Cyclophilin A allows the allosteric ...
Type de document :
Article dans une revue scientifique
DOI :
URL permanente :
Titre :
Cyclophilin A allows the allosteric regulation of a structural motif in the disordered domain 2 of NS5A and thereby fine-tunes HCV RNA replication
Auteur(s) :
Dujardin, Marie [Auteur]
Madan, Vanesa [Auteur]
Gandhi, Neha S. [Auteur]
Cantrelle, Francois-Xavier [Auteur]
Unité de Glycobiologie Structurale et Fonctionnelle - UMR 8576 [UGSF]
Unité de Glycobiologie Structurale et Fonctionnelle (UGSF) - UMR 8576
Launay, Hélène [Auteur]
Huvent, Isabelle [Auteur]
Unité de Glycobiologie Structurale et Fonctionnelle - UMR 8576 [UGSF]
Unité de Glycobiologie Structurale et Fonctionnelle (UGSF) - UMR 8576
Bartenschlager, Ralf [Auteur]
Lippens, Guy [Auteur]
Hanoulle, Xavier [Auteur]
Unité de Glycobiologie Structurale et Fonctionnelle - UMR 8576 [UGSF]
Unité de Glycobiologie Structurale et Fonctionnelle (UGSF) - UMR 8576
Madan, Vanesa [Auteur]
Gandhi, Neha S. [Auteur]
Cantrelle, Francois-Xavier [Auteur]
Unité de Glycobiologie Structurale et Fonctionnelle - UMR 8576 [UGSF]
Unité de Glycobiologie Structurale et Fonctionnelle (UGSF) - UMR 8576
Launay, Hélène [Auteur]
Huvent, Isabelle [Auteur]
Unité de Glycobiologie Structurale et Fonctionnelle - UMR 8576 [UGSF]
Unité de Glycobiologie Structurale et Fonctionnelle (UGSF) - UMR 8576
Bartenschlager, Ralf [Auteur]
Lippens, Guy [Auteur]
Hanoulle, Xavier [Auteur]
Unité de Glycobiologie Structurale et Fonctionnelle - UMR 8576 [UGSF]
Unité de Glycobiologie Structurale et Fonctionnelle (UGSF) - UMR 8576
Titre de la revue :
Journal of Biological Chemistry
Nom court de la revue :
J. Biol. Chem.
Numéro :
294
Pagination :
13171-13185
Éditeur :
American Society for Biochemistry & Molecular Biology (ASBMB)
Date de publication :
2019-07-17
Mot(s)-clé(s) en anglais :
intrinsically disordered protein
nuclear magnetic resonance (NMR)
prolyl isomerase
hepatitis C virus (HCV)
cyclophilin
allosteric regulation
conformer ensemble
nonstructural protein 5A (NS5A)
RNA replication
nuclear magnetic resonance (NMR)
prolyl isomerase
hepatitis C virus (HCV)
cyclophilin
allosteric regulation
conformer ensemble
nonstructural protein 5A (NS5A)
RNA replication
Discipline(s) HAL :
Sciences du Vivant [q-bio]
Chimie/Chimie théorique et/ou physique
Chimie/Chimie théorique et/ou physique
Résumé en anglais : [en]
Implicated in numerous human diseases, intrinsically disordered proteins (IDPs) are dynamic ensembles of interconverting conformers that often contain many proline residues. Whether and how proline conformation regulates ...
Lire la suite >Implicated in numerous human diseases, intrinsically disordered proteins (IDPs) are dynamic ensembles of interconverting conformers that often contain many proline residues. Whether and how proline conformation regulates the functional aspects of IDPs remains an open question, however. Here, we studied the disordered domain 2 of nonstructural protein 5A (NS5A-D2) of hepatitis C virus (HCV). NS5A-D2 comprises a short structural motif (PW-turn) embedded in a proline-rich sequence, whose interaction with the human prolyl isomerase cyclophilin A (CypA) is essential for viral RNA replication. Using NMR, we show here that the PW-turn motif exists in a conformational equilibrium between folded and disordered states. We found that the fraction of conformers in the NS5A-D2 ensemble that adopt the structured motif is allosterically modulated both by the cis/trans isomerization of the surrounding prolines that are CypA substrates and by substitutions conferring resistance to cyclophilin inhibitor. Moreover, we noted that this fraction is directly correlated with HCV RNA replication efficiency. We conclude that CypA can fine-tune the dynamic ensemble of the disordered NS5A-D2, thereby regulating viral RNA replication efficiency.Lire moins >
Lire la suite >Implicated in numerous human diseases, intrinsically disordered proteins (IDPs) are dynamic ensembles of interconverting conformers that often contain many proline residues. Whether and how proline conformation regulates the functional aspects of IDPs remains an open question, however. Here, we studied the disordered domain 2 of nonstructural protein 5A (NS5A-D2) of hepatitis C virus (HCV). NS5A-D2 comprises a short structural motif (PW-turn) embedded in a proline-rich sequence, whose interaction with the human prolyl isomerase cyclophilin A (CypA) is essential for viral RNA replication. Using NMR, we show here that the PW-turn motif exists in a conformational equilibrium between folded and disordered states. We found that the fraction of conformers in the NS5A-D2 ensemble that adopt the structured motif is allosterically modulated both by the cis/trans isomerization of the surrounding prolines that are CypA substrates and by substitutions conferring resistance to cyclophilin inhibitor. Moreover, we noted that this fraction is directly correlated with HCV RNA replication efficiency. We conclude that CypA can fine-tune the dynamic ensemble of the disordered NS5A-D2, thereby regulating viral RNA replication efficiency.Lire moins >
Langue :
Anglais
Comité de lecture :
Oui
Audience :
Internationale
Vulgarisation :
Non
Établissement(s) :
Université de Lille
CNRS
CNRS
Équipe(s) de recherche :
Chemical Glycobiology
Date de dépôt :
2020-12-14T12:30:43Z
2020-12-16T15:40:08Z
2020-12-16T15:40:08Z
Fichiers
- P19.36 Manuscript__rev.pdf
- Version soumise (preprint)
- Accès restreint
- Accéder au document