Surfactant Properties and Interface Induced Aggregation of Tau Proteins

Abstract

Hsp90 binds to and promotes the clearance of tau, which is thought to reduce the formation of neurotoxic aggregates. Tau is an intrinsically disordered protein and it is unclear what role, if any, Hsp90 has in controlling its structure and dynamics. Hsp90 cooperates with numerous co-chaperones such as the immunophilin FKBP51, which assists in regulating the folding and processing of client proteins like tau. Defining the precise interactions between tau and the Hsp90 chaperone network is important for understanding the role of tau in Alzheimer's Disease. In this study, nuclear magnetic resonance (NMR) spectroscopy was used to probe the interaction between 15N-labeled tau, Hsp90 and FKBP51. The results demonstrate that two hydrophobic hexapeptide motifs located at residues 275-280 and 306-311 in tau's C-terminus bind to Hsp90 and FKBP51. This was determined by observing a significant reduction in the intensity ratios of HSQC spectra for free tau and tau in complex with Hsp90 and FKBP51. Resonances that show reduced intensities in the absence of line broadening are probably undergoing chemical exchange with a bound conformation. Several residues near the N-terminus of the protein also show a similar reduction in intensity upon addition of Hsp90 and FKBP51. Formation of the ternary complex around the client protein tau is congruent with currently proposed models suggesting that the binding of FKBP51 and Hsp90 assist in tau regulation, thereby triggering its recycling back to the MT surface.