膜结合的hIAPP二元体中的结构多样性与明显的膜破坏机制相关
Qin Qiao1,2, Guanghong Wei3, Zhijian Song1,2
1Digital Medical Research Center, School of Basic Medical Sciences, Fudan University, Shanghai 200032, China. qinqiao@fudan.edu.cn.
Physical chemistry chemical physics : PCCP
|February 12, 2024
概括
人类小岛粉样多 (hIAPP) 在细胞膜上的聚合是II型糖尿病的关键. 最初的膜损伤是由随机卷轴和α-螺旋式hIAPP二极管插入膜引起的.
科学领域:
- 生物化学 生物化学
- 分子生物学分子生物学
- 膜生物物理学 膜生物物理学
背景情况:
- 在90%的II型糖尿病患者中发现人类小岛粉样蛋白聚 (hIAPP) 的粉样蛋白沉积物.
- 细胞膜上的hIAPP纤维化加速聚合并破坏膜完整性,导致胰腺β细胞亡.
- 精确的分子机制的hIAPP诱导的膜破坏,特别是在早期阶段,仍然不清楚.
研究的目的:
- 研究hIAPP二元化和初始膜破坏的分子机制.
- 阐明hIAPP聚合在阴离子POPG膜环境中的结构动态.
主要方法:
- 使用了广泛的全原子分子动力学模拟.
- 模拟的重点是离子POPG膜中的hIAPP二元化过程.
主要成果:
- 与单体相比,hIAPP二元体呈现出增加的α-螺旋和大量β-片结构.
- 随机卷轴和α-螺旋二次体穿透了膜内部,而β-板结构以强烈的疏水相互作用定位在表面.
- 观察到膜结合的hIAPP二元体的多样化的结构组合,共存的α和β结构.
结论:
- 膜损伤从随机卷轴/α螺旋结构的初始破坏进展到后期参与β-sheet结构.
- 插入随机卷轴和α螺旋 hIAPP 结构可能会引发膜损伤.
- 膜表面的β片结构与纤维素诱导的膜破坏的后期阶段有关.
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