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A Comparative Molecular Dynamics Study of Selected Point Mutations in the Shwachman–Bodian–Diamond Syndrome Protein SBDS

The Shwachman–Diamond Syndrome (SDS) is an autosomal recessive disease whose majority of patients display mutations in a ribosome assembly protein named Shwachman–Bodian–Diamond Syndrome protein (SBDS). A specific therapy for treating this rare disease is missing, due to the lack of knowledge of the...

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Autores principales: Spinetti, Elena, Delre, Pietro, Saviano, Michele, Siliqi, Dritan, Lattanzi, Gianluca, Mangiatordi, Giuseppe Felice
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9320453/
https://www.ncbi.nlm.nih.gov/pubmed/35887285
http://dx.doi.org/10.3390/ijms23147938
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author Spinetti, Elena
Delre, Pietro
Saviano, Michele
Siliqi, Dritan
Lattanzi, Gianluca
Mangiatordi, Giuseppe Felice
author_facet Spinetti, Elena
Delre, Pietro
Saviano, Michele
Siliqi, Dritan
Lattanzi, Gianluca
Mangiatordi, Giuseppe Felice
author_sort Spinetti, Elena
collection PubMed
description The Shwachman–Diamond Syndrome (SDS) is an autosomal recessive disease whose majority of patients display mutations in a ribosome assembly protein named Shwachman–Bodian–Diamond Syndrome protein (SBDS). A specific therapy for treating this rare disease is missing, due to the lack of knowledge of the molecular mechanisms responsible for its pathogenesis. Starting from the observation that SBDS single-point mutations, localized in different domains of the proteins, are responsible for an SDS phenotype, we carried out the first comparative Molecular Dynamics simulations on three SBDS mutants, namely R19Q, R126T and I212T. The obtained 450-ns long trajectories were compared with those returned by both the open and closed forms of wild type SBDS and strongly indicated that two distinct conformations (open and closed) are both necessary for the proper SBDS function, in full agreement with recent experimental observations. Our study supports the hypothesis that the SBDS function is governed by an allosteric mechanism involving domains I and III and provides new insights into SDS pathogenesis, thus offering a possible starting point for a specific therapeutic option.
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spelling pubmed-93204532022-07-27 A Comparative Molecular Dynamics Study of Selected Point Mutations in the Shwachman–Bodian–Diamond Syndrome Protein SBDS Spinetti, Elena Delre, Pietro Saviano, Michele Siliqi, Dritan Lattanzi, Gianluca Mangiatordi, Giuseppe Felice Int J Mol Sci Article The Shwachman–Diamond Syndrome (SDS) is an autosomal recessive disease whose majority of patients display mutations in a ribosome assembly protein named Shwachman–Bodian–Diamond Syndrome protein (SBDS). A specific therapy for treating this rare disease is missing, due to the lack of knowledge of the molecular mechanisms responsible for its pathogenesis. Starting from the observation that SBDS single-point mutations, localized in different domains of the proteins, are responsible for an SDS phenotype, we carried out the first comparative Molecular Dynamics simulations on three SBDS mutants, namely R19Q, R126T and I212T. The obtained 450-ns long trajectories were compared with those returned by both the open and closed forms of wild type SBDS and strongly indicated that two distinct conformations (open and closed) are both necessary for the proper SBDS function, in full agreement with recent experimental observations. Our study supports the hypothesis that the SBDS function is governed by an allosteric mechanism involving domains I and III and provides new insights into SDS pathogenesis, thus offering a possible starting point for a specific therapeutic option. MDPI 2022-07-19 /pmc/articles/PMC9320453/ /pubmed/35887285 http://dx.doi.org/10.3390/ijms23147938 Text en © 2022 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Spinetti, Elena
Delre, Pietro
Saviano, Michele
Siliqi, Dritan
Lattanzi, Gianluca
Mangiatordi, Giuseppe Felice
A Comparative Molecular Dynamics Study of Selected Point Mutations in the Shwachman–Bodian–Diamond Syndrome Protein SBDS
title A Comparative Molecular Dynamics Study of Selected Point Mutations in the Shwachman–Bodian–Diamond Syndrome Protein SBDS
title_full A Comparative Molecular Dynamics Study of Selected Point Mutations in the Shwachman–Bodian–Diamond Syndrome Protein SBDS
title_fullStr A Comparative Molecular Dynamics Study of Selected Point Mutations in the Shwachman–Bodian–Diamond Syndrome Protein SBDS
title_full_unstemmed A Comparative Molecular Dynamics Study of Selected Point Mutations in the Shwachman–Bodian–Diamond Syndrome Protein SBDS
title_short A Comparative Molecular Dynamics Study of Selected Point Mutations in the Shwachman–Bodian–Diamond Syndrome Protein SBDS
title_sort comparative molecular dynamics study of selected point mutations in the shwachman–bodian–diamond syndrome protein sbds
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9320453/
https://www.ncbi.nlm.nih.gov/pubmed/35887285
http://dx.doi.org/10.3390/ijms23147938
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