Peripheral region for core cross-β plays important role in amyloidogenicity
Peripheral region for core cross-β plays important role in amyloidogenicity
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DOI：
10.1016/j.bbrc.2006.02.012
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发表时间：
2006-04-14
影响因子：
3.1
通讯作者：
Ishimura, M
中科院分区：
文献类型：
--
作者：
Morii, H;Saiki, M;Ishimura, M
使用肽文库研究了与核心交叉P区相邻的外周序列的作用，所述肽文库在三个残基位置（X1-X3）处用Lys、Glu、Ser和Leu的所有可能组合构建，所述三个残基位置（X1-X3）形成与barnase衍生片段（A4-K22）的淀粉样蛋白核心序列连接的N-末端区域。通过对64个肽段的CD谱和硫磺素T结合试验，发现不仅肽段的组成，而且其外周区的序列也与淀粉样蛋白的形成有关。在淀粉样蛋白形成肽的外周区氨基酸残基的选择顺序为Leu> Ser >= Glu >> Lys。发现正电荷和负电荷的平衡对于淀粉样蛋白的形成是必不可少的，这表明淀粉样蛋白原纤维表面的静电相互作用与其稳定性有关。根据与纤维结合的硫磺素T的最大荧光波长，高度淀粉样蛋白生成肽被分为两类，其对外周序列（X1，X2和X3）表现出（Leu，Ser/Glu和Leu）和（Glu，Leu和Ser）的序列偏好。前一类可以合理地归属于沿原纤轴沿着具有深槽的结构模型。因此，外周序列调节原纤维中分子堆积的方式以及淀粉样变性。此外，外周序列的链最有可能形成硫磺素T结合位点。(c)2006年爱思唯尔公司All rights reserved.
The role of the peripheral sequence neighboring the core cross-P region was investigated using a peptide library constructed with all possible combinations of Lys, Glu, Ser, and Leu at three residue positions (X1-X3) forming the N-terminal region linked to the amyloid core sequence of the barnase-derived segment (A4-K22). By means of CD spectra and thioflavin T binding assay for 64 peptides, not only the composition but also the sequence in the peripheral region were found to be responsible for amyloid formation. The preferences of amino acid residues in the peripheral region of the amyloid-forming peptides were in the order of Leu approximate to Ser >= Glu >> Lys. A balance of positive and negative charges was found to be essential for amyloid formation, suggesting that the electrostatic interaction at the surface of the amyloid fibrils is relevant to their stability. On the basis of the maximum fluorescence wavelength of fibril-bound thioflavin T, the highly amyloidogenic peptides were classified into two classes, which exhibited the sequence preferences of (Leu, Ser/Glu, and Leu) and (Glu, Leu, and Ser) for the peripheral sequence (X1, X2, and X3). The former class can be rationally assigned to the structural model with deep grooves along the fibril axis. Thus, the peripheral sequence regulates the manner of molecular packing in the fibrils as well as the amyloiclogenicity. In addition, the chains of the peripheral sequence are most likely to form thioflavin T binding sites. (c) 2006 Elsevier Inc. All rights reserved.