP可以通过诱导过量的膜曲率来诱导孔的形成，并且可以用于指导可以防止IAPP的细胞毒性的化合物的设计。这一机制对于理解其他淀粉样蛋白的毒性可能很重要。我们的固态NMR结果还表明，使用bicelles来测量生物分子的亲和性的负或正弯曲的区域的膜，我们相信这将是有用的，在各种生物化学和生物物理的调查有关的细胞膜的可能性。
The death of insulin-producing β-cells is a key step in the pathogenesis of type 2 diabetes. The amyloidogenic peptide Islet Amyloid Polypeptide (IAPP, also known as amylin) has been shown to disrupt β-cell membranes leading to β-cell death. Despite the strong evidence linking IAPP to the destruction of β-cell membrane integrity and cell death, the mechanism of IAPP toxicity is poorly understood. In particular, the effect of IAPP on the bilayer structure has largely been uncharacterized. In this study, we have determined the effect of the amyloidogenic and toxic hIAPP1-37 peptide and the non-toxic and non-amyloidogenic rIAPP1-37 peptide on membranes by a combination of DSC and solid-state NMR spectroscopy. We also characterized the toxic but largely non-amyloidogenic rIAPP1-19 and hIAPP1-19 fragments. DSC shows that both amyloidogenic (hIAPP1-37) and largely non-amyloidogenic (hIAPP1-19 and rIAPP1-19) toxic versions of the peptide strongly favor the formation of negative curvature in lipid bilayers, while the non-toxic full-length rat IAPP1-37 peptide does not. This result was confirmed by solid-state NMR spectroscopy which shows that in bicelles composed of regions of high curvature and low curvature, non-toxic rIAPP1-37 binds to the regions of low curvature while toxic rIAPP1-19 binds to regions of high curvature. Similarly, solid-state NMR spectroscopy shows that the toxic rIAPP1-19 peptide significantly disrupts the lipid bilayer structure, whereas the non-toxic rIAPP1-37 does not have a significant effect. These results indicate IAPP may induce the formation of pores by the induction of excess membrane curvature and can be used to guide the design of compounds that can prevent the cell-toxicity of IAPP. This mechanism may be important to understand the toxicity of other amyloidogenic proteins. Our solid-state NMR results also demonstrate the possibility of using bicelles to measure the affinity of biomolecules for negatively or positively curved regions of the membrane, which we believe will be useful in a variety of biochemical and biophysical investigations related to the cell membrane.
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影响因子：
5.6
作者：
Domanov, Yegor A.;Kinnunen, Paavo K. J.
通讯作者：
Kinnunen, Paavo K. J.
影响因子：
15
作者：
Chimon, S;Ishii, Y
通讯作者：
Ishii, Y
影响因子：
3.4
作者：
Domanov, Yegor A.;Kinnunen, Paavo K. J.
通讯作者：
Kinnunen, Paavo K. J.
DOI：
10.1006/bbrc.1994.2089
发表时间：
1994-08-15
影响因子：
3.1
作者：
EPAND, RM;EPAND, RF
通讯作者：
EPAND, RF
影响因子：
15
作者：
Brender, Jeffrey R.;Lee, Edgar L.;Ramamoorthy, Ayyalusamy
通讯作者：
Ramamoorthy, Ayyalusamy