Departments of Chemistry and Biochemistry and Biological Chemistry, UCLA-DOE Institute, Molecular Biology Institute, and Howard Hughes Medical Institute, UCLA, Los Angeles, CA, USA.
Bio-X Institutes, Key Laboratory for the Genetics of Developmental and Neuropsychiatric Disorders, Ministry of Education, Shanghai Jiao Tong University, Shanghai, China.
Nat Struct Mol Biol. 2021 Sep;28(9):724-730. doi: 10.1038/s41594-021-00646-x. Epub 2021 Sep 9.
Amyloidosis of human islet amyloid polypeptide (hIAPP) is a pathological hallmark of type II diabetes (T2D), an epidemic afflicting nearly 10% of the world's population. To visualize disease-relevant hIAPP fibrils, we extracted amyloid fibrils from islet cells of a T2D donor and amplified their quantity by seeding synthetic hIAPP. Cryo-EM studies revealed four fibril polymorphic atomic structures. Their resemblance to four unseeded hIAPP fibrils varies from nearly identical (TW3) to non-existent (TW2). The diverse repertoire of hIAPP polymorphs appears to arise from three distinct protofilament cores entwined in different combinations. The structural distinctiveness of TW1, TW2 and TW4 suggests they may be faithful replications of the pathogenic seeds. If so, the structures determined here provide the most direct view yet of hIAPP amyloid fibrils formed during T2D.
人类胰岛淀粉样多肽（hIAPP）淀粉样变是 2 型糖尿病（T2D）的病理标志，这种流行病影响了近世界人口的 10%。为了可视化与疾病相关的 hIAPP 纤维，我们从 T2D 供体的胰岛细胞中提取淀粉样纤维，并通过接种合成的 hIAPP 来扩增其数量。冷冻电镜研究揭示了四种纤维多态性原子结构。它们与未接种的四种 hIAPP 纤维的相似性从几乎相同（TW3）到不存在（TW2）不等。hIAPP 多态性的多样组合似乎来自于三个不同的原纤维核心以不同的组合缠绕。TW1、TW2 和 TW4 的结构独特性表明它们可能是致病种子的忠实复制。如果是这样，那么这里确定的结构提供了迄今为止对 T2D 期间形成的 hIAPP 淀粉样纤维的最直接观察。
