title: HIV-1 Vpu protein antagonizes innate restriction factor BST-2 via lipid-embedded helix-helix interactions.
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, lipid-embedded 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.
authors.affiliation: Department of Medicine, University of California, San Diego, La Jolla, California, 92093.
authors.forename: Mark
authors.initials: M
authors.lastname: Skasko
authors.affiliation: Department of Chemistry and Biochemistry, University of California, San Diego, La Jolla, California 92093.
authors.forename: Yan
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Department of Chemistry and Biochemistry, University of California, San Diego, La Jolla, California 92093.
authors.forename: Ye
authors.initials: Y
authors.lastname: Tian
authors.affiliation: Department of Medicine, University of California, San Diego, La Jolla, California, 92093.
authors.forename: Andrey
authors.initials: A
authors.lastname: Tokarev
authors.affiliation: Department of Medicine, University of California, San Diego, La Jolla, California, 92093.
authors.forename: Jason
authors.initials: J
authors.lastname: Munguia
authors.affiliation: Department of Anatomy and Cell Biology, University of Kansas Medical Center, Kansas City, Kansas, 66160.
authors.forename: Autumn
authors.initials: A
authors.lastname: Ruiz
authors.affiliation: Department of Microbiology, Molecular Genetics, and Immunology, University of Kansas Medical Center, Kansas City, Kansas 66160.
authors.forename: Edward B
authors.initials: EB
authors.lastname: Stephens
authors.affiliation: Department of Chemistry and Biochemistry, University of California, San Diego, La Jolla, California 92093. Electronic address: sopella@ucsd.edu.
authors.forename: Stanley J
authors.initials: SJ
authors.lastname: Opella
authors.affiliation: Department of Medicine, University of California, San Diego, La Jolla, California, 92093; San Diego Veterans Affairs Healthcare System, San Diego, California 92161. Electronic address: jguatelli@ucsd.edu.
authors.forename: John
authors.initials: J
authors.lastname: Guatelli
mesh_terms: D000595:Amino Acid Sequence; D015703:Antigens, CD / Q000737:chemistry* / Q000276:immunology / Q000378:metabolism*; D002462:Cell Membrane / Q000378:metabolism / Q000821:virology; D058851:GPI-Linked Proteins / Q000737:chemistry / Q000276:immunology / Q000378:metabolism; D015497:HIV-1 / Q000276:immunology / Q000378:metabolism*; D006367:HeLa Cells; D054298:Human Immunodeficiency Virus Proteins / Q000737:chemistry* / Q000378:metabolism*; D006801:Humans; D057927:Hydrophobic and Hydrophilic Interactions; D007113:Immunity, Innate; D008051:Lipid Bilayers / Q000737:chemistry / Q000378:metabolism*; D008823:Micelles; D008958:Models, Molecular; D008969:Molecular Sequence Data; D019906:Nuclear Magnetic Resonance, Biomolecular; D011485:Protein Binding; D017433:Protein Structure, Secondary; D017434:Protein Structure, Tertiary; D013816:Thermodynamics; D054334:Viral Regulatory and Accessory Proteins / Q000737:chemistry* / Q000378:metabolism*; D000074010:Bone Marrow Stromal Antigen 2; D000086082:Viroporin Proteins
chemical_list: D015703:Antigens, CD; D058851:GPI-Linked Proteins; D054298:Human Immunodeficiency Virus Proteins; D008051:Lipid Bilayers; D008823:Micelles; D054334:Viral Regulatory and Accessory Proteins; C094572:BST2 protein, human; D000074010:Bone Marrow Stromal Antigen 2; C514859:vpu protein, Human immunodeficiency virus 1; D000086082:Viroporin Proteins
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