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Virus‐cell and cell‐cell fusion mediated by the HIV‐1 envelope glycoprotein is inhibited by short gp41 N‐terminal membrane‐anchored peptides lacking the critical pocket domain
Author(s) -
WexlerCohen Yael,
Ashkenazi Avraham,
Viard Mathias,
Blumenthal Robert,
Shai Yechiel
Publication year - 2010
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fj.09-151704
Subject(s) - gp41 , heptad repeat , lipid bilayer fusion , glycoprotein , microbiology and biotechnology , cell fusion , viral envelope , c terminus , peptide , n terminus , chemistry , cell membrane , cell , biology , peptide sequence , biochemistry , amino acid , membrane , gene , genetics , antigen , epitope
The interactions between the N‐ and C‐terminal heptad repeat (NHR and CHR) regions of the human immunodeficiency virus (HIV‐1) glycoprotein gp41 create a structure comprising a 6‐helix bundle (SHB). A sequence in the SHB named the “pocket” is crucial for the SHB's stability and for the fusion inhibitory activity of 36‐residue NHR peptide N36. We report that a short 27‐residue peptide, N27, which lacks the pocket sequence, exhibits potent inhibitory activity in both cell‐cell and virus‐cell fusion assays when fatty acids were conjugated to its N but not C terminus. Furthermore, mutations in the positions that prevent interaction with the CHR but not with the NHR resulted in a dramatic reduction in N27 activity. These data support a mechanism in which N27 mainly targets the CHR rather than the internal NHR coiled‐coil, reveal the N‐terminal edge of the endogenous core structure in situ and hence complement our recent findings of the C‐terminal edge of the core, and provide a new approach for designing short inhibitors from the NHR region of other lentiviruses due to similarities in their envelope proteins.—Wexler‐Cohen, Y., Ashkenazi, A., Viard, M., Blumenthal, R., Shai, Y. Virus‐cell and cell‐cell fusion mediated by the HIV‐1 envelope glycoprotein is inhibited by short gp41 N‐terminal membrane‐anchored peptides lacking the critical pocket domain. FASEB J . 24, 4196–4202 (2010). www.fasebj.org