Structure and assembly mechanisms of toxic human islet amyloid polypeptide oligomers associated with copper.
Structure and assembly mechanisms of toxic human islet amyloid polypeptide oligomers associated with copper.
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DOI：
10.1039/c6sc00153j
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发表时间：
2016-08-01
期刊：
影响因子：
8.4
通讯作者：
Kim HI
中科院分区：
文献类型：
--
作者：
Lee SJC;Choi TS;Lee JW;Lee HJ;Mun DG;Akashi S;Lee SW;Lim MH;Kim HI
hIAPP与Cu（ii）的分子相互作用介导了具有小尺寸和无规卷曲结构的非途径和毒性寡聚体的形成。淀粉样变性是一种涉及毒性淀粉样蛋白聚集体形成的临床病症。尽管它们的病理学意义，它是具有挑战性的定义淀粉样蛋白低聚物的结构特征，由于其亚稳态性质。在此，我们报告了在II型糖尿病中发现的人胰岛淀粉样多肽（hIAPP）寡聚体的结构和机制研究，在不存在和存在疾病相关金属离子的情况下[即，Cu（ii）和Zn（ii）]。这些金属离子显示出对hIAPP原纤化的抑制作用，并促进有毒寡聚体的产生。使用圆二色谱，透射电子显微镜，凝胶电泳，小角X-射线散射和离子迁移率质谱，我们研究了组装机制的hIAPP寡聚体在存在和不存在的金属离子。无金属的hIAPP和金属缔合的hIAPP单体的寡聚化均按照类似的生长模型开始。然而，在Cu（ii）的存在下，hIAPP单体自组装成具有无规卷曲结构的小球状聚集体（Rg = 45 μ π ι）。这种Cu（ii）-相关的hIAPP寡聚体显示出非途径聚集，并且被认为是对胰腺β-细胞有毒的终产物。另一方面，不含金属的hIAPP和Zn（ii）缔合的hIAPP单体产生相对较少的毒性聚集体，其最终生长成原纤维。我们认为，hIAPP与Cu（ii）的配位和相对高的稳定性（Ka，ca. 108 M-1）导致hIAPP寡聚体的构象异常和毒性。总体而言，通过结合多种生物物理方法，我们的研究表明，hIAPP和Cu（ii）之间的分子相互作用诱导hIAPP组装的不同途径。这项工作将推进我们的知识的构象基础，组装机制，和毒性的小可溶性淀粉样蛋白寡聚体。
The molecular interaction of hIAPP with Cu(ii) mediates the formation of off-pathway and toxic oligomers which have small-sized and random coil structures. Amyloidosis is a clinical disorder implicated with the formation of toxic amyloid aggregates. Despite their pathological significance, it is challenging to define the structural characteristics of amyloid oligomers owing to their metastable nature. Herein, we report structural and mechanistic investigations of human islet amyloid polypeptide (hIAPP) oligomers, found in type II diabetes mellitus, in both the absence and presence of disease-relevant metal ions [i.e., Cu(ii) and Zn(ii)]. These metal ions show suppressive effects on hIAPP fibrillation and facilitate the generation of toxic oligomers. Using circular dichroism spectroscopy, transmission electron microscopy, gel electrophoresis, small-angle X-ray scattering, and ion mobility-mass spectrometry, we investigated the assembly mechanisms of hIAPP oligomers in the presence and absence of metal ions. Oligomerization of both metal-free hIAPP and metal-associated hIAPP monomers is initiated following a similar growth model. However, in the presence of Cu(ii), hIAPP monomers self-assemble into small globular aggregates (Rg ∼ 45 Å) with a random coil structure. This Cu(ii)-associated hIAPP oligomer shows an off-pathway aggregation, and is suggested to be an end product which is toxic to pancreatic β-cells. On the other hand, metal-free hIAPP and Zn(ii)-associated hIAPP monomers generate relatively less toxic aggregates that eventually grow into fibrils. We suggest that the coordination of hIAPP to Cu(ii) and the relatively high stability (Ka, ca. 108 M–1) of hIAPP–Cu(ii) complexes result in the abnormal conformation and toxicity of hIAPP oligomers. Overall, through combining multiple biophysical methods, our studies suggest that molecular interactions between hIAPP and Cu(ii) induce a different pathway for hIAPP assembly. This work will advance our knowledge of the conformational basis, assembly mechanism, and toxicity of small soluble amyloid oligomers.
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影响因子：
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