Dynamic diagnosis of familial prion diseases supports the β2-α2 loop as a universal interference target.

<h4>Background</h4>Mutations in the cellular prion protein associated to familial prion disorders severely increase the likelihood of its misfolding into pathogenic conformers. Despite their postulation as incompatible elements with the native fold, these mutations rarely modify the nati...

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Autores principales:	Massimiliano Meli, Maria Gasset, Giorgio Colombo
Formato:	article
Lenguaje:	EN
Publicado:	Public Library of Science (PLoS) 2011
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/4c1449f8e06a455685d2994273fbe0f2
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spelling	oai:doaj.org-article:4c1449f8e06a455685d2994273fbe0f22021-11-18T06:54:56ZDynamic diagnosis of familial prion diseases supports the β2-α2 loop as a universal interference target.1932-620310.1371/journal.pone.0019093https://doaj.org/article/4c1449f8e06a455685d2994273fbe0f22011-04-01T00:00:00Zhttps://www.ncbi.nlm.nih.gov/pmc/articles/pmid/21552571/pdf/?tool=EBIhttps://doaj.org/toc/1932-6203<h4>Background</h4>Mutations in the cellular prion protein associated to familial prion disorders severely increase the likelihood of its misfolding into pathogenic conformers. Despite their postulation as incompatible elements with the native fold, these mutations rarely modify the native state structure. However they variably have impact on the thermodynamic stability and metabolism of PrP(C) and on the properties of PrP(Sc) aggregates. To investigate whether the pathogenic mutations affect the dynamic properties of the HuPrP(125-229) α-fold and find possible common patterns of effects that could help in prophylaxis we performed a dynamic diagnosis of ten point substitutions.<h4>Methodology/principal findings</h4>Using all-atom molecular dynamics simulations and novel analytical tools we have explored the effect of D178N, V180I, T183A, T188K, E196K, F198S, E200K, R208H, V210I and E211Q mutations on the dynamics of HuPrP(125-228) α-fold. We have found that while preserving the native state, all mutations produce dynamic changes which perturb the coordination of the α2-α3 hairpin to the rest of the molecule and cause the reorganization of the patches for intermolecular recognition, as the disappearance of those for conversion inhibitors and the emergence of an interaction site at the β2-α2 loop region.<h4>Conclusions/significance</h4>Our results suggest that pathogenic mutations share a common pattern of dynamical alterations that converge to the conversion of the β2-α2 loop into an interacting region that can be used as target for interference treatments in genetic diseases.Massimiliano MeliMaria GassetGiorgio ColomboPublic Library of Science (PLoS)articleMedicineRScienceQENPLoS ONE, Vol 6, Iss 4, p e19093 (2011)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Massimiliano Meli Maria Gasset Giorgio Colombo Dynamic diagnosis of familial prion diseases supports the β2-α2 loop as a universal interference target.
description	<h4>Background</h4>Mutations in the cellular prion protein associated to familial prion disorders severely increase the likelihood of its misfolding into pathogenic conformers. Despite their postulation as incompatible elements with the native fold, these mutations rarely modify the native state structure. However they variably have impact on the thermodynamic stability and metabolism of PrP(C) and on the properties of PrP(Sc) aggregates. To investigate whether the pathogenic mutations affect the dynamic properties of the HuPrP(125-229) α-fold and find possible common patterns of effects that could help in prophylaxis we performed a dynamic diagnosis of ten point substitutions.<h4>Methodology/principal findings</h4>Using all-atom molecular dynamics simulations and novel analytical tools we have explored the effect of D178N, V180I, T183A, T188K, E196K, F198S, E200K, R208H, V210I and E211Q mutations on the dynamics of HuPrP(125-228) α-fold. We have found that while preserving the native state, all mutations produce dynamic changes which perturb the coordination of the α2-α3 hairpin to the rest of the molecule and cause the reorganization of the patches for intermolecular recognition, as the disappearance of those for conversion inhibitors and the emergence of an interaction site at the β2-α2 loop region.<h4>Conclusions/significance</h4>Our results suggest that pathogenic mutations share a common pattern of dynamical alterations that converge to the conversion of the β2-α2 loop into an interacting region that can be used as target for interference treatments in genetic diseases.
format	article
author	Massimiliano Meli Maria Gasset Giorgio Colombo
author_facet	Massimiliano Meli Maria Gasset Giorgio Colombo
author_sort	Massimiliano Meli
title	Dynamic diagnosis of familial prion diseases supports the β2-α2 loop as a universal interference target.
title_short	Dynamic diagnosis of familial prion diseases supports the β2-α2 loop as a universal interference target.
title_full	Dynamic diagnosis of familial prion diseases supports the β2-α2 loop as a universal interference target.
title_fullStr	Dynamic diagnosis of familial prion diseases supports the β2-α2 loop as a universal interference target.
title_full_unstemmed	Dynamic diagnosis of familial prion diseases supports the β2-α2 loop as a universal interference target.
title_sort	dynamic diagnosis of familial prion diseases supports the β2-α2 loop as a universal interference target.
publisher	Public Library of Science (PLoS)
publishDate	2011
url	https://doaj.org/article/4c1449f8e06a455685d2994273fbe0f2
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Dynamic diagnosis of familial prion diseases supports the β2-α2 loop as a universal interference target.

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