PDF(Pubmed)
Abstract：
The deposition of islet amyloid polypeptide (hIAPP) fibrils is a hallmark of β-cell death in type II diabetes. In this study, we employ state-of-the-art MAS solid-state spectroscopy to investigate the previously elusive N-terminal region of hIAPP fibrils, uncovering both rigidity and heterogeneity. Comparative analysis between wild-type hIAPP and a disulfide-deficient variant (hIAPPC2S,C7S) unveils shared fibril core structures yet strikingly distinct dynamics in the N-terminus. Specifically, the variant fibrils exhibit extended β-strand conformations, facilitating surface nucleation. Moreover, our findings illuminate the pivotal roles of specific residues in modulating secondary nucleation rates. These results deepen our understanding of hIAPP fibril assembly and provide critical insights into the molecular mechanisms underpinning type II diabetes, holding promise for future therapeutic strategies.
摘要：
胰岛淀粉样多肽（hIAPP）原纤维的沉积是II型糖尿病中β细胞死亡的标志。在这项研究中,我们采用最先进的MAS固态光谱来研究hIAPP原纤维的先前难以捉摸的N末端区域，揭示刚性和异质性。野生型hIAPP和二硫键缺陷型变体(hIAPPC2S，C7S）揭示了共享的原纤维核心结构，但在N端却有着鲜明的动态。具体来说,变异的原纤维表现出延伸的β链构象，促进表面成核。此外，我们的发现阐明了特定残基在调节次级成核速率中的关键作用。这些结果加深了我们对hIAPP原纤维组装的理解，并提供了对支撑II型糖尿病的分子机制的关键见解。对未来的治疗策略抱有希望。
