A highly conserved gp120 inner domain residue modulates Env conformation and trimer stability

Shilei Ding, William D. Tolbert, Jérémie Prévost, Beatriz Pacheco, Mathieu Coutu, Olfa Debbeche, Shi-Hua Xiang, Marzena Pazgier, Andrés Finzi

Research output: Contribution to journalArticle

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Abstract

Previous studies have shown that highly conserved residues in the inner domain of gp120 are required for HIV-1 envelope glycoprotein (Env) transitions to the CD4-bound conformation (A. Finzi, S. H. Xiang, B. Pacheco, L. Wang, J. Haight, et al., Mol Cell 37:656-667, 2010, http://dx.doi.org/10.1016/j.molcel.2010.02.012; A. Desormeaux, M. Coutu, H. Medjahed, B. Pacheco, A. Herschhorn, et al., J Virol 87:2549-2562, 2013, http://dx.doi.org/10.1128/JVI.03104-12). Moreover, W69, a highly conserved residue located at the interface between layer 1 and layer 2 of the inner domain, was recently shown to be important for efficient Env recognition by CD4-induced (CD4i) antibodies capable of potent antibody-dependent cellular cytotoxicity (W. D. Tolbert, N. Gohain, M. Veillette, J. P. Chapleau, C. Orlandi, et al., 2016, Structure 24:697-709, http://dx.doi.org/10.1016/j.str.2016.03.005; S. Ding, M. Veillette, M. Coutu, J. Prevost, L. Scharf, et al., 2016, J Virol 90:2127-2134, http://dx.doi.org/10.1128/JVI.02779-15). We evaluated the contribution of the hydrophobicity of W69 to conformational changes of Env by replacing it with a series of residues with aliphatic or aromatic side chains of decreasing chain length. We have found that the hydrophobicity of residue 69 is important for Env processing, CD4 binding, and its transition to the CD4-bound conformation. The most deleterious effect was observed when W69 was replaced with alanine or glycine residues. However, the functions lost due to W69 mutations could be progressively restored with amino acids of increasing aliphatic chain length and fully recovered with residues bearing an aromatic ring. Interestingly, poor CD4 binding of W69A could be fully restored by introducing a compensatory mutation within layer 2 (S115W). Structural studies of HIV-1 gp120 coree W69A/S115W mutant bound to the CD4 peptide mimetic M48U1 and Fab of anti-cluster A antibody N60-i3 revealed no perturbations to the overall structure of the double mutant compared to the wild-type protein but identified higher mobility within the interface between layer 1 and layer 2, the bridging sheet region, and the CD4 binding site.

Original languageEnglish (US)
Pages (from-to)8395-8409
Number of pages15
JournalJournal of virology
Volume90
Issue number19
DOIs
StatePublished - Jan 1 2016

Fingerprint

Human immunodeficiency virus 1
hydrophobicity
Hydrophobic and Hydrophilic Interactions
antibodies
aromatic compounds
HIV-1
Antibodies
HIV Envelope Protein gp120
env Gene Products
mutation
mutants
Mutation
glycine (amino acid)
Alanine
Glycine
alanine
cytotoxicity
glycoproteins
binding sites
Binding Sites

ASJC Scopus subject areas

  • Microbiology
  • Immunology
  • Insect Science
  • Virology

Cite this

Ding, S., Tolbert, W. D., Prévost, J., Pacheco, B., Coutu, M., Debbeche, O., ... Finzi, A. (2016). A highly conserved gp120 inner domain residue modulates Env conformation and trimer stability. Journal of virology, 90(19), 8395-8409. https://doi.org/10.1128/JVI.01068-16

A highly conserved gp120 inner domain residue modulates Env conformation and trimer stability. / Ding, Shilei; Tolbert, William D.; Prévost, Jérémie; Pacheco, Beatriz; Coutu, Mathieu; Debbeche, Olfa; Xiang, Shi-Hua; Pazgier, Marzena; Finzi, Andrés.

In: Journal of virology, Vol. 90, No. 19, 01.01.2016, p. 8395-8409.

Research output: Contribution to journalArticle

Ding, S, Tolbert, WD, Prévost, J, Pacheco, B, Coutu, M, Debbeche, O, Xiang, S-H, Pazgier, M & Finzi, A 2016, 'A highly conserved gp120 inner domain residue modulates Env conformation and trimer stability', Journal of virology, vol. 90, no. 19, pp. 8395-8409. https://doi.org/10.1128/JVI.01068-16
Ding S, Tolbert WD, Prévost J, Pacheco B, Coutu M, Debbeche O et al. A highly conserved gp120 inner domain residue modulates Env conformation and trimer stability. Journal of virology. 2016 Jan 1;90(19):8395-8409. https://doi.org/10.1128/JVI.01068-16
Ding, Shilei ; Tolbert, William D. ; Prévost, Jérémie ; Pacheco, Beatriz ; Coutu, Mathieu ; Debbeche, Olfa ; Xiang, Shi-Hua ; Pazgier, Marzena ; Finzi, Andrés. / A highly conserved gp120 inner domain residue modulates Env conformation and trimer stability. In: Journal of virology. 2016 ; Vol. 90, No. 19. pp. 8395-8409.
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