Methionine Sulfoxides on Prion Protein Helix-3 Switch on the α-Fold Destabilization Required for Conversion

Giorgio Colombo, Massimiliano Meli, Giulia Morra, Ruth Gabizon and María Gasset

PLOS ONE, 2009, vol. 4, issue 1, 1-11

Abstract: Background: The conversion of the cellular prion protein (PrPC) into the infectious form (PrPSc) is the key event in prion induced neurodegenerations. This process is believed to involve a multi-step conformational transition from an α-helical (PrPC) form to a β-sheet-rich (PrPSc) state. In addition to the conformational difference, PrPSc 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) α-fold. Methodology/Principal Findings: 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/Significance: Our results suggest that the sulfoxidation of Helix-3 methionines might be the switch for triggering the initial α-fold destabilization required for the productive pathogenic conversion.

Date: 2009
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Persistent link: https://EconPapers.repec.org/RePEc:plo:pone00:0004296

DOI: 10.1371/journal.pone.0004296

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