Characterization of the interacting domain of the HIV-1 fusion peptide with the transmembrane domain of the T-cell receptor.
HIV infection is initiated by the fusion of the viral membrane with the target T-cell membrane. The HIV envelope glycoprotein, gp41, contains a fusion peptide (FP) in the N terminus that functions together with other gp41 domains to fuse the virion with the host cell membrane. We recently reported that FP co-localizes with CD4 and T-cell receptor (TCR) molecules, co-precipitates with TCR, and inhibits antigen-specific T-cell proliferation and pro-inflammatory cytokine secretion. Molecular dynamic simulation implicated an interaction between an alpha-helical transmembrane domain (TM) of the TCRalpha chain (designated CP) and the beta-sheet 5-13 region of the 16 N-terminal amino acids of FP (FP(1-16)). To correlate between the theoretical prediction and experimental data, we synthesized a series of mutants derived from the interacting motif GALFLGFLG stretch (FP(5-13)) and investigated them structurally and functionally. The data reveal a direct correlation between the beta-sheet structure of FP(5-13) and its mutants and their ability to interact with CP and induce immunosuppressive activity; the phenylalanines play an important role. Furthermore, studies with fluorescently labeled peptides revealed that this interaction leads to penetration of the N terminus of FP and its active analogues into the hydrophobic core of the membrane. A detailed understanding of the molecular interactions mediating the immunosuppressive activity of the FP(5-13) motif should facilitate evaluating its contribution to HIV pathology and its exploitation as an immunotherapeutic tool.
Cohen
Tomer
T
Departments of Biological Chemistry and Immunology, the Weizmann Institute of Science, Rehovot 76100, Israel.
Pevsner-Fischer
Meirav
M
Cohen
Noam
N
Cohen
Irun R
IR
Shai
Yechiel
Y
D000595:Amino Acid Sequence; D000818:Animals; D000906:Antibodies / Q000276:immunology; D017252:CD3 Complex / Q000276:immunology; D002462:Cell Membrane / Q000378:metabolism*; D049109:Cell Proliferation; D002478:Cells, Cultured; D015700:HIV Envelope Protein gp41 / Q000138:chemical synthesis / Q000737:chemistry* / Q000378:metabolism*; D015497:HIV-1 / Q000737:chemistry / Q000276:immunology; D008213:Lymphocyte Activation / Q000276:immunology; D051379:Mice; D008969:Molecular Sequence Data; D010743:Phospholipids / Q000737:chemistry / Q000378:metabolism; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D011948:Receptors, Antigen, T-Cell / Q000737:chemistry* / Q000276:immunology / Q000378:metabolism*; D017550:Spectroscopy, Fourier Transform Infrared; D013601:T-Lymphocytes / Q000166:cytology / Q000276:immunology / Q000378:metabolism
D000906:Antibodies; D017252:CD3 Complex; D015700:HIV Envelope Protein gp41; D010743:Phospholipids; D011948:Receptors, Antigen, T-Cell; C514787:gp41 protein, Human immunodeficiency virus 1