Background

Amylin is a 37-amino-acid peptide hormone co-secreted with insulin, which participates in glucose homeostasis. This hormone is able to aggregate in a β-sheet conformation and deposit in islet amyloids, a hallmark in type II diabetes. Since amylin is a gene-encoded hormone, this peptide has variants caused by point mutations that can impact its functions.

Methods

Here, we analyzed the structural effects caused by S20G and G33R point mutations which, according to the 1000 Genomes Project, have frequency in East Asian and European populations, respectively. The analyses were performed by means of aggrescan server, SNP functional effect predictors, and molecular dynamics.

Results

We found that both mutations have aggregation potential and cause changes in the monomeric forms when compared with wild-type amylin. Furthermore, comparative analyses with pramlintide, an amylin drug analogue, allowed us to infer that second α-helix maintenance may be related to the aggregation potential.

Conclusions

The S20G mutation has been described as pathologically related, which is in agreement with our findings. In addition, our data suggest that the G33R mutation might have a deleterious effect. The data presented here also provide new therapy opportunities, whether for creating more effective drugs for diabetes or implementing specific treatment for patients with these mutations.

General significance

Our data could help to better understand the impact of mutations on the wild-type amylin sequence, as a starting point for the evaluation and characterization of other variations. Moreover, these findings could improve the health of patients with type II diabetes.

中文翻译：

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胰淀素激素（II 型糖尿病相关肽）的罕见点突变驱动的结构效应

背景

胰淀素是一种 37 个氨基酸的肽激素，与胰岛素共同分泌，参与葡萄糖稳态。这种激素能够聚集成 β 折叠构象并沉积在胰岛淀粉样蛋白中，这是 II 型糖尿病的标志。由于胰淀素是一种基因编码的激素，因此该肽具有由可能影响其功能的点突变引起的变体。

方法

在这里，我们分析了 S20G 和 G33R 点突变引起的结构效应，根据 1000 基因组计划，它们分别在东亚和欧洲人群中出现频率。分析是通过聚集蛋白扫描服务器、SNP 功能效应预测器和分子动力学进行的。

结果

我们发现，与野生型胰淀素相比，这两种突变都具有聚集潜力并导致单体形式发生变化。此外，与普兰林肽（一种胰淀素药物类似物）的比较分析使我们能够推断第二个 α-螺旋维持可能与聚集潜力有关。

结论

S20G 突变已被描述为病理相关，这与我们的发现一致。此外，我们的数据表明 G33R 突变可能具有有害影响。此处提供的数据还提供了新的治疗机会，无论是为糖尿病开发更有效的药物，还是为具有这些突变的患者实施特定治疗。

一般意义

我们的数据可以帮助更好地了解突变对野生型胰淀素序列的影响，作为评估和表征其他变异的起点。此外，这些发现可以改善II型糖尿病患者的健康。