Characterization of the interacting domain of the HIV-1 fusion peptide with the transmembrane domain of the T-cell receptor

被引:14
作者
Cohen, Tomer [1 ]
Pevsner-Fischer, Meirav [2 ]
Cohen, Noam [2 ]
Cohen, Irun R. [2 ]
Shai, Yechiel [1 ]
机构
[1] Weizmann Inst Sci, Dept Biol Chem, IL-76100 Rehovot, Israel
[2] Weizmann Inst Sci, Dept Immunol, IL-76100 Rehovot, Israel
关键词
D O I
10.1021/bi800100p
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
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 TCR alpha chain (designated CP) and the beta-sheet 5-13 region of the 16 N-terminal amino acids of FP (FP1-16). To correlate between the theoretical prediction and experimental data, we synthesized a series of mutants derived from the interacting motif GALFLGFLG stretch (FP5-13) and investigated them structurally and functionally. The data reveal a direct correlation between the beta-sheet structure of FP5-13 and its mutants and their ability to interact with CP and induce immunosuppressive activity; the pherylalanines 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 FP5-13 Motif should facilitate evaluating its contribution to HIV. pathology and its exploitation as an immunotherapeutic tool.
引用
收藏
页码:4826 / 4833
页数:8
相关论文
共 56 条
[1]   Responsive gels formed by the spontaneous self-assembly of peptides into polymeric beta-sheet tapes [J].
Aggeli, A ;
Bell, M ;
Boden, N ;
Keen, JN ;
Knowles, PF ;
McLeish, TCB ;
Pitkeathly, M ;
Radford, SE .
NATURE, 1997, 386 (6622) :259-262
[2]   T-Cell inactivation and immunosuppressive activity induced by HIV gp41 via novel interacting motif [J].
Bloch, Itai ;
Quintana, Francisco J. ;
Gerber, Doron ;
Cohen, Tomer ;
Cohen, Irun R. ;
Shai, Yechiel .
FASEB JOURNAL, 2007, 21 (02) :393-401
[3]   A DISSECTION OF STEPS LEADING TO VIRAL ENVELOPE PROTEIN-MEDIATED MEMBRANE-FUSION [J].
BLUMENTHAL, R ;
SCHOCH, C ;
PURI, A ;
CLAGUE, MJ .
ANNALS OF THE NEW YORK ACADEMY OF SCIENCES-SERIES, 1991, 635 :285-296
[4]   AROMATIC-AROMATIC INTERACTION - A MECHANISM OF PROTEIN-STRUCTURE STABILIZATION [J].
BURLEY, SK ;
PETSKO, GA .
SCIENCE, 1985, 229 (4708) :23-28
[5]   Oligomeric structure of the human immunodeficiency virus type I envelope protein on the virion surface [J].
Center, RJ ;
Leapman, RD ;
Lebowitz, J ;
Arthur, LO ;
Earl, PL ;
Moss, B .
JOURNAL OF VIROLOGY, 2002, 76 (15) :7863-7867
[6]   Core structure of gp41 from the HIV envelope glycoprotein [J].
Chan, DC ;
Fass, D ;
Berger, JM ;
Kim, PS .
CELL, 1997, 89 (02) :263-273
[7]   The interactions of the N-terminal fusogenic peptide of HIV-1 gp41 with neutral phospholipids [J].
Curtain, C ;
Separovic, F ;
Nielsen, K ;
Craik, D ;
Zhong, Y ;
Kirkpatrick, A .
EUROPEAN BIOPHYSICS JOURNAL WITH BIOPHYSICS LETTERS, 1999, 28 (05) :427-436
[8]  
de Jong M D, 1996, Antivir Ther, V1, P33
[9]   Fusion peptides and the mechanism of viral fusion [J].
Epand, RM .
BIOCHIMICA ET BIOPHYSICA ACTA-BIOMEMBRANES, 2003, 1614 (01) :116-121
[10]   Specificity in transmembrane helix-helix interactions can define a hierarchy of stability for sequence variants [J].
Fleming, KG ;
Engelman, DM .
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 2001, 98 (25) :14340-14344