Dengue virus NS4A cytoplasmic domain binding to liposomes is sensitive to membrane curvature

Yu Fu Hung, Melanie Schwarten, Sven Schünke, Pallavi Thiagarajan-Rosenkranz, Silke Hoffmann, Ella H. Sklan, Dieter Willbold, Bernd W. Koenig

Research output: Contribution to journalArticlepeer-review

Abstract

Dengue virus (DENV) infection is a growing public health threat with more than one-third of the world's population at risk. Non-structural protein 4A (NS4A), one of the least characterized viral proteins, is a highly hydrophobic transmembrane protein thought to induce the membrane alterations that harbor the viral replication complex. The NS4A N-terminal (amino acids 1-48), has been proposed to contain an amphipathic α-helix (AH). Mutations (L6E; M10E) designed to reduce the amphipathic character of the predicted AH, abolished viral replication and reduced NS4A oligomerization. Nuclear magnetic resonance (NMR) spectroscopy was used to characterize the N-terminal cytoplasmic region (amino acids 1-48) of both wild type and mutant NS4A in the presence of SDS micelles. Binding of the two N-terminal NS4A peptides to liposomes was studied as a function of membrane curvature and lipid composition. The NS4A N-terminal was found to contain two AHs separated by a non-helical linker. The above mentioned mutations did not significantly affect the helical secondary structure of this domain. However, they reduced the affinity of the N-terminal NS4A domain for lipid membranes. Binding of wild type NS4A(1-48) to liposomes is highly dependent on membrane curvature.

Original languageEnglish
Pages (from-to)1119-1126
Number of pages8
JournalBiochimica et Biophysica Acta - Biomembranes
Volume1848
Issue number5
DOIs
StatePublished - May 2015

Keywords

  • Amphipathic helix
  • Curvature sensing
  • Dengue virus
  • NMR spectroscopy
  • Non-structural protein NS4A
  • Peptide membrane interaction

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