The neuropancreatic polypeptide hormone amylin forms pancreatic islet amyloid in type-2 diabetes. Islet amyloid formation contributes to β-cell death in the disease and to the failure of islet transplants, but the features which influence amylin amyloidogenicity are not understood. We constructed an amino acid sequence alignment of 202 sequences of amylin and used the alignment to design consensus sequences of vertebrate amylins, mammalian amylins, and primate amylins. Amylin is highly conserved, but there are differences between human amylin and each consensus sequence, ranging from one to six substitutions. Biophysical analysis shows that all of the consensus sequences form amyloid but do so more slowly than human amylin in vitro. The rate of amyloid formation by the primate consensus sequence is 3- to 4-fold slower than human amylin; the mammalian consensus sequence is approximately 20- to 25-fold slower, and the vertebrate consensus sequence is approximately 6-fold slower. All of the consensus sequences are moderately less toxic than human amylin toward a cultured β-cell line, with the vertebrate consensus sequence displaying the largest reduction in toxicity of 3- to 4-fold. All of the consensus sequences activate a human amylin receptor and exhibit only modest reductions in activity, ranging from 3- to 4-fold as judged by a cAMP production assay. The analysis argues that there is no strong selective evolutionary pressure to avoid the formation of islet amyloid and provides information relevant to the design of less amyloidogenic amylin variants.

中文翻译：

---

Amylin共识序列的分析表明，人Amylin并非最优化以最大程度地减少淀粉样蛋白的形成，并为调节淀粉样蛋白原性的因素提供线索。

在2型糖尿病中，神经胰多肽激素胰岛淀粉样多肽形成胰岛淀粉样蛋白。胰岛淀粉样蛋白的形成导致该疾病中β细胞的死亡以及胰岛移植的失败，但是影响淀粉样蛋白淀粉样蛋白原性的特征尚不清楚。我们构建了202个胰岛淀粉样多肽序列的氨基酸序列比对，并用于设计脊椎动物胰岛淀粉样多肽，哺乳动物胰岛淀粉样多肽和灵长类胰岛淀粉样多肽的共有序列。胰岛淀粉样多肽高度保守，但是人胰岛淀粉样多肽和每个共有序列之间存在差异，范围从一到六个取代。生物物理分析表明，所有共有序列均形成淀粉样蛋白，但在体外比人淀粉样蛋白的形成速度更慢。灵长类共有序列形成淀粉样蛋白的速度比人胰岛淀粉样蛋白慢3-4倍。哺乳动物共有序列慢约20至25倍，脊椎动物共有序列慢约6倍。所有共有序列对培养的β细胞系的毒性均低于人胰岛淀粉样多肽，而脊椎动物共有序列显示出最大的3-4倍毒性降低。所有共有序列均激活人胰岛淀粉样多肽受体，并仅表现出适度的活性降低，通过cAMP产生分析可判断为3至4倍。该分析认为，没有强烈的选择性进化压力来避免胰岛淀粉样蛋白的形成，并提供了与设计较少淀粉样蛋白的淀粉样蛋白变体相关的信息。