Conformational stabilization as a strategy to prevent nucleophosmin mislocalization in leukemia

Abstract Nucleophosmin (NPM) is a nucleolar protein involved in ribosome assembly and cell homeostasis. Mutations in the C-terminal domain of NPM that impair native folding and localization are associated with acute myeloid leukemia (AML). We have performed a high-throughput screening searching for...

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Autores principales:	María A. Urbaneja, Lars Skjærven, Oscar Aubi, Jarl Underhaug, David J. López, Igor Arregi, Marián Alonso-Mariño, Andoni Cuevas, José A. Rodríguez, Aurora Martinez, Sonia Bañuelos
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2017
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/84e9066a4962437e9c1ac1b64a684a28
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spelling	oai:doaj.org-article:84e9066a4962437e9c1ac1b64a684a282021-12-02T15:04:58ZConformational stabilization as a strategy to prevent nucleophosmin mislocalization in leukemia10.1038/s41598-017-14497-42045-2322https://doaj.org/article/84e9066a4962437e9c1ac1b64a684a282017-10-01T00:00:00Zhttps://doi.org/10.1038/s41598-017-14497-4https://doaj.org/toc/2045-2322Abstract Nucleophosmin (NPM) is a nucleolar protein involved in ribosome assembly and cell homeostasis. Mutations in the C-terminal domain of NPM that impair native folding and localization are associated with acute myeloid leukemia (AML). We have performed a high-throughput screening searching for compounds that stabilize the C-terminal domain. We identified three hit compounds which show the ability to increase the thermal stability of both the C-terminal domain as well as full-length NPM. The best hit also seemed to favor folding of an AML-like mutant. Computational pocket identification and molecular docking support a stabilization mechanism based on binding of the phenyl/benzene group of the compounds to a particular hydrophobic pocket and additional polar interactions with solvent-accessible residues. Since these results indicate a chaperoning potential of our candidate hits, we tested their effect on the subcellular localization of AML-like mutants. Two compounds partially alleviated the aggregation and restored nucleolar localization of misfolded mutants. The identified hits appear promising as pharmacological chaperones aimed at therapies for AML based on conformational stabilization of NPM.María A. UrbanejaLars SkjærvenOscar AubiJarl UnderhaugDavid J. LópezIgor ArregiMarián Alonso-MariñoAndoni CuevasJosé A. RodríguezAurora MartinezSonia BañuelosNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 7, Iss 1, Pp 1-13 (2017)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q María A. Urbaneja Lars Skjærven Oscar Aubi Jarl Underhaug David J. López Igor Arregi Marián Alonso-Mariño Andoni Cuevas José A. Rodríguez Aurora Martinez Sonia Bañuelos Conformational stabilization as a strategy to prevent nucleophosmin mislocalization in leukemia
description	Abstract Nucleophosmin (NPM) is a nucleolar protein involved in ribosome assembly and cell homeostasis. Mutations in the C-terminal domain of NPM that impair native folding and localization are associated with acute myeloid leukemia (AML). We have performed a high-throughput screening searching for compounds that stabilize the C-terminal domain. We identified three hit compounds which show the ability to increase the thermal stability of both the C-terminal domain as well as full-length NPM. The best hit also seemed to favor folding of an AML-like mutant. Computational pocket identification and molecular docking support a stabilization mechanism based on binding of the phenyl/benzene group of the compounds to a particular hydrophobic pocket and additional polar interactions with solvent-accessible residues. Since these results indicate a chaperoning potential of our candidate hits, we tested their effect on the subcellular localization of AML-like mutants. Two compounds partially alleviated the aggregation and restored nucleolar localization of misfolded mutants. The identified hits appear promising as pharmacological chaperones aimed at therapies for AML based on conformational stabilization of NPM.
format	article
author	María A. Urbaneja Lars Skjærven Oscar Aubi Jarl Underhaug David J. López Igor Arregi Marián Alonso-Mariño Andoni Cuevas José A. Rodríguez Aurora Martinez Sonia Bañuelos
author_facet	María A. Urbaneja Lars Skjærven Oscar Aubi Jarl Underhaug David J. López Igor Arregi Marián Alonso-Mariño Andoni Cuevas José A. Rodríguez Aurora Martinez Sonia Bañuelos
author_sort	María A. Urbaneja
title	Conformational stabilization as a strategy to prevent nucleophosmin mislocalization in leukemia
title_short	Conformational stabilization as a strategy to prevent nucleophosmin mislocalization in leukemia
title_full	Conformational stabilization as a strategy to prevent nucleophosmin mislocalization in leukemia
title_fullStr	Conformational stabilization as a strategy to prevent nucleophosmin mislocalization in leukemia
title_full_unstemmed	Conformational stabilization as a strategy to prevent nucleophosmin mislocalization in leukemia
title_sort	conformational stabilization as a strategy to prevent nucleophosmin mislocalization in leukemia
publisher	Nature Portfolio
publishDate	2017
url	https://doaj.org/article/84e9066a4962437e9c1ac1b64a684a28
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Conformational stabilization as a strategy to prevent nucleophosmin mislocalization in leukemia

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