Methionine sulfoxides on prion protein Helix-3 switch on the alpha-fold destabilization required for conversion.
BACKGROUND
The conversion of the cellular prion protein (PrP(C)) into the infectious form (PrP(Sc)) is the key event in prion induced neurodegenerations. This process is believed to involve a multi-step conformational transition from an alpha-helical (PrP(C)) form to a beta-sheet-rich (PrP(Sc)) state. In addition to the conformational difference, PrP(Sc) exhibits as covalent signature the sulfoxidation of M213. To investigate whether such modification may play a role in the misfolding process we have studied the impact of methionine oxidation on the dynamics and energetics of the HuPrP(125-229) alpha-fold.


RESULTS
Using molecular dynamics simulation, essential dynamics, correlated motions and signal propagation analysis, we have found that substitution of the sulfur atom of M213 by a sulfoxide group impacts on the stability of the native state increasing the flexibility of regions preceding the site of the modification and perturbing the network of stabilizing interactions. Together, these changes favor the population of alternative states which maybe essential in the productive pathway of the pathogenic conversion. These changes are also observed when the sulfoxidation is placed at M206 and at both, M206 and M213.


CONCLUSIONS
Our results suggest that the sulfoxidation of Helix-3 methionines might be the switch for triggering the initial alpha-fold destabilization required for the productive pathogenic conversion.
Colombo
Giorgio
G
Isto di Chimica del Riconoscimento Molecolare, Consiglio Nazionale delle Ricerche, Milano, Italy. g.colombo@icrm.cnr.it
Meli
Massimiliano
M
Morra
Giulia
G
Gabizon
Ruth
R
Gasset
María
M
D001665:Binding Sites; D003198:Computer Simulation; D006801:Humans; D008715:Methionine / Q000031:analogs & derivatives* / Q000737:chemistry / Q000378:metabolism; D008954:Models, Biological; D008958:Models, Molecular; D015233:Models, Statistical; D010100:Oxygen / Q000737:chemistry; D018621:PrPC Proteins / Q000378:metabolism*; D018620:PrPSc Proteins / Q000737:chemistry*; D011487:Protein Conformation; D017510:Protein Folding; D017433:Protein Structure, Secondary; D013696:Temperature
D018621:PrPC Proteins; D018620:PrPSc Proteins; D008715:Methionine; D010100:Oxygen; C013111:methionine sulfoxide