Evidence of π-stacking interactions in the self-assembly of hIAPP(22-29).
Evidence of π-stacking interactions in the self-assembly of hIAPP(22-29).
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DOI：
10.1002/prot.24229
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发表时间：
2013-04
影响因子：
2.9
通讯作者：
Desamero, Ruel Z. B.
中科院分区：
文献类型：
--
作者：
Profit, Adam A.;Felsen, Valentina;Chinwong, Justina;Mojica, Elmer-Rico E.;Desamero, Ruel Z. B.
关键词：
芳香氨基酸在淀粉样蛋白形成中的作用是一个有争议的话题。为了阐明芳香性对hIAPP22-29自组装的贡献，合成了Phe-23芳环上对位含给电子基团(EDGs)或吸电子基团(EWGs)的多肽类似物，并用浊度测量结合拉曼光谱和荧光光谱对其进行了表征。结果表明，在Phe-23的芳香环上掺入EDGs几乎取消了hIAPP22-29形成淀粉样蛋白的能力。含有EWGs的多肽仍能形成聚集体。这些聚集体具有丰富的β-Sheet二级结构。聚集体的电子显微镜图像证实了淀粉样纤维的存在。在含有EDGs的多肽和具有EWGs的多肽之间观察到的淀粉样变性倾向的差异似乎不是基于多肽疏水性的差异。荧光和拉曼光谱研究表明，芳环周围的环境变得更加疏水，聚集后变得有序化。此外，含有EWG的多肽类似物的拉曼测量确凿地表明，在聚集时，-C=C-环模式(约1600厘米−1)发生了明显的下移，这以前已被证明是π堆积的标志。虽然以前的工作已经证明π-堆积并不是纤化的绝对要求，但我们的发现表明，Phe-23也通过π-堆积作用促进纤维的形成，而且不仅是这种残基的疏水性与hIAPP22-29的自组装有关。
The role aromatic amino acids play in the formation of amyloid is a subject of controversy. In an effort to clarify the contribution of aromaticity to the self-assembly of hIAPP22–29, peptide analogs containing electron donating groups (EDGs) or electron withdrawing groups (EWGs) as substituents on the aromatic ring of Phe-23 at the para position have been synthesized and characterized using turbidity measurements in conjunction with Raman, and fluorescence spectroscopy. Results indicate the incorporation of EDGs on the aromatic ring of Phe-23 virtually abolish the ability of hIAPP22–29 to form amyloid. Peptides containing EWGs were still capable of forming aggregates. These aggregates were found to be rich in β-sheet secondary structure. TEM images of the aggregates confirm the presence of amyloid fibrils. The observed difference in amyloidogenic propensity between peptides containing EDGs and those with EWGs appears not to be based on differences in peptide hydrophobicity. Fluorescence and Raman spectroscopic investigations reveal that the environment surrounding the aromatic ring becomes more hydrophobic and ordered upon aggregation. Furthermore, Raman measurements of peptide analogs containing EWGs, conclusively demonstrate a distinct downshift in the -C=C- ring mode (ca. 1600 cm−1) upon aggregation that has previously been shown to be indicative of π-stacking. While previous work has demonstrated that π-stacking is not an absolute requirement for fibrillization, our findings indicate that Phe-23 also contributes to fibril formation through π-stacking interactions and that it is not only the hydrophobic nature of this residue that is relevant in the self-assembly of hIAPP22–29.
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影响因子：
8
作者：
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DOI：
10.1073/pnas.84.23.8628
发表时间：
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影响因子：
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作者：
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通讯作者：
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