Elucidation of the Aggregation Pathways of Helix鈥揟urn鈥揌elix Peptides: Stabilization at the Turn Region Is Critical for Fibril Formation

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• 作者：Thanh D. Do ; Ali Chamas ; Xueyun Zheng ; Aaron Barnes ; Dayna Chang ; Tjitske Veldstra ; Harmeet Takhar ; Nicolette Dressler ; Benjamin Trapp ; Kylie Miller ; Audrene McMahon ; Stephen C. Meredith ; Joan-Emma Shea ; Kristi Lazar Cantrell ; Michael T. Bowers
• 刊名：Biochemistry
• 出版年：2015
• 出版时间：July 7, 2015
• 年：2015
• 卷：54
• 期：26
• 页码：4050-4062
• 全文大小：706K
• ISSN：1520-4995

文摘

Aggregation of proteins to fiberlike aggregates often involves a transformation of native monomers to 尾-sheet-rich oligomers. This general observation underestimates the importance of 伪-helical segments in the aggregation cascade. Here, using a combination of experimental techniques and accelerated molecular dynamics simulations, we investigate the aggregation of a 43-residue, apolipoprotein A-I mimetic peptide and its E21Q and D26N mutants. Our study indicates a strong propensity of helical segments not to adopt cross-尾-fibrils. The helix鈥搕urn鈥揾elix monomeric conformation of the peptides is preserved in the mature fibrils. Furthermore, we reveal opposite effects of mutations on and near the turn region in the self-assembly of these peptides. We show that the E21鈥揜24 salt bridge is a major contributor to helix鈥搕urn鈥揾elix folding, subsequently leading to abundant fibril formation. On the other hand, the K19鈥揇26 interaction is not required to fold the native helix鈥搕urn鈥揾elix peptide. However, removal of the charged D26 residue decreases the stability of the helix鈥搕urn鈥揾elix monomer and consequently reduces the level of aggregation. Finally, we provide a more refined assembly model for the helix鈥搕urn鈥揾elix peptides from apolipoprotein A-I based on the parallel stacking of helix鈥搕urn鈥揾elix dimers.