The mechanism of inhibition of HIV-1 env-mediated cell-cell fusion by recombinant cores of gp41 ectodomain

Ruben M. Markosyan, Xiuwen Ma, Min Lu, Fredric S. Cohen, Grigory B. Melikyan

Research output: Contribution to journalArticlepeer-review

22 Scopus citations

Abstract

N36(L6)C34 is a recombinant protein that forms a six-helix bundle with high thermal stability. It consists of the N-terminal heptad-repeat region (N36 peptide) and the C-terminal heptad-repeat region (C34) of HIV-1 gp41, connected by six polar amino acids. The protein inhibits HIV-1 envelope-induced membrane fusion. Whether inhibition occurs while N36(L6)C34 is in its six-helix bundle configuration was investigated. Mutating a critical residue within the N36 region to promote dissociation of C34 from the grooves of the N36 coiled coil reduced bundle stability and increased the inhibition of fusion. In contrast, mutating a key residue within the C34 region to reduce bundle stability decreased inhibitory potency. The data provide strong evidence that the proteins inhibit fusion while they expose their C34 segments, rather than as six-helix bundles. Thus, despite high thermal stability of the bundle, the recombinants' less folded structures are present in sufficient concentration to inhibit fusion at physiological temperatures.

Original languageEnglish (US)
Pages (from-to)174-184
Number of pages11
JournalVirology
Volume302
Issue number1
DOIs
StatePublished - 2002
Externally publishedYes

ASJC Scopus subject areas

  • Virology

Keywords

  • Fluorescence microscopy
  • Fusion inhibitory peptides
  • Fusion intermediates
  • Membrane fusion
  • Six-helix bundle
  • Thermal unfolding

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