Residue-specific mobility changes in soluble oligomers of the prion protein define regions involved in aggregation

Publication date: September 2018Source: Biochimica et Biophysica Acta (BBA) - Proteins and Proteomics, Volume 1866, Issue 9Author(s): John Paul Glaves, Carol L. Ladner-Keay, Trent C. Bjorndahl, David S. Wishart, Brian D. SykesAbstractPrion (PrP) diseases are neurodegenerative diseases characterized by the formation of β-sheet rich, insoluble and protease resistant protein deposits (called PrPSc) that occur throughout the brain. Formation of synthetic or in vitro PrPSc can occur through on-pathway toxic oligomers. Similarly, toxic and infectious oligomers identified in cell and animal models of prion disease indicate that soluble oligomers are likely intermediates in the formation of insoluble PrPSc. Despite the critical role of prion oligomers in disease progression, little is known about their structure. In order, to obtain structural insight into prion oligomers, we generated oligomers by shaking-induced conversion of recombinant, monomeric prion protein PrPc (spanning residues 90–231). We then obtained two-dimensional solution NMR spectra of the PrPc monomer, a 40% converted oligomer, and a 94% converted oligomer. Heteronuclear single-quantum correlation (1H–15N) studies revealed that, in comparison to monomeric PrPc, the oligomer has intense amide peak signals in the N-terminal (residues 90–114) and C-terminal regions (residues 226–231). Furthermore, a core region with decreased mobility is revealed from residues ~127 to 225. Within this core oligomer region with...
Source: Biochimica et Biophysica Acta (BBA) Proteins and Proteomics - Category: Biochemistry Source Type: research