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Abstract: Propagation of transmissible spongiform encephalopathies is believed to involve
the conversion of the cellular prion protein, PrPC, into a misfolded oligomeric form,
PrPSc. An important step towards understanding the mechanism of this conversion is to
study the folding pathway(s) and the stability of PrPC.
In the first part of this work, we examined the kinetics of folding and unfolding
reactions for the recombinant wild type human prion protein fragment 90-231. The
stopped flow data provided clear evidence for the existence of an intermediate on the
refolding pathway of the prion protein as indicated by a pronounced curvature in chevron
plots and the presence of significant burst phase amplitudes in the refolding kinetics. The
protein folding studies were then extended to prion protein variants carrying mutations
associated with inherited prion diseases. Analysis of kinetic data clearly indicates the
presence of partially structured intermediates on the refolding pathway of each PrP
variant studied. For the majority of PrP variants tested, mutations linked to familial prion
diseases resulted in a pronounced increase in the thermodynamic stability - and thus the
population - of the folding intermediate. These data strongly suggest that partially folded
intermediates of PrP may play a crucial role in prion protein conversion, serving as direct
precursors of the pathogenic PrPSc isoform.
Previous studies indicate that salts promote the conformational conversion of the
recombinant prion protein into a PrPSc-like form. To gain insight into the mechanism of
this effect, we studied the influence of a number of salts on the thermodynamic stability
of the recombinant human prion protein. Chemical unfolding studies in urea showed that
at low concentrations (< 50 mM), all salts tested significantly reduced the thermodynamic
stability of the protein. At higher salt concentrations, the destabilizing effect was
gradually reversed, and salts acted according to their ranking in the Hofmeister series.
The observations indicate that electrostatic interactions play an unusually important role
in the stability of the prion protein and that ions present in the cellular environment may
control the PrPC to PrPSc conversion by modulating the thermodynamic stability of the
native PrPC isoform.

Keywords: prion protein, ultra-fast folding, kinetics, amyloid fibers, salt effect

URL: http://

Posted by Adrian C Apetri


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