TitleIdentification and structural characterization of the precursor conformation of the prion protein which directly initiates misfolding and oligomerization.
Publication TypeJournal Article
Year of Publication2017
AuthorsMoulick R, Udgaonkar JB
JournalJ Mol Biol
Date Published2017 Jan 29

To identify and structurally characterize the precursor conformation of the prion protein (PrP), from which misfolding and aggregation directly commence, has been a long-standing goal. Misfolding converts the α-helical, non-pathogenic functional form of PrP to pathogenic, β-structured oligomeric and amyloidogenic forms, which are the cause of prion diseases. Susceptibility to sporadic prion disease correlates well with the propensity of PrP to misfold to cytotoxic, proteinase-K resistant oligomeric conformations, at low pH. In this study, mutagenesis at the hydrophobic core of the mouse prion protein has been shown to stabilize a monomeric, unfolding intermediate (I), which is populated significantly at equilibrium at low pH. Importantly, the rate of formation of β-structured oligomers at low pH is found to correlate well with the extent to which this intermediate is populated. The misfolding process is limited by dimerization of I, indicating that I is the monomeric precursor conformation which directly initiates misfolding. Structural and thermodynamic characterization by native state hydrogen-deuterium exchange-mass spectrometry studies indicate that the precursor conformation is a partially unfolded form of PrP which forms under misfolding-prone solvent conditions.

Alternate JournalJ. Mol. Biol.
PubMed ID28147229