Two Misfolding Routes for the Prion Protein around pH 4.5

Abstract

Using molecular dynamics simulations, we show that the prion protein (PrP) exhibits a dual behavior, with two possible transition routes, upon protonation of H187 around pH 4.5, which mimics specific conditions encountered in endosomes. Our results suggest a picture in which the protonated imidazole ring of H187 experiences an electrostatic repulsion with the nearby guanidinium group of R136, to which the system responds by pushing either H187 or R136 sidechains away from their native cavities. The regions to which H187 and R136 are linked, namely the C-terminal part of H2 and the loop connecting S1 to H1, respectively, are affected in a different manner depending on which pathway is taken. Specific in vivo or in vitro conditions, such as the presence of molecular chaperones or a particular experimental setup, may favor one transition pathway over the other, which can result in very different monomers. This has some possible connections with the observation of various fibril morphologies and the outcome of prion strains. In addition, the finding that the interaction of H187 with R136 is a weak point in mammalian PrP is supported by the absence of the residue pair in non-mammalian species that are known to be resistant to prion diseases.

The Role of the Carbohydrate Recognition Domain of Placental Protein 13 (PP13) in Pregnancy Evaluated with Recombinant PP13 and the DelT221 PP13 Variant

“…Already in E. coli, the expressed DelT 221 protein was routed into inclusion bodies, a phenomenon that was previously reported in relation to the expression of misfolded proteins by Kraft et al 2010 [31] and by Gerrec et al 2013 [32]. It appears that the bacteria “conceived” the truncated protein variant as “junk” and therefore removed it by routing it into the inclusion bodies.…”

“…High concentrations of urea were used to refold the protein in bacteria, and recover it out of the inclusion bodies to enable its purification. It remains to be seen what the degradation process of the mutated protein is in human placenta and how to gain its recovery in human with a potential procedure for pH changes [32] or the formation of multi-vascular bodies as described by Wang et al 2011 [33] . At present we assume that the cytoplasm recognized the misfolded mutated DelT 221 at a “control checkpoint” already at the endoplasmic reticulum or the Golgi and routes it for a fast turnover to avoid potential toxic effects.…”

Molecular dynamics studies on the NMR and X-ray structures of rabbit prion proteins

“…Recently, Garrec et al (2013) reported that the salt linkage of HIS187 and ARG136 of mouse PrP causes "two misfolding routes for the prion protein" (Garrec et al (2013)). For RaPrP C , we found that at HIS187 the salt bridge HIS186-ARG155 contributes to the structural stability (Table 1).…”

Destabilization of polar interactions in the prion protein triggers misfolding and oligomerization

“…At low pH, physiological amounts of salt trigger PrP misfolding and oligomerization. Computational studies have shown that movement of β1‐α1‐β2 away from the rest of the CTD and breakage of long‐range salt bridges is an important step that precedes misfolding of PrP 15,61,62 . These observations are corroborated by biophysical studies 29 .…”