NMR Structure of the Human Prion Protein with the Pathological Q212P Mutation Reveals Unique Structural Features

Abstract

Prion diseases are fatal neurodegenerative disorders caused by an aberrant accumulation of the misfolded cellular prion protein (PrPC) conformer, denoted as infectious scrapie isoform or PrPSc. In inherited human prion diseases, mutations in the open reading frame of the PrP gene (PRNP) are hypothesized to favor spontaneous generation of PrPSc in specific brain regions leading to neuronal cell degeneration and death. Here, we describe the NMR solution structure of the truncated recombinant human PrP from residue 90 to 231 carrying the Q212P mutation, which is believed to cause Gerstmann-Sträussler-Scheinker (GSS) syndrome, a familial prion disease. The secondary structure of the Q212P mutant consists of a flexible disordered tail (residues 90–124) and a globular domain (residues 125–231). The substitution of a glutamine by a proline at the position 212 introduces novel structural differences in comparison to the known wild-type PrP structures. The most remarkable differences involve the C-terminal end of the protein and the β2–α2 loop region. This structure might provide new insights into the early events of conformational transition of PrPC into PrPSc. Indeed, the spontaneous formation of prions in familial cases might be due to the disruptions of the hydrophobic core consisting of β2–α2 loop and α3 helix.

The Methionine-aromatic Motif Plays a Unique Role in Stabilizing Protein Structure

“…In a second example, mutation of prion protein Met-129 is an allelic risk factor for the development of neurodegenerative diseases, such as Alzheimer (39) as well as fatal familial insomnia and familial Creutzfield-Jacob (40). This Met residue in the wild type prion protein (PDB code 2kun) has three aromatic tyrosine residues within 10 Å, the closest at 5.5 Å separation (41). Another example, a known mutation of the RET proto-oncogene resulting in an M918T mutation within RET protein, is associated with the development of thyroid carcinoma (42,43), and Met-918 in the wild type structure (PDB code 2x2k) has six aromatic groups within 10 Å, with the nearest at 5.4 Å (44).…”

A review on the salt bridge ASP177-ARG163 (O–N) of wild-type rabbit prion protein

“…We have found one focus of prion protein structures is at the β2-α2 loop and its interacted Cterminal of H3 (Biljan et al, 2012a(Biljan et al, & 2012b(Biljan et al, & 2011Calzolai et al, 2000;Christen et al, 2009Christen et al, & 2012Damberger et al, 2011;Gossert et al, 2005;Ilc et al, 2010;Lee et al, 2010;Wen et al, 2010aWen et al, & 2010bKong et al, 2013;Perez et al, 2010Perez et al, & 2008Sweeting et al, 2013;Zahn et al, 2003;Zhang et al, 2000;Kurt et al, 2014aKurt et al, & 2014b. This article found there is a SB ASP177-ARG163 (O-N) in RaPrP C , which just keeps this loop being linked.…”

Molecular Genetics of Gerstmann-Straussler-Scheinker Disease and Creutzfeld-Jakob Disease

“…PrP plaques were visible in both brain and the cerebellum but density of them was the lowest among all GSS families [135]. NMR structure of truncated peptide HuPrP (90-231) revealed different fold from that of the known structures of human PrP c [138]. In particular, α3 helix does not exhibit regular helical conformation in two residues 221…”