Polyphosphate-Induced Aggregation-Prone Conformations of Tau

Abstract

Tau is an intrinsically disordered protein expressed in the axons of neurons, where it functions to stabilize microtubules. In neurodegenerative diseases known as tauopathies, tau forms aggregated, cytosolic inclusions consisting of paired helical filaments. In vitro, a variety of anionic polymers have been shown to induce aggregation of tau,including polyphosphate. However, whether or not these inducers share a common mechanism is unknown. Here we used single molecule FRET to characterize conformational changes in tau upon binding to polyphosphate, contrasting the 2N3R and 2N4R isoforms. Our measurements determined that the positively charged microtubule-binding region of tau and the proline-rich region preceding it compact in the presence of polyphosphate, suggesting that these regions interact electrostatically with polyphosphate. The negatively charged N-terminal region was extended in the presence of polyphosphate, resulting in the loss of long-range contacts found in solution. These findings largely corroborate with a model for the aggregation-prone state of tau in the presence of heparin; comparison between the two models may elucidate generalizable features of tau's aggregation-prone state. Furthermore, as the ratio of 2N3R and 2N4R isoforms is imbalanced in some tauopathies, their comparison may provide insight into how this perturbation contributes to aggregate formation.