title: Interaction between the NS4B amphipathic helix, AH2, and charged lipid headgroups alters membrane morphology and AH2 oligomeric state--Implications for the Hepatitis C virus life cycle.
abstract: The non-structural protein 4B (NS4B) from Hepatitis C virus (HCV) plays a pivotal role in the remodelling of the host cell's membranes, required for the formation of the viral replication complex where genome synthesis occurs. NS4B is an integral membrane protein that possesses a number of domains vital for viral replication. Structural and biophysical studies have revealed that one of these, the second amphipathic N-terminal helix (AH2), plays a key role in these remodelling events. However, there is still limited understanding of the mechanism through which AH2 promotes these changes. Here we report on solid-state NMR and molecular dynamics studies that demonstrate that AH2 promotes the clustering of negatively charged lipids within the bilayer, a process that reduces the strain within the bilayer facilitating the remodelling of the lipid bilayer. Furthermore, the presence of negatively charged lipids within the bilayer appears to promote the disassociation of AH2 oligomers, highlighting a potential role for lipid recruitment in regulating NS protein interactions.
authors.affiliation: Centre for Biological Sciences/Institute for Life Sciences, University of Southampton, Highfield Campus, Southampton SO17 1BJ, UK.
authors.forename: Esther L
authors.initials: EL
authors.lastname: Ashworth Briggs
authors.affiliation: Centre for Biological Sciences/Institute for Life Sciences, University of Southampton, Highfield Campus, Southampton SO17 1BJ, UK; School of Medicine, University of Southampton, Southampton SO16 6YD, UK.
authors.forename: Rafael G B
authors.initials: RG
authors.lastname: Gomes
authors.affiliation: School of Chemistry, University of Southampton, Southampton SO17 1BJ, UK.
authors.forename: Malaz
authors.initials: M
authors.lastname: Elhussein
authors.affiliation: Centre for Biological Sciences/Institute for Life Sciences, University of Southampton, Highfield Campus, Southampton SO17 1BJ, UK.
authors.forename: William
authors.initials: W
authors.lastname: Collier
authors.affiliation: Centre for Biological Sciences/Institute for Life Sciences, University of Southampton, Highfield Campus, Southampton SO17 1BJ, UK.
authors.forename: I Stuart
authors.initials: IS
authors.lastname: Findlow
authors.affiliation: School of Chemistry, University of Southampton, Southampton SO17 1BJ, UK.
authors.forename: Syma
authors.initials: S
authors.lastname: Khalid
authors.affiliation: School of Medicine, University of Southampton, Southampton SO16 6YD, UK. Electronic address: C.J.McCormick@soton.ac.uk.
authors.forename: Chris J
authors.initials: CJ
authors.lastname: McCormick
authors.affiliation: Centre for Biological Sciences/Institute for Life Sciences, University of Southampton, Highfield Campus, Southampton SO17 1BJ, UK. Electronic address: P.T.Williamson@soton.ac.uk.
authors.forename: Philip T F
authors.initials: PT
authors.lastname: Williamson
mesh_terms: D002462:Cell Membrane / Q000378:metabolism*; D016174:Hepacivirus / Q000254:growth & development / Q000378:metabolism*; D008051:Lipid Bilayers; D008563:Membrane Lipids / Q000737:chemistry / Q000378:metabolism*; D056004:Molecular Dynamics Simulation; D019906:Nuclear Magnetic Resonance, Biomolecular; D011487:Protein Conformation; D055503:Protein Multimerization; D013329:Structure-Activity Relationship; D013499:Surface Properties; D017361:Viral Nonstructural Proteins / Q000737:chemistry / Q000378:metabolism*; D014779:Virus Replication
chemical_list: D008051:Lipid Bilayers; D008563:Membrane Lipids; C080107:NS4B protein, flavivirus; D017361:Viral Nonstructural Proteins
keywords: Hepatitis C Virus; Membrane biophysics; Membrane remodelling; Molecular dynamics; Solid-state NMR