alexa The peculiar nature of unfolding of the human prion protein.
Genetics & Molecular Biology

Genetics & Molecular Biology

Journal of Molecular Biomarkers & Diagnosis

Author(s): Baskakov IV, Legname G, Gryczynski Z, Prusiner SB

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Abstract Spontaneous conformational transition of the prion protein from an alpha-helical isoform to a beta-sheet-rich isoform underlies the pathogenesis of sporadic prion diseases. To study the rate-limiting steps of spontaneous conversion, the formation of amyloid fibrils by the recombinant human PrP C-terminal fragment spanning residues 90-231 (recPrP) was monitored in the presence of urea. The kinetics of spontaneous fibril formation displayed sigmoidal behavior involving a lag phase. The shortest lag phase was observed at partially denaturing conditions, close to the concentration of urea corresponding to the middle point of unfolding. This result indicates that unfolding intermediates may be important for the conversion. To test whether unfolding intermediates are formed, we employed size-exclusion chromatography and circular dichroism spectroscopy to monitor urea denaturation of recPrP. Both techniques showed a single sigmoidal transition with very similar thermodynamic parameters of denaturation and that the transition can be described by a simple equilibrium between folded and denatured states. Detailed analyses of data, however, revealed that the dimensions of both the native and denatured species gradually increases with urea. Expansion of the native species is also accompanied by an increase in efficiency of the energy transfer from a single Trp residue to 1-anilinonaphthalene-8-sulfonate dye as measured by fluorescence. These data illustrate that thermodynamic character of the native ensemble changes gradually with environmental conditions. Such behavior is consistent with the thermodynamically variable model, and may be linked to the ability of PrP to adopt distinct abnormal conformations under pathologic conditions.
This article was published in Protein Sci and referenced in Journal of Molecular Biomarkers & Diagnosis

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