Computational studies of tau protein : implications for the pathogenesis and treatment of neurodegenerative diseases

[摘要] (cont.) conformations within an IDP and uses these structures to construct ensembles that are consistent with experimental data. This method is tested on a region of another IDP, p21 Wafl/Cipl/Sdil(14 5 -164 ), for which crystal structures of substrate-bound conformations are available. Residual conformational preferences identified using EMW were found to be comparable to crystal structures from substrate-bound conformations of p21 Wafl/Cipl/Sdil( 14 5 -164 ). By applying EMW to tau, we find disease-associated forms of tau exhibit a conformational preference for extended conformations near the aggregation-initiating region. Since an increased preference for extended states may facilitate the propagation of cross-[beta] conformation associated with aggregated forms of tau, these results help to explain how local conformational preferences in disease-associated states can promote the formation of tau aggregates. Finally, we examine limitations of the current methods for characterizing IDPs such as tau and discuss future directions in the modeling of these proteins.

[发布机构] Massachusetts Institute of Technology