Format

Send to:

Choose Destination
See comment in PubMed Commons below
PLoS Comput Biol. 2013;9(5):e1003057. doi: 10.1371/journal.pcbi.1003057. Epub 2013 May 16.

Two misfolding routes for the prion protein around pH 4.5.

Author information

  • 1Laboratory of Computational Chemistry and Biochemistry - Institute of Chemical Sciences and Engineering, École Polytechnique Fédérale de Lausanne, Lausanne, Switzerland.

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 [Formula: see text] 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 [Formula: see text] residue pair in non-mammalian species that are known to be resistant to prion diseases.

PMID:
23696721
[PubMed - indexed for MEDLINE]
PMCID:
PMC3656106
Free PMC Article
PubMed Commons home

PubMed Commons

0 comments
How to join PubMed Commons

    Supplemental Content

    Full text links

    Icon for Public Library of Science Icon for PubMed Central
    Loading ...
    Write to the Help Desk