HIV-1 fusion peptide targets the TCR and inhibits antigen-specific T cell activation

Quintana, Francisco J.; Gerber, Doron; Kent, Sally C.; Cohen, Irun R.; Shai, Yechiel

doi:10.1172/jci23956

Cited by 62 publications

(110 citation statements)

References 59 publications

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“…The structure and function of the HIV-1 gp41 molecule have been extensively studied (10,15,25,35,51,55,56,66,67). Considerable evidence suggests that during the fusion process gp41 likely exists in at least three conformations: (i) a metastable prefusogenic state, which is stabilized by interactions with gp120 subunit; (ii) a prehairpin intermediate, formed by insertion of the hydrophobic fusion peptide into the target cell membrane and concurrent folding of the N-terminal trimeric coiled coil; and (iii) the fusogenic trimer-of-hairpins form, in which two ␣-helical regions, the NHR (adjacent to the Nterminal fusion peptide) and the CHR (near the C-terminal transmembrane segment), associate to form a highly stable six-helix bundle, bringing the viral and cellular membranes into close apposition (6).…”

Section: Discussionmentioning

confidence: 99%

Conserved Salt Bridge between the N- and C-Terminal Heptad Repeat Regions of the Human Immunodeficiency Virus Type 1 gp41 Core Structure Is Critical for Virus Entry and Inhibition

Liu

et al. 2008

J Virol

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The fusogenic human immunodeficiency virus type 1 (HIV-1) gp41 core structure is a stable six-helix bundle formed by its N-and C-terminal heptad repeat sequences. Notably, the negatively charged residue Asp 632 located at the pocket-binding motif in the C-terminal heptad repeat interacts with the positively charged residue Lys 574 in the pocket formation region of the N-terminal heptad repeat to form a salt bridge. We previously demonstrated that the residue Lys 574 plays an essential role in six-helix bundle formation and virus infectivity and is a key determinant of the target for anti-HIV fusion inhibitors. In this study, the functionality of residue Asp 632 has been specifically characterized by mutational analysis and biophysical approaches. We show that Asp 632 substitutions with positively charged residues (D632K and D632R) or a hydrophobic residue (D632V) could completely abolish Env-mediated viral entry, while a protein with a conserved substitution (D632E) retained its activity. Similar to the Lys 574 mutations, nonconserved substitutions of Asp 632 also severely impaired the ␣-helicity, stability, and conformation of six-helix bundles as shown by N36 and C34 peptides as a model system. Furthermore, nonconserved substitutions of Asp 632 significantly reduced the potency of C34 to sequestrate six-helix bundle formation and to inhibit HIV-1-mediated cell-cell fusion and infection, suggesting its importance for designing antiviral fusion inhibitors. Taken together, these data suggest that the salt bridge between the N-and C-terminal heptad repeat regions of the fusion-active HIV-1 gp41 core structure is critical for viral entry and inhibition.Infection with human immunodeficiency virus type 1 (HIV-1) is mediated by its envelope glycoprotein (Env), a type I transmembrane protein which is originally synthesized as the single, glycosylated, polyprotein precursor gp160 and subsequently cleaved by a cellular protease to yield gp120 and gp41 subunits (13,14,20,46,48). Upon binding of the HIV-1 Env surface subunit gp120 to the cell receptor CD4 and subsequently to a coreceptor (CCR5 or CXCR4), its transmembrane subunit gp41 is released to mediate fusion of viral and cellular membranes (20,25,54). Structurally, HIV-1 gp41 consists of extracellular, transmembrane, and cytoplasmic domains (Fig. 1A). Its extracellular domain (ectodomain) contains four major functional regions: a hydrophobic, glycine-rich fusion peptide; an N-terminal heptad repeat (NHR) (also called HR1), a C-terminal heptad repeat (CHR) (also called HR2), and a tryptophan-rich region. In the early 1990s, several peptides derived from the NHR (N peptides) and CHR (C peptides) were found to have potent anti-HIV activity (30,43,68,69). Although their mechanism of action was not known at that time, the unprecedented anti-HIV activity of these peptides opened a new avenue for developing antiviral drugs. A C peptide known as T20 (brand name, Fuzeon) has been successfully developed as a novel class of anti-HIV drugs for clinical use (36,37,50).The findin...

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Section: Discussionmentioning

confidence: 99%

Conserved Salt Bridge between the N- and C-Terminal Heptad Repeat Regions of the Human Immunodeficiency Virus Type 1 gp41 Core Structure Is Critical for Virus Entry and Inhibition

Liu

et al. 2008

J Virol

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“…71 Recently, inhibition of antigen-but not anti-CD3-stimulated T-cell activation has been reported for the fusion peptide (FP) found in the N terminus of the HIV envelope glycoprotein 41 (gp41). 139 However, the mode of action of this peptide had remained unknown until 2006 when the SCHOOL model was first applied to this area. 72 Within the model, the molecular mechanisms of action for TCR CP and HIV gp41 FP are similar.…”

Section: School Platform Of Receptor Signalingmentioning

confidence: 99%

The SCHOOL of nature: II. Protein order, disorder, and oligomericity in transmembrane signaling

Sigalov¹

2010

Self/Nonself

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“…Recent studies [26][27][28][29][30] suggest that in order to establish a successful infection, viruses have evolved the strategy to attack this Achilles' heel of MIRRs and disrupt functional coupling between two aspects of receptor machinery: recognition and signaling. This allows viruses to cheat the immune system and enter response to different ligands is higher with the more different signaling subunits (or ITAMs on the same subunit) the MIRR complex has.…”

Section: Intrareceptor Transmembranementioning

confidence: 99%

Cells diversify transmembrane signaling through the controlled chaos of protein disorder

Sigalov

2011

Self/Nonself

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C ell surface receptors function to transduce signals across the cell membrane leading to a variety of biologic responses. Structurally, these integral proteins can be classified into two main families, depending on whether extracellular ligand-binding and intracellular signaling domains are located on the same protein chain (single-chain receptors, SRs) or on separate subunits (multichain receptors, MRs). Since most MRs are immune receptors, they are all commonly referred to as multichain immune recognition receptors (MIRRs). Recent studies reveal that, in contrast to well-structured signaling domains of SRs, those of MIRRs represent intrinsically disordered regions, the regions that lack a well-defined threedimensional structure under physiological conditions. Why did nature separate recognition and signaling functions of MIRRs? Why for MIRRs did nature select to provide highly specific signaling through the chaos of protein disorder? What mechanisms could control this chaos in the process of transmembrane signal transduction to provide the specificity and diversity of the immune response? Here, I summarize recent findings that may not only shed light on these and other questions but also add significantly to our understanding of receptor signaling, a fundamental process that plays a critical role in health and disease.

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HIV-1 fusion peptide targets the TCR and inhibits antigen-specific T cell activation

Cited by 62 publications

References 59 publications

Conserved Salt Bridge between the N- and C-Terminal Heptad Repeat Regions of the Human Immunodeficiency Virus Type 1 gp41 Core Structure Is Critical for Virus Entry and Inhibition

Conserved Salt Bridge between the N- and C-Terminal Heptad Repeat Regions of the Human Immunodeficiency Virus Type 1 gp41 Core Structure Is Critical for Virus Entry and Inhibition

The SCHOOL of nature: II. Protein order, disorder, and oligomericity in transmembrane signaling

Cells diversify transmembrane signaling through the controlled chaos of protein disorder

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