Methionine sulfoxides on prion protein Helix-3 switch on the alpha-fold destabilization required for conversion.

<h4>Background</h4>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...

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Autores principales:	Giorgio Colombo, Massimiliano Meli, Giulia Morra, Ruth Gabizon, María Gasset
Formato:	article
Lenguaje:	EN
Publicado:	Public Library of Science (PLoS) 2009
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/c425c946907e434aaea9eb0c690a3e14
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spelling	oai:doaj.org-article:c425c946907e434aaea9eb0c690a3e142021-11-25T06:17:37ZMethionine sulfoxides on prion protein Helix-3 switch on the alpha-fold destabilization required for conversion.1932-620310.1371/journal.pone.0004296https://doaj.org/article/c425c946907e434aaea9eb0c690a3e142009-01-01T00:00:00Zhttps://www.ncbi.nlm.nih.gov/pmc/articles/pmid/19172188/?tool=EBIhttps://doaj.org/toc/1932-6203<h4>Background</h4>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.<h4>Methodology/principal findings</h4>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.<h4>Conclusions/significance</h4>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.Giorgio ColomboMassimiliano MeliGiulia MorraRuth GabizonMaría GassetPublic Library of Science (PLoS)articleMedicineRScienceQENPLoS ONE, Vol 4, Iss 1, p e4296 (2009)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Giorgio Colombo Massimiliano Meli Giulia Morra Ruth Gabizon María Gasset Methionine sulfoxides on prion protein Helix-3 switch on the alpha-fold destabilization required for conversion.
description	<h4>Background</h4>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.<h4>Methodology/principal findings</h4>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.<h4>Conclusions/significance</h4>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.
format	article
author	Giorgio Colombo Massimiliano Meli Giulia Morra Ruth Gabizon María Gasset
author_facet	Giorgio Colombo Massimiliano Meli Giulia Morra Ruth Gabizon María Gasset
author_sort	Giorgio Colombo
title	Methionine sulfoxides on prion protein Helix-3 switch on the alpha-fold destabilization required for conversion.
title_short	Methionine sulfoxides on prion protein Helix-3 switch on the alpha-fold destabilization required for conversion.
title_full	Methionine sulfoxides on prion protein Helix-3 switch on the alpha-fold destabilization required for conversion.
title_fullStr	Methionine sulfoxides on prion protein Helix-3 switch on the alpha-fold destabilization required for conversion.
title_full_unstemmed	Methionine sulfoxides on prion protein Helix-3 switch on the alpha-fold destabilization required for conversion.
title_sort	methionine sulfoxides on prion protein helix-3 switch on the alpha-fold destabilization required for conversion.
publisher	Public Library of Science (PLoS)
publishDate	2009
url	https://doaj.org/article/c425c946907e434aaea9eb0c690a3e14
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Methionine sulfoxides on prion protein Helix-3 switch on the alpha-fold destabilization required for conversion.

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