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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.
Afiliação
  • Spinetti E; Department of Physics, Trento Institute for Fundamental Physics and Applications, Frankfurt Institute for Advanced Studies, Ruth-Moufang-Straße 1, 60438 Frankfurt am Main, Germany.
  • Delre P; Institute of Crystallography, National Research Council of Italy, Via Amendola, 122/o, 70126 Bari, Italy.
  • Saviano M; Institute of Crystallography, National Research Council of Italy, Via Vivaldi, 43, 81100 Caserta, Italy.
  • Siliqi D; Institute of Crystallography, National Research Council of Italy, Via Amendola, 122/o, 70126 Bari, Italy.
  • Lattanzi G; Department of Physics, Trento Institute for Fundamental Physics and Applications, Frankfurt Institute for Advanced Studies, Ruth-Moufang-Straße 1, 60438 Frankfurt am Main, Germany.
  • Mangiatordi GF; Institute of Crystallography, National Research Council of Italy, Via Amendola, 122/o, 70126 Bari, Italy.
Int J Mol Sci ; 23(14)2022 Jul 19.
Article em En | MEDLINE | ID: mdl-35887285
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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Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Doenças da Medula Óssea / Simulação de Dinâmica Molecular Limite: Humans Idioma: En Ano de publicação: 2022 Tipo de documento: Article

Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Doenças da Medula Óssea / Simulação de Dinâmica Molecular Limite: Humans Idioma: En Ano de publicação: 2022 Tipo de documento: Article