Nucleation of β-rich oligomers and β-barrels in the early aggregation of human islet amyloid polypeptide.
Nucleation of β-rich oligomers and β-barrels in the early aggregation of human islet amyloid polypeptide.
复制标题
DOI：
10.1016/j.bbadis.2018.11.021
复制
发表时间：
2019-02-01
期刊：
影响因子：
--
通讯作者：
Ding F
中科院分区：
文献类型：
--
作者：
Sun Y;Kakinen A;Xing Y;Pilkington EH;Davis TP;Ke PC;Ding F
人胰岛淀粉样多肽(HIAPP)自组装成富含β-Sheet的淀粉样蛋白聚集体与2型糖尿病(T2D)胰腺β细胞死亡相关。先前对hIAPP聚集的实验研究报告了在快速转化为富含α片状的淀粉样纤维之前，β-螺旋中间体的早期积累，这也得到了我们的透射电子显微镜和傅里叶变换红外光谱的实验表征的证实。尽管越来越多的证据表明早期hIAPP聚集的小分子寡聚体在细胞毒性中起着关键作用，但这些寡聚体中间产物的结构及其构象转化仍然未知，阻碍了我们对T2D疾病机制的理解和针对这些早期聚集物种的治疗设计。我们进一步应用大规模离散分子动力学模拟来研究全长hIAPP的齐聚作用，采用了多个多肽增加的分子系统。我们发现齐聚过程是动态的，涉及到频繁的低聚物之间的交换。平均而言，低聚物具有比α-Sheet更多的β-螺旋，这与基于系综的实验测量一致。然而，在~4-6%的独立模拟中，观察到了预期作为纤化中间体的富含β的低聚物，特别是在五聚体和六聚体模拟中。这些富含β的低聚物可以采用β-Barrel构象，最近被认为是有毒的低聚物种类，但通过计算只在短淀粉样蛋白片段的聚集体中观察到。自由能分析表明，这些富含β的低聚物具有较高的能量，支持低聚物在淀粉样蛋白聚集中的成核构象变化。具有明确三维结构的全长hIAPP的β-Barrel寡聚体可能在T2D病因学中发挥重要的病理作用，并可能成为T2D的治疗靶点。
The self-assembly of human islet amyloid polypeptide (hIAPP) into β-sheet rich amyloid aggregfiates is associated with pancreatic β-cell death in type 2 diabetes (T2D). Prior experimental studies of hIAPP aggregation reported the early accumulation of α-helical intermediates before the rapid conversion into β-sheet rich amyloid fibrils, as also corroborated by our experimental characterizations with transmission electron microscopy and Fourier transform infrared spectroscopy. Although increasing evidence suggests that small oligomers populating early hIAPP aggregation play crucial roles in cytotoxicity, structures of these oligomer intermediates and their conformational conversions remain unknown, hindering our understanding of T2D disease mechanism and therapeutic design targeting these early aggregation species. We further applied large-scale discrete molecule dynamics simulations to investigate the oligomerization of full-length hIAPP, employing multiple molecular systems of increasing number of peptides. We found that the oligomerization process was dynamic, involving frequent inter-oligomeric exchanges. On average, oligomers had more α-helices than β-sheets, consistent with ensemble-based experimental measurements. However, in ~4–6% independent simulations, β-rich oligomers expected as the fibrillization intermediates were observed, especially in the pentamer and hexamer simulations. These β-rich oligomers could adopt β-barrel conformations, recently postulated to be the toxic oligomer species but only observed computationally in the aggregates of short amyloid protein fragments. Free-energy analysis revealed high energies of these β-rich oligomers, supporting the nucleated conformational changes of oligomers in amyloid aggregation. β-barrel oligomers of full-length hIAPP with well-defined three-dimensional structures may play an important pathological role in T2D etiology and may be a therapeutic target for the disease.
登录
查看更多内容
人类 IAPP 中淀粉样蛋白的形成机制：二聚体具有 β 链单体-单体界面。
影响因子：
15
作者：
Dupuis NF;Wu C;Shea JE;Bowers MT
通讯作者：
Bowers MT
影响因子：
15
作者：
Do TD;LaPointe NE;Nelson R;Krotee P;Hayden EY;Ulrich B;Quan S;Feinstein SC;Teplow DB;Eisenberg D;Shea JE;Bowers MT
通讯作者：
Bowers MT
影响因子：
46.2
作者：
DeToma AS;Salamekh S;Ramamoorthy A;Lim MH
通讯作者：
Lim MH
淀粉样蛋白生成被脯氨酸取代所消除，但通过脂质结合而增强。
影响因子：
4.3
作者：
Jiang, Ping;Xu, Weixin;Mu, Yuguang
通讯作者：
Mu, Yuguang
影响因子：
2.9
作者：
Fox, Ayano;Snollaerts, Thibaut;Casanova, Camille Errecart;Calciano, Anastasia;Nogaj, Luiza A.;Moffet, David A.
通讯作者：
Moffet, David A.