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首页> 外文期刊>Journal of Molecular Biology >Glucagon fibril polymorphism reflects differences in protofilament backbone structure.
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Glucagon fibril polymorphism reflects differences in protofilament backbone structure.

机译：胰高血糖素原纤维的多态性反映了原丝骨架结构的差异。

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摘要

Amyloid fibrils formed by the 29-residue peptide hormone glucagon at different concentrations have strikingly different morphologies when observed by transmission electron microscopy. Fibrils formed at low concentration (0.25 mg/mL) consist of two or more protofilaments with a regular twist, while fibrils at high concentration (8 mg/mL) consist of two straight protofilaments. Here, we explore the structural differences underlying glucagon polymorphism using proteolytic degradation, linear and circular dichroism, Fourier transform infrared spectroscopy (FTIR), and X-ray fiber diffraction. Morphological differences are perpetuated at all structural levels, indicating that the two fibril classes differ in terms of protofilament backbone regions, secondary structure, chromophore alignment along the fibril axis, and fibril superstructure. Straight fibrils show a conventional beta-sheet-rich far-UV circular dichroism spectrum whereas that of twisted fibrils is dominated by contributions from beta-turns. Fourier transform infrared spectroscopy confirms this and also indicates a more dense backbone with weaker hydrogen bonding for the twisted morphology. According to linear dichroism, the secondary structural elements and the aromatic side chains in the straight fibrils are more highly ordered with respect to the alignment axis than the twisted fibrils. A series of highly periodical reflections in the diffractogram of the straight fibrils can be fitted to the diffraction pattern expected from a cylinder. Thus, the highly integrated structural organization in the straight fibril leads to a compact and highly uniform fibril with a well-defined edge. Prolonged proteolytic digestion confirmed that the straight fibrils are very compact and stable, while parts of the twisted fibril backbone are much more readily degraded. Differences in the digest patterns of the two morphologies correlate with predictions from two algorithms, suggesting that the polymorphism is inherent in the glucagon sequence. Glucagon provides a striking illustration of how the same short sequence can be folded into two remarkably different fibrillar structures.
机译：当通过透射电子显微镜观察时，由29个残基的肽激素胰高血糖素以不同浓度形成的淀粉样原纤维具有显着不同的形态。低浓度（0.25 mg / mL）形成的原纤维由两个或多个规则弯曲的原丝组成，而高浓度（8 mg / mL）的原纤维由两个直的原丝组成。在这里，我们使用蛋白水解降解，线性和圆二色性，傅立叶变换红外光谱（FTIR）和X射线纤维衍射探索胰高血糖素多态性背后的结构差异。形态差异在所有结构水平上都存在，表明这两种原纤维类别在原丝骨架区域，二级结构，沿原纤维轴的生色团排列和原纤维上层结构方面有所不同。直原纤维表现出常规的富含β-折叠的远紫外圆二色性光谱，而扭曲原纤维的光谱则主要受β-转角的影响。傅里叶变换红外光谱证实了这一点，并且还表明了扭曲形态的骨架密度更高，氢键更弱。根据线性二色性，相对于取向轴，直原纤维中的二级结构元素和芳族侧链比扭曲原纤维更加有序。直原纤维的衍射图中的一系列高度周期性的反射可以拟合到圆柱体预期的衍射图上。因此，在直原纤维中高度集成的结构组织导致具有明确边缘的致密且高度均匀的原纤维。长时间的蛋白水解消化证实直原纤维非常紧密和稳定，而扭曲的原纤维主链的部分则更容易降解。两种形态的摘要模式的差异与两种算法的预测相关，这表明多态性是胰高血糖素序列固有的。胰高血糖素提供了惊人的例证，说明如何将相同的短序列折叠成两个明显不同的原纤维结构。

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