Prions stability

These results indicate that is it possible to change the fold of a protein by changing a restricted set of residues. They also confirm the validity of the rules for stability of helical folds that have been obtained by analysis of experimentally determined protein structures. One obvious impliction of this work is that it might be possible, by just changing a few residues in Janus, to design a mutant that flip-flops between a helical and p sheet structures. Such a polypeptide would be a very interesting model system for prions and other amyloid proteins. 

How pathogenic mutations in PRNP cause prion disease has yet to be resolved. However, in most cases the mutation is thought to lead to an increased tendency of PrPc to form PrPSc, although there is evidence to suggest that this may not be solely attributable to decreased thermodynamic stability of mutated PrPc. Experimentally manipulated mutations of the prion gene can lead to spontaneous neurodegeneration without the formation... 

In consideration of thermal stability, a calorimetric investigation of Ure2p prion domain-containing filaments detected no evidence of these domains denaturing up to 105°C (Baxa et al., 2004). In comparison, most proteins denature at temperatures of 50—70°C and rarely exceed 80—90°C, except for proteins of extreme thermophiles. 

Stability, folding, dimerization, and assembly properties of the yeast prion... 

Zhu, L., Zhang, X. J., Wang, L. Y., Zhou, J. M., and Perrett, S. (2003). Relationship between stability of folding intermediates and amyloid formation for the yeast prion Ure2p A quantitative analysis of the effects of pH and buffer system./ Mol. Biol. 328, 235-254. 

Several studies since then have supported this suggestion, and now it is widely accepted that conformational change/structural perturbation is a prerequisite for amyloid formation. Structural perturbation involves destabilization of the native state, thus forming nonnative states or partially unfolded intermediates (kinetic or thermodynamic intermediates), which are prone to aggregation. Mild to harsh conditions such as low pH, exposure to elevated temperatures, exposure to hydrophobic surfaces and partial denaturation using urea and guanidinium chloride are used to achieve nonnative states. Stabilizers of intermediate states such as trimethylamine N-oxide (TMAO) are also used for amyloidogenesis. However, natively unfolded proteins, such as a-synuclein, tau protein and yeast prion, require some structural stabilization for the formation of partially folded intermediates that are competent for fibril formation. Conditions for partial structural consolidation include low pH, presence of sodium dodecyl sulfate (SDS), temperature or chemical chaperones. 

Gilis D, Rooman M, PoPMuSiC, an algorithm for predicting protein mutant stability changes application to prion proteins. Protein Eng. 2000 13 849-856. 

The pathogenesis of another well-known neurodegenerative disease (Jacob Creutzfeld disease) seems to be strongly linked to the presence of prion proteins in the brain. These macromolecules contain multiple Met residues, some of them in close vicinity. Such structure should favour stabilization of MetS as intramolecular (S.-.S) complexes. Since weak intramolecular non-bonded S O and S N interactions have been recently suggested in proteins [14], stabilization of MetS +through formation of S.-.N- and/or S.-.O-complexes might potentially accelerate oxidation processes in proteins.The first experimental evidence... 

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