A尾 鈥淪tretching-and-Packing鈥?Cross-Seeding Mechanism Can Trigger Tau Protein Aggregation

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• 作者：Ruxi Qi ; Yin Luo ; Guanghong Wei ; Ruth Nussinov ; Buyong Ma
• 刊名：The Journal of Physical Chemistry Letters
• 出版年：2015
• 出版时间：August 20, 2015
• 年：2015
• 卷：6
• 期：16
• 页码：3276-3282
• 全文大小：479K
• ISSN：1948-7185

文摘

There are synergistic effects of A尾 and tau protein in Alzheimer鈥檚 disease. A尾_1鈥?2 protofibril seeds induce conversion of human tau protein into 尾-sheet-rich toxic tau oligomers. However, the molecular mechanisms underlying such a conformational conversion are unclear. Here, we use extensive all atom replica exchange molecular dynamics simulations to investigate the effects of preformed A尾_1鈥?2 protofibril on two monomeric tau constructs: K18 and K19. We found that A尾 oligomer stretches tau conformation and drastically reduces the metastable secondary structures/hydrogen bonding/salt-bridge networks in tau monomers and exposes their fibril nucleating motifs ²⁷⁵VQIINK²⁸⁰ and ³⁰⁶VQIVYK³¹¹. A尾 interacting patches around Tyr10/Ile41 contribute significantly to the interactions with K18 and K19. A尾 cross-seeded tau aggregation can adopt a 鈥渟tretching-and-packing鈥?mechanism, paving the way for the next, prion-like growth step. The results provide a mechanism on the atomic level to experimental observations that tau pathogenesis is promoted by A尾_1鈥?2 but not by A尾_1鈥?0.