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Deciphering the folding transition state structure and denatured state properties of Nucleophosmin C-terminal domain

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Zeitschriftentitel: Proceedings of the National Academy of Sciences
Personen und Körperschaften: Scaloni, Flavio, Federici, Luca, Brunori, Maurizio, Gianni, Stefano
In: Proceedings of the National Academy of Sciences, 107, 2010, 12, S. 5447-5452
Format: E-Article
Sprache: Englisch
veröffentlicht:
Proceedings of the National Academy of Sciences
Schlagwörter:
Multidisciplinary
author_facet Scaloni, Flavio
Federici, Luca
Brunori, Maurizio
Gianni, Stefano
Scaloni, Flavio
Federici, Luca
Brunori, Maurizio
Gianni, Stefano
author Scaloni, Flavio
Federici, Luca
Brunori, Maurizio
Gianni, Stefano
spellingShingle Scaloni, Flavio
Federici, Luca
Brunori, Maurizio
Gianni, Stefano
Proceedings of the National Academy of Sciences
Deciphering the folding transition state structure and denatured state properties of Nucleophosmin C-terminal domain
Multidisciplinary
author_sort scaloni, flavio
spelling Scaloni, Flavio Federici, Luca Brunori, Maurizio Gianni, Stefano 0027-8424 1091-6490 Proceedings of the National Academy of Sciences Multidisciplinary http://dx.doi.org/10.1073/pnas.0910516107 <jats:p>Nucleophosmin (NPM1), one of the most abundant nucleolar proteins, is a frequent target of oncogenic mutations in acute myeloid leukaemia (AML). Mutation-induced changes at the C-terminal domain of NPM1 (Cter-NPM1) compromise its stability and cause the aberrant translocation of NPM1 to the cytosol. Hence, this protein represents a suitable candidate to investigate the relations between folding and disease. Since Cter-NPM1 folds via a compact denatured state, stabilization of the folded state of the mutated variants demands detailed structural information on both the native and denatured states. Here, we present the characterization of the complete folding pathway of Cter-NPM1 and provide molecular details for both the transition and the denatured states. The structure of the transition state was assessed by Φ-value analysis, whereas residual structure in the denatured state was mapped by evaluating the effect of mutations as modulated by conditions promoting denatured state compaction. Data reveal that folding of Cter-NPM1 proceeds via an extended nucleus and that the denatured state retains significant malleable structure at the interface between the second and third helices. Our observations constitute the essential prerequisite for structure-based drug-design studies, aimed at identifying molecules that may rescue pathological NPM1 mutants by stabilizing the native-like state.</jats:p> Deciphering the folding transition state structure and denatured state properties of Nucleophosmin C-terminal domain Proceedings of the National Academy of Sciences
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title Deciphering the folding transition state structure and denatured state properties of Nucleophosmin C-terminal domain
title_unstemmed Deciphering the folding transition state structure and denatured state properties of Nucleophosmin C-terminal domain
title_full Deciphering the folding transition state structure and denatured state properties of Nucleophosmin C-terminal domain
title_fullStr Deciphering the folding transition state structure and denatured state properties of Nucleophosmin C-terminal domain
title_full_unstemmed Deciphering the folding transition state structure and denatured state properties of Nucleophosmin C-terminal domain
title_short Deciphering the folding transition state structure and denatured state properties of Nucleophosmin C-terminal domain
title_sort deciphering the folding transition state structure and denatured state properties of nucleophosmin c-terminal domain
topic Multidisciplinary
url http://dx.doi.org/10.1073/pnas.0910516107
publishDate 2010
physical 5447-5452
description <jats:p>Nucleophosmin (NPM1), one of the most abundant nucleolar proteins, is a frequent target of oncogenic mutations in acute myeloid leukaemia (AML). Mutation-induced changes at the C-terminal domain of NPM1 (Cter-NPM1) compromise its stability and cause the aberrant translocation of NPM1 to the cytosol. Hence, this protein represents a suitable candidate to investigate the relations between folding and disease. Since Cter-NPM1 folds via a compact denatured state, stabilization of the folded state of the mutated variants demands detailed structural information on both the native and denatured states. Here, we present the characterization of the complete folding pathway of Cter-NPM1 and provide molecular details for both the transition and the denatured states. The structure of the transition state was assessed by Φ-value analysis, whereas residual structure in the denatured state was mapped by evaluating the effect of mutations as modulated by conditions promoting denatured state compaction. Data reveal that folding of Cter-NPM1 proceeds via an extended nucleus and that the denatured state retains significant malleable structure at the interface between the second and third helices. Our observations constitute the essential prerequisite for structure-based drug-design studies, aimed at identifying molecules that may rescue pathological NPM1 mutants by stabilizing the native-like state.</jats:p>
