Fibril formation rewires interactome of the Alzheimer protein Tau by π-stacking

Abstract

Aggregation of the Tau protein defines progression of neurodegenerative diseases, including Alzheimer's Disease. Tau assembles into oligomers and fibrils. The molecular basis of their toxicity is poorly understood. Here we show that p-stacking by Arginine side chains rewires the interactome of Tau upon aggregation. Oligomeric nano-aggregates scavenge the COPI complex, fibrils attract proteins involved in microtubule binding, RNA binding and phosphorylation. The aberrant interactors have disordered regions with unusual sequence features. Arginines are crucial to initiate such aberrant interactions. Remarkably, substitution of Arginines by Lysines abolishes scavenging, which indicates a key role for the pi-stacking of the Arginine side chain. The molecular chaperone Hsp90 tames such re-arrangements, which suggests that the natural protein quality control system can suppress aberrant interactions. Together, our data present a molecular mode of action for derailment of protein-protein interaction in neurodegeneration.

The mechanism of Hsp90-induced oligomerizaton of Tau

“…Notably, the formation of high-molecular weight Tau aggregates and fibrils was prevented in the presence of Hsp90. Electron micrographs of K18 Tau fragments in the presence of Hsp90 also show the formation of small protein conglomerates, while fibril formation is prevented (43).…”