Prion diseases are associated with a conformational switch in the prion protein (PrP) from its normal cellular form (denoted PrPC) to a disease-associated “scrapie” form (PrPSc). A number of PrPSc-like conformations can be generated by incubating recombinant PrPC at low pH, indicating that protonation of key residues is likely to destabilize PrPC, facilitating its conversion to PrPSc. Here, we examine the stability of human PrPC with pH and find that PrPC fold stability is significantly reduced by the protonation of two histidine residues, His187 and His155. Mutation of His187 to an arginine, which imposes a permanently positively charged residue in this region of the protein, has a dramatic effect on the folding of PrPC, resulting in a molecule that displays a markedly increased propensity to oligomerize. The oligomeric form is characterized by an increased β-sheet content, loss of fixed side chain interactions, and partial proteinase resistance. Hence, the protonation state of H187 appears to be crucial in determining the conformation of PrP; the unprotonated form favors native PrPC, while the protonated form favors PrPSc-like conformations. These results are relevant to the pathogenic H187R mutation found in humans, which is associated with an inherited prion disease [also termed Gerstmann-Strussler-Scheinker (GSS) syndrome] with unusual features such as childhood neuropsychiatric illness. Our data imply that the intrinsic instability of the PrPC conformation in this variant is caused by a positive charge at this site in the protein. This mutation is distinct from all those associated with GSS, which have much more subtle physical consequences. The degree of instability might be the cause of the unusually early onset of mental disturbance in affected individuals.
|Translated title of the contribution||The H187R mutation of the human prion protein induces conversion of recombinant prion protein to the PrPSc-like form|
|Pages (from-to)||8729 - 8738|
|Number of pages||10|
|Early online date||18 Aug 2010|
|Publication status||Published - Oct 2010|