Electrostatic Interactions between Tau Peptides and Model Biological Membranes: A Folding-Upon-Binding Mechanism

Abstract

Found in neuronal cells of the central nervous system, tau proteins primarily function in cytoskeletal stability by associating with microtubules. During Alzheimer's disease and other tauopathies, misfolded tau proteins form neurofibrillary tangles (NFTs), thus impairing neuronal function and causing various neurodegenerative effects. The microtubule binding domain of tau consists of four repeat segments (R1-R4), and aggregation of these segments has previously been observed within NFTs. Previous research has also found misfolded tau components associated with the Golgi membrane, but not the plasma membrane. Here, we have used circular dicroism (CD) and isothermal titration calorimetry (ITC) to examine interactions between repeat segments R1-R4 and lipid bilayers of varying charge (DOPC and DOPC/DOPG 80:20). Our data indicate that significant structural changes are induced by charged membrane mimics and an entropy-driven binding process occurs during this interaction. Indeed, binding of tau occurs concomitantly with a classical hydrophobic effect. Thus, we propose a folding-upon-binding event occurring between negatively-charged membranes and the more promiscuous tau repeat segments. Results from calcein leakage assays and membrane fusion FRET measurements will also be presented to further probe the mechanism of bilayer disruption. These results will help explain a possible mechanism of tau misfolding during Alzheimer's disease, and are potentially beneficial to design strategies that prevent or reverse the aggregation process.