HIV-1 Vpu protein antagonizes innate restriction factor BST-2 via lipid-embedded helix-helix interactions

Mark Skasko, Yan Wang, Ye Tian, Andrey Tokarev, Jason Munguia, Autumn Ruiz, Edward B. Stephens, Stanley J. Opella, Ohn Guatelli

Research output: Contribution to journalArticle

89 Scopus citations

Abstract

The Vpu protein of HIV-1 antagonizes BST-2 (tetherin), a broad spectrum effector of the innate immune response to viral infection, by an intermolecular interaction that maps genetically to the α-helical transmembrane domains (TMDs) of each protein. Here we utilize NMR spectroscopy to describe key features of the helix-helix pairing that underlies this interaction. The antagonism of BST-2 involves a sequence of three alanines and a tryptophan spaced at four residue intervals within the Vpu TMD helix. Responsiveness to Vpu involves bulky hydrophobic residues in the C-terminal region of the BST-2 TMD helix that likely fit between the alanines on the interactive face of Vpu. These aspects of Vpu and BST-2 form an anti-parallel, lipidembedded helix-helix interface. Changes in human BST-2 that mimic sequences found in nonhuman primate orthologs unresponsive to Vpu change the tilt angle of the TMD in the lipid bilayer without abrogating its intrinsic ability to interact with Vpu. These data explain the mechanism by which HIV-1 evades a key aspect of innate immunity and the species specificity of Vpu using an anti-parallel helix-helix packing model.

Original languageEnglish (US)
Pages (from-to)58-67
Number of pages10
JournalJournal of Biological Chemistry
Volume287
Issue number1
DOIs
StatePublished - Jan 2 2012

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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    Skasko, M., Wang, Y., Tian, Y., Tokarev, A., Munguia, J., Ruiz, A., Stephens, E. B., Opella, S. J., & Guatelli, O. (2012). HIV-1 Vpu protein antagonizes innate restriction factor BST-2 via lipid-embedded helix-helix interactions. Journal of Biological Chemistry, 287(1), 58-67. https://doi.org/10.1074/jbc.M111.296772