Conformational and assembly studies of two tau repeats: 2R and 3R.

摘要

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 alpha-helix and beta-turn structure into a full alpha-helix. The high alpha-helical propensity of 2R and 3R is consistant with tau's biological role as a natively unfolded protein that binds to the alpha-helical C-terminus of tubulin, thereby stabilizing microtubules. The increase in alpha-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.