Phosphorylation as a tool to modulate aggregation propensity and to predict fibril architecture.
Phosphorylation as a tool to modulate aggregation propensity and to predict fibril architecture.
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DOI：
10.1002/cbic.201100607
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发表时间：
2012-01-23
期刊：
影响因子：
3.2
通讯作者：
Warriner, Stuart L.
中科院分区：
文献类型：
--
作者：
Valette, Nathalie M.;Radford, Sheena E.;Harris, Sarah A.;Warriner, Stuart L.
尽管翻译后修饰在控制蛋白质和肽的溶解度和构象性质中的重要性，但不同肽序列的聚集倾向如何通过化学修饰来调节仍不清楚。在这里，我们研究了磷酸化对13个残基的合成肽的聚集倾向的影响，在不同的pH值下，在7个不同的位点掺入一个或多个磷酸基团。原纤维形成被证明是抑制时，一个单一的磷酸基团被引入在所有七个位置的肽序列在pH 7.5，当磷酸基团是完全充电。相比之下，当在pH 1.1下分析相同的肽时，当磷酸盐完全质子化时，来自所有七种肽序列的原纤维迅速形成。在中间pH值（pH 3.6）下，当磷酸基团是单阴离子时，发现肽的聚集倾向高度依赖于磷酸基团在肽序列中的位置。使用这些信息，结合分子动力学（MD）模拟的肽序列，我们提供的证据与肽形成淀粉样蛋白纤维与7类架构一致。结果突出了磷酸化作为可逆地控制肽序列在合成期间和合成后的聚集动力学的方法的潜在效用。此外，通过利用磷酸基团作为pH的函数采用不同电荷状态的能力，并将实验见解与随着pH变化从MD模拟计算的原子信息相结合，我们展示了如何使用所得信息来预测与两个数据集一致的原纤维结构，并使用这些来合理化它们的原纤化动力学对磷酸基团的位置及其电荷状态的敏感性。
Despite the importance of post-translational modifications in controlling the solubility and conformational properties of proteins and peptides, precisely how the aggregation propensity of different peptide sequences is modulated by chemical modification remains unclear. Here we have investigated the effect of phosphorylation on the aggregation propensity of a 13-residue synthetic peptide incorporating one or more phosphate groups at seven different sites at various pH values. Fibril formation was shown to be inhibited when a single phosphate group was introduced at all seven locations in the peptide sequence at pH 7.5, when the phosphate group is fully charged. By contrast, when the same peptides were analysed at pH 1.1, when the phosphate is fully protonated, fibrils from all seven peptide sequences form rapidly. At intermediate pH values (pH 3.6) when the phosphate group is mono-anionic, the aggregation propensity of the peptides was found to be highly dependent on the position of the phosphate group in the peptide sequence. Using this information, combined with molecular dynamics (MD) simulations of the peptide sequence, we provide evidence consistent with the peptide forming amyloid fibrils with a class 7 architecture. The results highlight the potential utility of phosphorylation as a method of reversibly controlling the aggregation kinetics of peptide sequences both during and after synthesis. Moreover, by exploiting the ability of the phosphate group to adopt different charge states as a function of pH, and combining experimental insights with atomistic information calculated from MD simulations as pH is varied, we show how the resulting information can be used to predict fibril structures consistent with both datasets, and use these to rationalise their sensitivity of fibrillation kinetics both to the location of the phosphate group and its charge state.
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影响因子：
8
作者：
Cho, Min-Kyu;Kim, Hai-Young;Zweckstetter, Markus
通讯作者：
Zweckstetter, Markus
DOI：
10.1016/s0006-291x(84)80190-4
发表时间：
1984-01-01
影响因子：
3.1
作者：
GLENNER, GG;WONG, CW
通讯作者：
WONG, CW
DOI：
10.1073/pnas.252625999
发表时间：
2002-12-24
影响因子：
11.1
作者：
Jaroniec, CP;MacPhee, CE;Griffin, RG
通讯作者：
Griffin, RG
影响因子：
2.9
作者：
Conway, KA;Harper, JD;Lansbury, PT
通讯作者：
Lansbury, PT
影响因子：
4.4
作者：
JORGENSEN, WL;CHANDRASEKHAR, J;KLEIN, ML
通讯作者：
KLEIN, ML