| First Author | Khan MQ | Year | 2010 |
| Journal | Proc Natl Acad Sci U S A | Volume | 107 |
| Issue | 46 | Pages | 19808-13 |
| PubMed ID | 21041683 | Mgi Jnum | J:245333 |
| Mgi Id | MGI:5917947 | Doi | 10.1073/pnas.1005267107 |
| Citation | Khan MQ, et al. (2010) Prion disease susceptibility is affected by beta-structure folding propensity and local side-chain interactions in PrP. Proc Natl Acad Sci U S A 107(46):19808-13 |
| abstractText | Prion diseases occur when the normally alpha-helical prion protein (PrP) converts to a pathological beta-structured state with prion infectivity (PrP(Sc)). Exposure to PrP(Sc) from other mammals can catalyze this conversion. Evidence from experimental and accidental transmission of prions suggests that mammals vary in their prion disease susceptibility: Hamsters and mice show relatively high susceptibility, whereas rabbits, horses, and dogs show low susceptibility. Using a novel approach to quantify conformational states of PrP by circular dichroism (CD), we find that prion susceptibility tracks with the intrinsic propensity of mammalian PrP to convert from the native, alpha-helical state to a cytotoxic beta-structured state, which exists in a monomer-octamer equilibrium. It has been controversial whether beta-structured monomers exist at acidic pH; sedimentation equilibrium and dual-wavelength CD evidence is presented for an equilibrium between a beta-structured monomer and octamer in some acidic pH conditions. Our X-ray crystallographic structure of rabbit PrP has identified a key helix-capping motif implicated in the low prion disease susceptibility of rabbits. Removal of this capping motif increases the beta-structure folding propensity of rabbit PrP to match that of PrP from mouse, a species more susceptible to prion disease. |
