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| Item Type: | Article |
|---|---|
| Title: | Phospholipid-driven conformational switching of HCV NS5A links protein folding to replication membrane remodeling |
| Creators: |
Bulankina, Anna V.  ORCID: https://orcid.org/0009-0003-0992-7320, Richter, Rebecca M. ORCID: https://orcid.org/0000-0002-3831-7666, Nettles, James H. ORCID: https://orcid.org/0000-0002-5683-8481, Yamane, Daisuke ORCID: https://orcid.org/0000-0003-1592-9368, Grimm, Christian, Karami, Yasaman ORCID: https://orcid.org/0000-0001-8413-2665, Stanton, Richard A. ORCID: https://orcid.org/0000-0003-4810-7002, Introini, Bianca, Hermann, Jonas, Charif, Hanaa, König, Mia S. ORCID: https://orcid.org/0009-0009-5173-1798, Stroß, Claudia, Ortiz, Cristina, Kraus, Nico ORCID: https://orcid.org/0000-0002-5162-1048, Wood, Daniel, Galceran, Facundo ORCID: https://orcid.org/0000-0001-5023-0582, Abele, Rupert ORCID: https://orcid.org/0000-0001-6899-293X, Maigret, Bernard ORCID: https://orcid.org/0000-0002-1983-1950, Schinazi, Raymond F. ORCID: https://orcid.org/0000-0002-6688-3614, Zeuzem, Stefan, Biondi, Ricardo M. ORCID: https://orcid.org/0000-0002-8873-7167, Yi, MinKyung, Tampé, Robert ORCID: https://orcid.org/0000-0002-0403-2160, Kudryashev, Mikhail ORCID: https://orcid.org/0000-0003-3550-6274 and Welsch, Christoph ORCID: https://orcid.org/0000-0002-1823-4863
|
| Abstract: | Phospholipids are essential for RNA virus replication, yet their role in modulating conformational dynamics of membrane-associated viral proteins remains poorly understood. For NS5A, a key replication factor of hepatitis C virus, previous crystallographic models fail to capture the lipid-driven conformational mechanics we uncover here. Using structural informatics and biochemical probing of pharmacophore-guided mutants in defined lipid environments, we evaluated competing NS5A domain 1 dimerization models. Our data reveal an alternative membrane-specific fold stabilized by polyproline hinges and phospholipids (PIPs) such as phosphatidylinositol-4-phosphate, a host lipid enriched at replication membranes. PIP binding promotes a conformational switch that drives dimerization, linking lipid sensing to membrane remodeling and host factor recruitment. This reciprocal mechanism—where a lipid allosterically modulates a viral protein that reshapes membranes—is blocked by the antiviral pibrentasvir. These findings define a lipid-driven structural switch that governs NS5A pleiotropy and highlight dynamic lipid-protein interfaces as targets for antiviral intervention. |
| Keywords: | Cell Membrane, Hepacivirus, Molecular Models, Phosphatidylinositol Phosphates, Phospholipids, Protein Binding, Protein Conformation, Protein Folding, Protein Multimerization, RNA-Dependent RNA Polymerase, Viral Nonstructural Proteins, Virus Replication |
| Source: | Science Advances |
| ISSN: | 2375-2548 |
| Publisher: | American Association for the Advancement of Science |
| Volume: | 12 |
| Number: | 14 |
| Page Range: | eaeb8863 |
| Date: | 3 April 2026 |
| Official Publication: | https://doi.org/10.1126/sciadv.aeb8863 |
| PubMed: | View item in PubMed |
| Related to: |
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