Effect of Proline Mutations on the Monomer Conformations of Amylin
Effect of Proline Mutations on the Monomer Conformations of Amylin
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DOI：
10.1016/j.bpj.2013.07.029
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发表时间：
2013-09-03
影响因子：
3.4
通讯作者：
de Pablo, Juan J.
中科院分区：
文献类型：
--
作者：
Chiu, Chi-cheng;Singh, Sadanand;de Pablo, Juan J.
人类胰岛淀粉样多肽(HIAPP)的形成与II型糖尿病的胰岛β细胞丢失有关。大鼠胰淀素在六个残基上与人胰淀素不同，不会导致淀粉样纤维的形成。普拉林肽是一种人胰淀素的合成类似物，与大鼠胰淀素有三个脯氨酸取代。普拉林肽形成淀粉样聚集体的倾向要小得多，已被广泛用于淀粉替代治疗。众所周知，这三种脯氨酸可以减弱β-折叠的形成。然而，这些脯氨酸替换对全长hIAPP的详细影响仍然知之甚少。在这项工作中，我们使用分子模拟和偏置交换动力学来研究脯氨酸取代对hIAPP单体构象的影响。我们的结果表明，hIAPP可以采用不同的β-折叠构象，其中一些已经在实验中报道。脯氨酸取代干扰了长β-折叠的形成，降低了它们的稳定性。更重要的是，我们发现普拉林肽的三个脯氨酸取代都是抑制β构象和稳定α-螺旋构象所必需的。较少的取代位不会产生明显的抑制作用。
The formation of human islet amyloid polypeptide (hIAPP) is implicated in the loss of pancreatic beta-cells in type II diabetes. Rat amylin, which differs from human amylin at six residues, does not lead to formation of amyloid fibrils. Pramlintide is a synthetic analog of human amylin that shares three proline substitutions with rat amylin. Pramlintide has a much smaller propensity to form amyloid aggregates and has been widely prescribed in amylin replacement treatment. It is known that the three prolines attenuate beta-sheet formation. However, the detailed effects of these proline substitutions on full-length hIAPP remain poorly understood. In this work, we use molecular simulations and bias-exchange metadynamics to investigate the effect of proline substitutions on the conformation of the hIAPP monomer. Our results demonstrate that hIAPP can adopt various beta-sheet conformations, some of which have been reported in experiments. The proline substitutions perturb the formation of long beta-sheets and reduce their stability. More importantly, we find that all three proline substitutions of pramlintide are required to inhibit beta conformations and stabilize the alpha-helical conformation. Fewer substitutions do not have a significant inhibiting effect.