Similar folds with different stabilization mechanisms: the cases of Prion and Doppel proteins.
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.


CONCLUSIONS
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.
Colacino
Stefano
S
Istituto di Chimica del Riconoscimento Molecolare, CNR, Via Mario Bianco 9, 10131 Milano, Italy. colastef@infinito.it
Tiana
Guido
G
Colombo
Giorgio
G
D000595:Amino Acid Sequence; D003198:Computer Simulation; D019143:Evolution, Molecular; D058851:GPI-Linked Proteins; D008958:Models, Molecular; D008962:Models, Theoretical; D008969:Molecular Sequence Data; D018583:Pliability; D011328:Prions / Q000737:chemistry*; D011489:Protein Denaturation; D017510:Protein Folding; D017433:Protein Structure, Secondary; D017386:Sequence Homology, Amino Acid; D013696:Temperature
D058851:GPI-Linked Proteins; C501125:PRND protein, human; D011328:Prions