Comparative analysis of the structural dynamics of the Doppel protein and the C-terminus of the cellular prion protein.

Abstract

The Doppel protein is the closest related protein on the phylogenetic tree to the prion protein. While the misfolding and aggregation of the prion protein is the hallmark of prion diseases, there is no reported evidence of an equivalent pathological process for the Doppel protein. Although the two proteins share only 25% sequence similarity, the folded C-terminus of the prion protein demonstrates a consistent topology with the Doppel protein. Despite the resemblance in topology, previous studies suggest that the Doppel protein has a higher energy barrier against misfolding than prion protein. However, the factors that mold the energy barrier remain unknown. Our goal is to decipher the role of structural dynamics and primary residue sequence of the native fold in shaping the misfolding energy barrier of each protein. Understanding the driving forces that stabilize similar native topologies will provide insight into subtle interactions that potentially trigger pathological prion protein misfolding. To perform a comparative analysis of the structural dynamics of the proteins, we used structural bioinformatics techniques. Our preliminary results indicate that the pattern of backbone local mobility of both proteins is similar: a flexible α-helix 1, and a somewhat rigid cluster that includes the β-sheets and α-helices 2 and 3. We also observed that the main modes of deformations are qualitatively similar between the two proteins. We will discuss the key features of the residue connectivity that determine the common topology despite differences in primary structure and propose target druggable residue interactions that may prevent prion protein misfolding.