Aβ "stretching-and-Packing" Cross-Seeding Mechanism Can Trigger Tau Protein Aggregation

Ruxi Qi, Yin Luo, Guanghong Wei, Ruth Nussinov, Buyong Ma

Research output: Contribution to journalArticlepeer-review

Abstract

There are synergistic effects of Aβ and tau protein in Alzheimer's disease. Aβ1-42 protofibril seeds induce conversion of human tau protein into β-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 Aβ1-42 protofibril on two monomeric tau constructs: K18 and K19. We found that Aβ 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. Aβ interacting patches around Tyr10/Ile41 contribute significantly to the interactions with K18 and K19. Aβ cross-seeded tau aggregation can adopt a "stretching-and-packing" 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 Aβ1-42 but not by Aβ1-40.

Original languageEnglish
Pages (from-to)3276-3282
Number of pages7
JournalJournal of Physical Chemistry Letters
Volume6
Issue number16
DOIs
StatePublished - 20 Aug 2015

Keywords

  • Alzheimer's disease
  • cross-seeding
  • prion
  • tau K18/K19

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