The Effects of Trimethylamine N-Oxide on the Structural Stability of Prion Protein

Abstract

Transmissible spongiform encephalopathies (TSEs) are diseases that affect the central nervous system in both humans and animals. TSEs can be ascribed to conformational conversion of prion protein (PrP). “Prion” stands for “proteinaceous infectious particle”, which was discovered in the disease-transmitting material of infectious brain tissues and named by Prusiner (Prusiner 1982). The normal, cellular form of PrP (PrPC) is a α-helix-rich glycoprotein attached to the outer cell surface by a glycophosphatidyl inositol linkage. The biological role of PrPC remains ambiguous. Since Cu2+ is unique among divalent metal ions in its ability to bind to PrPC in the octarepeat region (four copies of the repeat ProHisGlyGlyGlyTrpGlyGln) in the N-terminal domain (Whittal et al. 2000), the prion protein has been suggested to play a role in maintaining cellular copper concentration and signal transduction (Brown et al. 1998; Mouillet-Richard et al. 2000). PrPC is non-infectious, whereas the abnormal and infectious, Scrapie isoform of PrP (PrPSc) has been considered to be the major infectious component of the genetic, sporadic and transmissible fatal neuro degenerative prion diseases that affect both human and animals (Prusiner 1998). PrPSc is rich in β-sheet structures and it has a pronounced tendency to misfold and to subsequently aggregate into highly stable and insoluble amyloid plaques. This PrPSc plagess are resistant to digestion by proteinase K, whereas PrPC is sensitive to digestion by proteinase K (Prusiner 1998). PrPSc is responsible for many diseases in humans, including Kuru, Gerstmann-Straussler-Scheinker disease (GSS), fatal familial insomnia (FFI), CreutzfeldtJakob disease (CJD) and the BSE-related, variant Creutzfeldt-Jakob disease (vCJD) (Horwich & Weissman 1997; Prusiner 1997; Will et al. 1996). The infectious nature of these fatal diseases differ from other infectious diseases in that the pathogen is a proteinaceous particle rather than typical pathogens, such as viruses, bacteria and fungi. Therefore, a “proteinonly“ hypothesis has been proposed (Griffith 1967; Prusiner 1998). A protein designated as “protein X“ has been proposed to be involved in structural conversion of PrPC into PrPSc (Telling et al. 1995) in the protein-only model. After decades of study on prion proteins, protein X has not been identified. Thus, the mechanism of how PrPC is converted into PrPSc remains ambiguous. The structure of prion proteins has been studied in human (Calzolai & Zahn 2003; Donne et al. 1997; Zahn et al. 2000), hamster (James et al. 1997) and mouse sequences (Gossert et al.