ArticleThe Journal of biological chemistry2015
A Proline-Tryptophan Turn in the Intrinsically Disordered Domain 2 of NS5A Protein Is Essential for Hepatitis C Virus RNA Replication.
Article in The Journal of biological chemistry, 2015. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 14 papers.
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Who cites it
14 citing papers in PubMed, 24 citations in OpenAlex.
- Picosecond Dynamics of a Small Molecule in Its Bound State with an Intrinsically Disordered Protein.Journal of the American Chemical Society · 2024Article
- Regulatory Role of Phospholipids in Hepatitis C Virus Replication and Protein Function.Pathogens (Basel, Switzerland) · 2022Review
- Domain 2 of Hepatitis C Virus Protein NS5A Activates Glucokinase and Induces Lipogenesis in Hepatocytes.International journal of molecular sciences · 2022Article
- Mutations in Spliceosomal Genes PPIL1 and PRP17 Cause Neurodegenerative Pontocerebellar Hypoplasia with Microcephaly.Neuron · 2021Article
- ISGylation of Hepatitis C Virus NS5A Protein Promotes Viral RNA Replication via Recruitment of Cyclophilin A.Journal of virology · 2020Article
- Cyclophilin A allows the allosteric regulation of a structural motif in the disordered domain 2 of NS5A and thereby fine-tunes HCV RNA replication.The Journal of biological chemistry · 2019Article
- Structure determination of UL49.5 transmembrane protein from bovine herpesvirus 1 by NMR spectroscopy and molecular dynamics.Biochimica et biophysica acta. Biomembranes · 2019Article
- Atomistic molecular dynamics simulations of bioactive engrailed 1 interference peptides (EN1-iPeps).Oncotarget · 2018Article
- NMR and circular dichroism data for domain 2 of the HCV NS5A protein phosphorylated by the Casein Kinase II.Data in brief · 2018Article
- Interaction study between HCV NS5A-D2 and NS5B usingJournal of biomolecular NMR · 2018Article
- NMR reveals the intrinsically disordered domain 2 of NS5A protein as an allosteric regulator of the hepatitis C virus RNA polymerase NS5B.The Journal of biological chemistry · 2017Article
- My Cousin, My Enemy: quasispecies suppression of drug resistance.Current opinion in virology · 2016Review
- Chaperones in hepatitis C virus infection.World journal of hepatology · 2016Review
- Binding Mechanisms of Intrinsically Disordered Proteins: Theory, Simulation, and Experiment.Frontiers in molecular biosciences · 2016Review
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Authors and funding
11 authors at 6 institutions in 2 countries.
Funding
No grant is acknowledged in the PubMed record.
Abstract
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 Pro(314)-Trp(316) 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 Pro(314) 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.
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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.