Abnormal aggregation of tau protein is pathologically linked to Alzheimer's disease, while the aggregation of the prion-like RNA-binding protein (RBP) CPEB3 is functional and is associated with long-term memory. However, the interaction between these two memory-related proteins has not yet been explored. Our residue-specific NMR relaxation study revealed that the first prion domain of CPEB3 (PRD1) interacts with the VQIVYKPVDLSKV segment of tau and prevents the aggregation of tau-K18. Notably, this interaction is synergistic as it not only inhibits tau-K18 aggregation but also enhances PRD1 fibril formation. We also studied the interaction of different PRD1 subdomains with tau-K18 to elucidate the precise region of PRD1 that inhibits tau-K18 aggregation. This revealed that the PRD1-Q region is responsible for preventing tau-K18 aggregation. Inspired by this, we synthesized a 15 amino acid Poly-Q peptide that inhibits tau-K18 aggregation, suggesting its potential as a small drug-like molecule for Alzheimer's disease therapeutics.
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