Cross-Seeding Interaction between 尾-Amyloid and Human Islet Amyloid Polypeptide

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• 作者：Rundong Hu ; Mingzhen Zhang ; Hong Chen ; Binbo Jiang ; Jie Zheng
• 刊名：ACS Chemical Neuroscience
• 出版年：2015
• 出版时间：October 21, 2015
• 年：2015
• 卷：6
• 期：10
• 页码：1759-1768
• 全文大小：496K
• ISSN：1948-7193

文摘

Alzheimer鈥檚 disease (AD) and type 2 diabetes (T2D) are two common protein misfolding diseases. Increasing evidence suggests that these two diseases may be correlated with each other via cross-sequence interactions between 尾-amyloid peptide (A尾) associated with AD and human islet amyloid polypeptide (hIAPP) associated with T2D. However, little is known about how these two peptides work and how they interact with each other to induce amyloidogenesis. In this work, we study the effect of cross-sequence interactions between A尾 and hIAPP peptides on hybrid amyloid structures, conformational changes, and aggregation kinetics using combined experimental and simulation approaches. Experimental results confirm that A尾 and hIAPP can interact with each other to aggregate into hybrid amyloid fibrils containing 尾-sheet-rich structures morphologically similar to pure A尾 and hIAPP. The cross-seeding of A尾 and hIAPP leads to the coexistence of both a retarded process at the initial nucleation stage and an accelerated process at the fibrillization stage, in conjunction with a conformational transition from random structures to 伪-helix to 尾-sheet. Further molecular dynamics simulations reveal that A尾 and hIAPP oligomers can efficiently cross-seed each other via the association of two highly similar U-shaped 尾-sheet structures; thus, conformational compatibility between A尾 and hIAPP aggregates appears to play a key role in determining barriers to cross-seeding. The cross-seeding effects in this work may provide new insights into the molecular mechanisms of interactions between AD and T2D.