Abstract
The human immunodeficiency virus, type 1 (HIV-1) gp41 core plays an important role in fusion between viral and target cell membranes. A single chain polypeptide, N36(L8)C34, which forms a six-helix bundle in physiological solution, can be used as a model of gp41 core. Here we identified from a 12-mer phage peptide library a positive phage clone displaying a peptide sequence with high binding activity to the HIV-1 gp41 core. The peptide sequence contains a putative gp41-binding motif, PhiXXXXPhiXPhi (X is any amino acid residue, and Phi is any one of the aromatic amino acid residues Trp, Phe, or Tyr). This motif also exists in the scaffolding domain of caveolin-1 (Cav-1), a known gp41-binding protein. Cav-1-(61-101) and Cav-1-(82-101), two recombinant fusion proteins containing the Cav-1 scaffolding domain, bound significantly to the gp41 expressed in mammalian cells and interacted with the polypeptide N36(L8)C34. These results suggest that the scaffolding domain of Cav-1 may bind to the gp41 core via the motif. This interaction may be essential for formation of fusion pore or endocytosis of HIV-1 and affect the pathogenesis of HIV-1 infection. Further characterization of the gp41 core-binding motifs may shed light on the alternative mechanism by which HIV-1 enters into the target cell.
Highlights
CCR5) (2), resulting in a series of conformational changes of the Env transmembrane subunit gp41, i.e. insertion of the gp41 N-terminal fusion peptide into the target cell membrane, and association between the N- and C-terminal heptad repeat (NHR and CHR, respectively) regions to form a six-helix bundle (6-HB; known as trimer-of-hetero-dimers or trimer-ofhairpins) consisting of three NHR helices as the central trimeric coiled-coil domain and three CHR helices as the outer coiledcoil layer (3–5)
The single chain polypeptide N36(L6)C34 in which the C terminus of N36 is connected to the N terminus of C34 by a 6-amino acid linker (SGGRGG) could form the trimer-ofhairpins structure (8)
It is speculated that gp41 core may participate in the formation of the fusion pore in the target cell membrane (14)
Summary
CCR5) (2), resulting in a series of conformational changes of the Env transmembrane subunit gp41, i.e. insertion of the gp41 N-terminal fusion peptide into the target cell membrane, and association between the N- and C-terminal heptad repeat (NHR and CHR, respectively) regions to form a six-helix bundle (6-HB; known as trimer-of-hetero-dimers or trimer-ofhairpins) consisting of three NHR helices as the central trimeric coiled-coil domain and three CHR helices as the outer coiledcoil layer (3–5). To deter- gp41 and the control CHO-EE cells, which express no Env, mine whether this sequence is responsible for binding of the respectively, were incubated with 5 g/ml of soluble CD4 at phage clone gcb-1 to N36(L8)C34, we synthesized a peptide, 37 °C for 30 min to induce shedding of gp120 and an designated JCH-1, containing this sequence (Table 1) and increased exposure of gp41 (20).
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