
@article {12889,
	title = {Identification and structural characterization of the precursor conformation of the prion protein which directly initiates misfolding and oligomerization.},
	journal = {J Mol Biol},
	year = {2017},
	month = {2017 Jan 29},
	abstract = {<p>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.</p>
},
	issn = {1089-8638},
	doi = {10.1016/j.jmb.2017.01.019},
	author = {Moulick, Roumita and Udgaonkar, Jayant B}
}