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author Scaloni, Flavio, Federici, Luca, Brunori, Maurizio, Gianni, Stefano
author_facet Scaloni, Flavio, Federici, Luca, Brunori, Maurizio, Gianni, Stefano, Scaloni, Flavio, Federici, Luca, Brunori, Maurizio, Gianni, Stefano
author_sort scaloni, flavio
container_issue 12
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container_title Proceedings of the National Academy of Sciences
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description <jats:p>Nucleophosmin (NPM1), one of the most abundant nucleolar proteins, is a frequent target of oncogenic mutations in acute myeloid leukaemia (AML). Mutation-induced changes at the C-terminal domain of NPM1 (Cter-NPM1) compromise its stability and cause the aberrant translocation of NPM1 to the cytosol. Hence, this protein represents a suitable candidate to investigate the relations between folding and disease. Since Cter-NPM1 folds via a compact denatured state, stabilization of the folded state of the mutated variants demands detailed structural information on both the native and denatured states. Here, we present the characterization of the complete folding pathway of Cter-NPM1 and provide molecular details for both the transition and the denatured states. The structure of the transition state was assessed by Φ-value analysis, whereas residual structure in the denatured state was mapped by evaluating the effect of mutations as modulated by conditions promoting denatured state compaction. Data reveal that folding of Cter-NPM1 proceeds via an extended nucleus and that the denatured state retains significant malleable structure at the interface between the second and third helices. Our observations constitute the essential prerequisite for structure-based drug-design studies, aimed at identifying molecules that may rescue pathological NPM1 mutants by stabilizing the native-like state.</jats:p>
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spelling Scaloni, Flavio Federici, Luca Brunori, Maurizio Gianni, Stefano 0027-8424 1091-6490 Proceedings of the National Academy of Sciences Multidisciplinary http://dx.doi.org/10.1073/pnas.0910516107 <jats:p>Nucleophosmin (NPM1), one of the most abundant nucleolar proteins, is a frequent target of oncogenic mutations in acute myeloid leukaemia (AML). Mutation-induced changes at the C-terminal domain of NPM1 (Cter-NPM1) compromise its stability and cause the aberrant translocation of NPM1 to the cytosol. Hence, this protein represents a suitable candidate to investigate the relations between folding and disease. Since Cter-NPM1 folds via a compact denatured state, stabilization of the folded state of the mutated variants demands detailed structural information on both the native and denatured states. Here, we present the characterization of the complete folding pathway of Cter-NPM1 and provide molecular details for both the transition and the denatured states. The structure of the transition state was assessed by Φ-value analysis, whereas residual structure in the denatured state was mapped by evaluating the effect of mutations as modulated by conditions promoting denatured state compaction. Data reveal that folding of Cter-NPM1 proceeds via an extended nucleus and that the denatured state retains significant malleable structure at the interface between the second and third helices. Our observations constitute the essential prerequisite for structure-based drug-design studies, aimed at identifying molecules that may rescue pathological NPM1 mutants by stabilizing the native-like state.</jats:p> Deciphering the folding transition state structure and denatured state properties of Nucleophosmin C-terminal domain Proceedings of the National Academy of Sciences
spellingShingle Scaloni, Flavio, Federici, Luca, Brunori, Maurizio, Gianni, Stefano, Proceedings of the National Academy of Sciences, Deciphering the folding transition state structure and denatured state properties of Nucleophosmin C-terminal domain, Multidisciplinary
title Deciphering the folding transition state structure and denatured state properties of Nucleophosmin C-terminal domain
title_full Deciphering the folding transition state structure and denatured state properties of Nucleophosmin C-terminal domain
title_fullStr Deciphering the folding transition state structure and denatured state properties of Nucleophosmin C-terminal domain
title_full_unstemmed Deciphering the folding transition state structure and denatured state properties of Nucleophosmin C-terminal domain
title_short Deciphering the folding transition state structure and denatured state properties of Nucleophosmin C-terminal domain
title_sort deciphering the folding transition state structure and denatured state properties of nucleophosmin c-terminal domain
title_unstemmed Deciphering the folding transition state structure and denatured state properties of Nucleophosmin C-terminal domain
topic Multidisciplinary
url http://dx.doi.org/10.1073/pnas.0910516107