Molecular dynamics simulations show how the FMRP Ile304Asn mutation destabilizes the KH2 domain structure and affects its function.

Détails

ID Serval
serval:BIB_E7AAE90F7978
Type
Article: article d'un périodique ou d'un magazine.
Collection
Publications
Titre
Molecular dynamics simulations show how the FMRP Ile304Asn mutation destabilizes the KH2 domain structure and affects its function.
Périodique
Journal of biomolecular structure & dynamics
Auteur⸱e⸱s
Di Marino D., Achsel T., Lacoux C., Falconi M., Bagni C.
ISSN
1538-0254 (Electronic)
ISSN-L
0739-1102
Statut éditorial
Publié
Date de publication
2014
Volume
32
Numéro
3
Pages
337-350
Langue
anglais
Notes
Publication types: Journal Article ; Research Support, Non-U.S. Gov't
Publication Status: ppublish
Résumé
Mutations or deletions of FMRP, involved in the regulation of mRNA metabolism in brain, lead to the Fragile X syndrome (FXS), the most frequent form of inherited intellectual disability. A severe manifestation of the disease has been associated with the Ile304Asn mutation, located on the KH2 domain of the protein. Several hypotheses have been proposed to explain the possible molecular mechanism responsible for the drastic effect of this mutation in humans. Here, we performed a molecular dynamics simulation and show that the Ile304Asn mutation destabilizes the hydrophobic core producing a partial unfolding of two α-helices and a displacement of a third one. The affected regions show increased residue flexibility and motion. Molecular docking analysis revealed strongly reduced binding to a model single-stranded nucleic acid in agreement with known data that the two partially unfolded helices form the RNA-binding surface. The third helix, which we show here to be also affected, is involved in the PAK1 protein interaction. These two functional binding sites on the KH2 domain do not overlap spatially, and therefore, they can simultaneously bind their targets. Since the Ile304Asn mutation affects both binding sites, this may justify the severe clinical manifestation observed in the patient in which both mRNA metabolism activity and cytoskeleton remodeling would be affected.

Mots-clé
Binding Sites, Fragile X Mental Retardation Protein/chemistry, Fragile X Mental Retardation Protein/genetics, Fragile X Syndrome/genetics, Humans, Molecular Docking Simulation, Molecular Dynamics Simulation, Mutation, Protein Structure, Tertiary, Protein Unfolding
Pubmed
Création de la notice
06/03/2017 17:23
Dernière modification de la notice
20/08/2019 16:10
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