Inhibition of NAPP amyloid-fibril formation and apoptotic cell death by a designed hIAPP amyloid-core-containing hexapeptide
Inhibition of NAPP amyloid-fibril formation and apoptotic cell death by a designed hIAPP amyloid-core-containing hexapeptide
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DOI：
10.1016/j.chembiol.2005.05.010
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发表时间：
2005-07-01
影响因子：
--
通讯作者：
Kapurniotu, A
中科院分区：
文献类型：
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作者：
Tatarek-Nossol, M;Yan, LM;Kapurniotu, A
II型糖尿病的发病机制与37残基人胰岛淀粉样多肽（hIAPP）聚集成细胞毒性P片聚集体和原纤维有关。我们最近的研究表明，在含有β片和淀粉样蛋白核的序列hIAPP（22-27）或NFGAIL中引入两个n -甲基，可将该淀粉样蛋白和细胞毒性序列转化为非淀粉样蛋白和非细胞毒性的NF(N-Me)GA(N-Me)IL。在这里，我们发现NF(N-Me) GA(N-Me)IL能够与高亲和力的全长hIAPP结合并抑制其纤维形成。NF(N-Me)GA (N-Me)IL也抑制hiapp介导的细胞凋亡。相比之下，未经修饰的NFGAIL不会抑制hIAPP淀粉样蛋白的形成和细胞毒性，这表明n -甲基化赋予NFGAIL NF(N-Me)GA(N-Me)IL的特性。这些结果支持hIAPP淀粉样蛋白核心序列的合理n -甲基化可能是设计胰腺淀粉样蛋白诊断和治疗II型糖尿病的有价值的策略。
The pathogenesis of type II diabetes is associated with the aggregation of the 37-residue human islet amyloid polypeptide (hIAPP) into cytotoxic P sheet aggregates and fibrils. We have recently shown that introduction of two N-methyl rests in the beta sheet- and amyloid-core-containing sequence hIAPP(22-27), or NFGAIL converted this amyloidogenic and cytotoxic sequence into nonamyloidogenic and noncytotoxic NF(N-Me)GA(N-Me)IL. Here, we show that NF(N-Me) GA(N-Me)IL is able to bind with high-affinity full-length hIAPP and to inhibit its fibrillogenesis. NF(N-Me)GA (N-Me)IL also inhibits hIAPP-mediated apoptotic beta cell death. By contrast, unmodified NFGAIL does not inhibit hIAPP amyloidogenesis and cytotoxicity, suggesting that N-methylation conferred on NFGAIL the properties of NF(N-Me)GA(N-Me)IL. These results support the concept that rational N-methylation of hIAPP amyloid-core sequences may be a valuable strategy to design pancreatic-amyloid diagnostics and therapeutics for type II diabetes.