Identification and structural characterization of the precursor conformation of the prion protein which directly initiates misfolding and oligomerization.
|Title||Identification and structural characterization of the precursor conformation of the prion protein which directly initiates misfolding and oligomerization.|
|Publication Type||Journal Article|
|Year of Publication||2017|
|Authors||Moulick R, Udgaonkar JB|
|Journal||J Mol Biol|
|Date Published||2017 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 Journal||J. Mol. Biol.|