Molecular basis for insulin fibril assembly
Molecular basis for insulin fibril assembly
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DOI：
10.1073/pnas.0910080106
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发表时间：
2009-11-10
影响因子：
11.1
通讯作者：
Eisenberg, David
中科院分区：
文献类型：
--
作者：
Ivanova, Magdalena I.;Sievers, Stuart A.;Eisenberg, David
在称为注射性淀粉样变性的罕见疾病中，可以观察到胰岛素的细胞外原纤维。我们发现，具有序列 LVEALYL 的胰岛素 B 链片段是最小的片段，它能够以摩尔比依赖的方式成核并抑制全长胰岛素的纤维化，表明该片段是胰岛素原纤维交叉 β 脊柱的中心。与蛋白质的其余部分分离后，LVEALYL 形成具有纤维状形态的微晶聚集体，我们以 1 埃的分辨率确定了其结构。 LVEALYL 片段堆叠成一对紧密交叉的 β 片层，每对都显示出类淀粉样原纤维典型的干燥空间拉链界面。这种结构产生了与电子显微镜、X 射线纤维衍射和生化研究一致的人胰岛素原纤维模型。
In the rare medical condition termed injection amyloidosis, extracellular fibrils of insulin are observed. We found that the segment of the insulin B-chain with sequence LVEALYL is the smallest segment that both nucleates and inhibits the fibrillation of full-length insulin in a molar ratio-dependent manner, suggesting that this segment is central to the cross-beta spine of the insulin fibril. In isolation from the rest of the protein, LVEALYL forms microcrystalline aggregates with fibrillar morphology, the structure of which we determined to 1 angstrom resolution. The LVEALYL segments are stacked into pairs of tightly interdigitated beta-sheets, each pair displaying the dry steric zipper interface typical of amyloid-like fibrils. This structure leads to a model for fibrils of human insulin consistent with electron microscopic, x-ray fiber diffraction, and biochemical studies.