Fibril Structure of Human Islet Amyloid Polypeptide
Fibril Structure of Human Islet Amyloid Polypeptide
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DOI：
10.1074/jbc.m111.327817
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发表时间：
2012-02-17
影响因子：
4.8
通讯作者：
Langen, Ralf
中科院分区：
文献类型：
--
作者：
Bedrood, Sahar;Li, Yiyu;Langen, Ralf
人胰岛淀粉样多肽（hIAPP）的错误折叠和淀粉样纤维的形成被认为在2型糖尿病的发病机制中是重要的，但是错误折叠形式的结构仍然知之甚少。在这里，我们开发了一种方法，结合位点定向自旋标记与连续波和脉冲EPR调查当地的二级结构，并确定相对于彼此的二级结构元素的相对取向。这些数据表明，单个hIAPP分子在原纤维内占据发夹折叠。这个折叠包含两个β链，它们比以前模型预期的要远得多。以EPR数据为约束条件，通过计算精化得到原子结构模型。由此产生的家庭的结构表现出左手螺旋扭曲，与扭曲的形态观察到的电子显微镜。原纤维原丝含有堆叠的hIAPP单体，其形成围绕彼此扭转的相对β-片层。单体的两条β链采用平面外的位置，并交错约三个肽层（类似于15埃）。这些结果提供了hIAPP原纤维形成的机制，并且可以解释原纤维的显著稳定性。因此，结构模型作为理解和防止hIAPP错误折叠的起点。
Misfolding and amyloid fibril formation by human islet amyloid polypeptide (hIAPP) are thought to be important in the pathogenesis of type 2 diabetes, but the structures of the misfolded forms remain poorly understood. Here we developed an approach that combines site-directed spin labeling with continuous wave and pulsed EPR to investigate local secondary structure and to determine the relative orientation of the secondary structure elements with respect to each other. These data indicated that individual hIAPP molecules take up a hairpin fold within the fibril. This fold contains two beta-strands that are much farther apart than expected from previous models. Atomistic structural models were obtained using computational refinement with EPR data as constraints. The resulting family of structures exhibited a left-handed helical twist, in agreement with the twisted morphology observed by electron microscopy. The fibril protofilaments contain stacked hIAPP monomers that form opposing beta-sheets that twist around each other. The two beta-strands of the monomer adopt out-of-plane positions and are staggered by about three peptide layers (similar to 15 angstrom). These results provide a mechanism for hIAPP fibril formation and could explain the remarkable stability of the fibrils. Thus, the structural model serves as a starting point for understanding and preventing hIAPP misfolding.