Conformational And Assembly Studies Of Two Tau Repeats: 2R and 3R

Abstract

Our aim was to investigate the conformational properties of two tau fragments, 2R and 3R, in response to increasing amounts of a hydrogen-bond stabilizing solvent trifluoroethanol. 2R and 3R contain two or three of the microtubule binding domain repeats respectively, which are known to form the core of Pair Helical Filaments (PHFs) found in an Alzheimer's Disease brain. Using Circular Dichroism and Fourier Transform Infrared spectroscopy we find that upon increasing the trifluoroethanol concentration, a conformational transition occurs from mostly random coil with residual a-helix and b-turn structure into a full a-helix. The high a-helical propensity of 2R and 3R is consistant with tau's biological role as a natively unfolded protein that binds to the a-helical C-terminus of tubulin, thereby stabilizing microtubules. The increase in a-helix content correlates with the formation of fibrillar aggregates in vitro. Atomic Force Microscopy shows that these aggregates show morphological traits with ex vivo PHFs.