Article,
Similar folds with different stabilization mechanisms: the cases of prion and doppel proteins
BMC STRUCTURAL BIOLOGY, (July 2006)
DOI: {10.1186/1472-6807-6-17}
Abstract
Background: Protein misfolding is the main cause of a group of fatal
neurodegenerative diseases in humans and animals. In particular, in
Prion- related diseases the normal cellular form of the Prion Protein
PrP (PrPC) is converted into the infectious PrPSc through a
conformational process during which it acquires a high beta-sheet
content. Doppel is a protein that shares a similar native fold, but
lacks the scrapie isoform. Understanding the molecular determinants of
these different behaviours is important both for biomedical and
biophysical research.
Results: In this paper, the dynamical and energetic properties of the
two proteins in solution is comparatively analyzed by means of long
time scale explicit solvent, all- atom molecular dynamics in different
temperature conditions. The trajectories are analyzed by means of a
recently introduced energy decomposition approach (Tiana et al, Prot.
Sci. 2004) aimed at identifying the key residues for the stabilization
and folding of the protein. Our analysis shows that Prion and Doppel
have two different cores stabilizing the native state and that the
relative contribution of the nucleus to the global stability of the
protein for Doppel is sensitively higher than for PrP. Moreover, under
misfolding conditions the Doppel core is conserved, while the energy
stabilization network of PrP is disrupted.
Conclusion: These observations suggest that different sequences can
share similar native topology with different stabilizing interactions
and that the sequences of the Prion and Doppel proteins may have
diverged under different evolutionary constraints resulting in
different folding and stabilization mechanisms.
