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| Item Type: | Article |
|---|---|
| Title: | Phospholipid-driven conformational switching of HCV NS5A links protein folding to replication membrane remodeling |
| Creators Name: | Bulankina, Anna V., Richter, Rebecca M., Nettles, James H., Yamane, Daisuke, Grimm, Christian, Karami, Yasaman, Stanton, Richard A., Introini, Bianca, Hermann, Jonas, Charif, Hanaa, König, Mia S., Stroß, Claudia, Ortiz, Cristina, Kraus, Nico, Wood, Daniel, Galceran, Facundo, Abele, Rupert, Maigret, Bernard, Schinazi, Raymond F., Zeuzem, Stefan, Biondi, Ricardo M., Yi, MinKyung, Tampé, Robert, Kudryashev, Mikhail and Welsch, Christoph |
| 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 |
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