Competing Interactions Stabilize Pro- and Anti-aggregant Conformations of Human Tau

Aggregation of Tau into amyloid-like fibrils is a key process in neurodegenerative diseases such as Alzheimer. To understand how natively disordered Tau stabilizes conformations that favor pathological aggregation, we applied single-molecule force spectroscopy. Intramolecular interactions that fold polypeptide stretches of similar to 19 and similar to 42 amino acids in the functionally important repeat domain of full-length human Tau (hTau40) support aggregation. In contrast, the unstructured N terminus randomly folds long polypeptide stretches > 100 amino acids that prevent aggregation. The pro-aggregant mutant hTau40 Delta K280 observed in frontotemporal dementia favored the folding of short polypeptide stretches and suppressed the folding of long ones. This trend was reversed in the anti-aggregant mutant hTau40 Delta K280/PP. The aggregation inducer heparin introduced strong interactions in hTau40 and hTau40 Delta K280 that stabilized aggregation-prone conformations. We show that the conformation and aggregation of Tau are regulated through a complex balance of different intra-and intermolecular interactions.