The prion protein can exist both in a normal cellular and in a pathogenic conformational
isoform. The latter is responsible for the development of different neurodegenerative diseases,
for example Creutzfeldt-Jakob disease or fatal familial insomnia. To convert the native benign
state of the protein into a highly ordered fibrillar aggregate large-scale rearrangements of the
tertiary structure are necessary during the conversion process and intermediates that are at
least partially unfolded are present during fibril formation. In addition to the sporadic
conversion into the pathogenic isoform, more than 20 familial diseases are known that are
caused by single point mutations increasing the probability of aggregation and
neurodegeneration. Here, we demonstrate that the chemically denatured states of the mouse
and human prion proteins have very similar structural and dynamic characteristics. Initial
studies on the single point mutants E196K, F198S, V203I and R208H of the oxidized mouse
construct which are related to human prion diseases reveal significant differences in the rate
of aggregation. While for mutants V203I and R208H aggregation is slower than for the
wildtype, the constructs E196K and F198S show accelerated aggregation. These differences
in aggregation behaviour are not correlated with the thermal stability of the mutants indicating
different mechanisms promoting the conformational conversion process.
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