A Proline-Tryptophan Turn in the Intrinsically ...
Document type :
Article dans une revue scientifique
DOI :
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Title :
A Proline-Tryptophan Turn in the Intrinsically Disordered Domain 2 of NS5A Protein Is Essential for Hepatitis C Virus RNA Replication
Author(s) :
Dujardin, Marie [Auteur]
Unité de Glycobiologie Structurale et Fonctionnelle - UMR 8576 [UGSF]
Madan, Vanesa [Auteur]
Universität Heidelberg [Heidelberg] = Heidelberg University
Montserret, Roland [Auteur]
Institut de biologie et chimie des protéines [Lyon] [IBCP]
Ahuja, Puneet [Auteur]
Unité de Glycobiologie Structurale et Fonctionnelle - UMR 8576 [UGSF]
Huvent, Isabelle [Auteur]
Unité de Glycobiologie Structurale et Fonctionnelle - UMR 8576 [UGSF]
Launay, Hélène [Auteur]
Unité de Glycobiologie Structurale et Fonctionnelle - UMR 8576 [UGSF]
Leroy, Arnaud [Auteur]
Université Paris-Sud - Paris 11 [UP11]
Bartenschlager, Ralf [Auteur]
Universität Heidelberg [Heidelberg] = Heidelberg University
Penin, François [Auteur]
Institut de biologie et chimie des protéines [Lyon] [IBCP]
Lippens, Guy [Auteur]
Unité de Glycobiologie Structurale et Fonctionnelle - UMR 8576 [UGSF]
Hanoulle, Xavier [Auteur]
Unité de Glycobiologie Structurale et Fonctionnelle - UMR 8576 [UGSF]
Unité de Glycobiologie Structurale et Fonctionnelle - UMR 8576 [UGSF]
Madan, Vanesa [Auteur]
Universität Heidelberg [Heidelberg] = Heidelberg University
Montserret, Roland [Auteur]
Institut de biologie et chimie des protéines [Lyon] [IBCP]
Ahuja, Puneet [Auteur]
Unité de Glycobiologie Structurale et Fonctionnelle - UMR 8576 [UGSF]
Huvent, Isabelle [Auteur]
![refId](/themes/Mirage2//images/idref.png)
Unité de Glycobiologie Structurale et Fonctionnelle - UMR 8576 [UGSF]
Launay, Hélène [Auteur]
Unité de Glycobiologie Structurale et Fonctionnelle - UMR 8576 [UGSF]
Leroy, Arnaud [Auteur]
Université Paris-Sud - Paris 11 [UP11]
Bartenschlager, Ralf [Auteur]
Universität Heidelberg [Heidelberg] = Heidelberg University
Penin, François [Auteur]
Institut de biologie et chimie des protéines [Lyon] [IBCP]
Lippens, Guy [Auteur]
Unité de Glycobiologie Structurale et Fonctionnelle - UMR 8576 [UGSF]
Hanoulle, Xavier [Auteur]
![refId](/themes/Mirage2//images/idref.png)
Unité de Glycobiologie Structurale et Fonctionnelle - UMR 8576 [UGSF]
Journal title :
THE JOURNAL OF BIOLOGICAL CHEMISTRY
Volume number :
290
Pages :
19104-19120
Publication date :
2015-07-31
ISSN :
0021-9258, 1083-351X
English keyword(s) :
cyclophilin
hepatitis C virus (HCV)
intrinsically disordered protein
nuclear magnetic resonance (NMR)
prolyl isomerase
protein motif
viral protein
RNA replication
hepatitis C virus (HCV)
intrinsically disordered protein
nuclear magnetic resonance (NMR)
prolyl isomerase
protein motif
viral protein
RNA replication
HAL domain(s) :
Chimie/Chimie théorique et/ou physique
English abstract : [en]
Hepatitis C virus (HCV) nonstructural protein 5A (NS5A) and its interaction with the human chaperone cyclophilin A are both targets for highly potent and promising antiviral drugs that are in the late stages of clinical ...
Show more >Hepatitis C virus (HCV) nonstructural protein 5A (NS5A) and its interaction with the human chaperone cyclophilin A are both targets for highly potent and promising antiviral drugs that are in the late stages of clinical development. Despite its high interest in regards to the development of drugs to counteract the worldwide HCV burden, NS5A is still an enigmatic multifunctional protein poorly characterized at the molecular level. NS5A is required for HCV RNA replication and is involved in viral particle formation and regulation of host pathways. Thus far, no enzymatic activity or precise molecular function has been ascribed to NS5A that is composed of a highly structured domain 1 (D1), as well as two intrinsically disordered domains 2 (D2) and 3 (D3), representing half of the protein. Here, we identify a short structural motif in the disordered NS5A-D2 and report its NMR structure. We show that this structural motif, a minimal Pro314–Trp316 turn, is essential for HCV RNA replication, and its disruption alters the subcellular distribution of NS5A. We demonstrate that this Pro-Trp turn is required for proper interaction with the host cyclophilin A and influences its peptidyl-prolyl cis/trans isomerase activity on residue Pro314 of NS5A-D2. This work provides a molecular basis for further understanding of the function of the intrinsically disordered domain 2 of HCV NS5A protein. In addition, our work highlights how very small structural motifs present in intrinsically disordered proteins can exert a specific function.Show less >
Show more >Hepatitis C virus (HCV) nonstructural protein 5A (NS5A) and its interaction with the human chaperone cyclophilin A are both targets for highly potent and promising antiviral drugs that are in the late stages of clinical development. Despite its high interest in regards to the development of drugs to counteract the worldwide HCV burden, NS5A is still an enigmatic multifunctional protein poorly characterized at the molecular level. NS5A is required for HCV RNA replication and is involved in viral particle formation and regulation of host pathways. Thus far, no enzymatic activity or precise molecular function has been ascribed to NS5A that is composed of a highly structured domain 1 (D1), as well as two intrinsically disordered domains 2 (D2) and 3 (D3), representing half of the protein. Here, we identify a short structural motif in the disordered NS5A-D2 and report its NMR structure. We show that this structural motif, a minimal Pro314–Trp316 turn, is essential for HCV RNA replication, and its disruption alters the subcellular distribution of NS5A. We demonstrate that this Pro-Trp turn is required for proper interaction with the host cyclophilin A and influences its peptidyl-prolyl cis/trans isomerase activity on residue Pro314 of NS5A-D2. This work provides a molecular basis for further understanding of the function of the intrinsically disordered domain 2 of HCV NS5A protein. In addition, our work highlights how very small structural motifs present in intrinsically disordered proteins can exert a specific function.Show less >
Language :
Anglais
Audience :
Non spécifiée
ANR Project :
Administrative institution(s) :
CNRS
Université de Lille
Université de Lille
Research team(s) :
RMN et interactions moléculaires
Submission date :
2020-02-12T15:44:55Z
2021-05-18T13:08:45Z
2021-06-02T06:44:57Z
2021-05-18T13:08:45Z
2021-06-02T06:44:57Z
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