The amyloid formation mechanism in human IAPP: dimers have β-strand monomer-monomer interfaces.
The amyloid formation mechanism in human IAPP: dimers have β-strand monomer-monomer interfaces.
复制标题
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。
DOI：
10.1021/ja1081537
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发表时间：
2011-05-18
影响因子：
15
通讯作者：
Bowers MT
中科院分区：
文献类型：
--
作者：
Dupuis NF;Wu C;Shea JE;Bowers MT
人IAPP的早期寡聚化(HIAPP)是导致胰腺β细胞死亡的原因，越来越多地被认为是与II型糖尿病(T2D)相关的主要病理过程。然而，组装机制仍然知之甚少，这在很大程度上是因为传统技术无法探索早期低聚物种的分布或详细结构。在这里，我们描述了分离的和未修饰的人二聚体(HIAPP)和非淀粉样变性大鼠IAPP(RIAPP)的第一个实验数据。实验表明，人IAPP二聚体比大鼠IAPP形成的二聚体更长，可能是从延伸的单体下来的。独立的全原子分子动力学模拟表明，rIAPP形成紧凑的螺旋和富卷曲的二聚体，而hIAPP形成的β链丰富的二聚体通常更长。此外，模拟还表明，HIAPP二聚体的单体-单体界面主要由β-链组成，β-链可以在二聚过程中招募螺旋或螺旋结构的区域。我们的富含β的界面与文献中提出的N末端螺旋到螺旋的界面形成了对比，但它与现有的关于hIAPP的自我相互作用模式、突变效应和突变区域N-甲基化的抑制效应的实验数据是一致的。
Early oligomerization of human IAPP (hIAPP) is responsible for β-cell death in the pancreas and is increasingly considered a primary pathological process linked to Type II Diabetes (T2D). However, the assembly mechanism remains poorly understood, largely due to the inability of conventional techniques to probe either distributions or detailed structures of early oligomeric species. Here, we describe the first experimental data on the isolated and unmodified dimers of human (hIAPP) and non-amyloidogenic rat IAPP (rIAPP). The experiments reveal that the human IAPP dimers are more extended than those formed by rat IAPP and likely descend from extended monomers. Independent all-atom molecular dynamics simulations show that rIAPP forms compact helix and coil rich dimers, whereas hIAPP forms β-strand rich dimers that are generally more extended. Additionally, the simulations reveal that the monomer-monomer interfaces of the hIAPP dimers are dominated by β-strands and that β-strands can recruit coil or helix structured regions during the dimerization process. Our β-rich interface contrasts with an N-terminal helix-to-helix interface proposed in the literature but it is consistent with existing experimental data on the self-interaction pattern of hIAPP, mutation effects and inhibition effects of the N-methylation in the mutation region.
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DOI：
10.1073/pnas.0507471103
发表时间：
2006-02-14
影响因子：
11.1
作者：
Yan, LM;Tatarek-Nossol, M;Kapurniotu, A
通讯作者：
Kapurniotu, A
影响因子：
8
作者：
Wiltzius, Jed J. W.;Sievers, Stuart A.;Eisenberg, David
通讯作者：
Eisenberg, David
影响因子：
2.9
作者：
Luca, Sorin;Yau, Wai-Ming;Tycko, Robert
通讯作者：
Tycko, Robert
影响因子：
5.6
作者：
Kayed, R;Bernhagen, J;Kapurniotu, A
通讯作者：
Kapurniotu, A
影响因子：
--
作者：
Tatarek-Nossol, M;Yan, LM;Kapurniotu, A
通讯作者：
Kapurniotu, A