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A peptide from the heptad repeat of human immunodeficiency virus gp41 shows both membrane binding and coiled-coil

M Rabenstein1, Y K Shin

  • 1Department of Chemistry, University of California, Berkeley 94720, USA.

Biochemistry
|October 17, 1995
PubMed

Insights

The heptad repeat of human immunodeficiency virus type 1 (HIV-1) envelope glycoprotein gp41 forms a coiled coil and binds to host cell membranes, facilitating viral entry. Mutations destabilizing the coiled coil reduce membrane binding.

Area of Science:

  • Structural biology
  • Virology
  • Biophysics

Background:

  • The envelope glycoprotein gp41 of HIV-1 mediates viral entry through membrane fusion.
  • A critical leucine zipper-like heptad repeat region (residues 553-590) in gp41 is essential for its function.
  • Understanding the structure and membrane interactions of this region is key to HIV-1 inhibition.

Purpose of the Study:

  • To investigate the solution structure and membrane-binding properties of the gp41 heptad repeat region.
  • To determine how mutations affecting coiled-coil stability impact membrane binding.
  • To elucidate the dual role of the heptad repeat in viral fusion.

Main Methods:

  • Synthesis and nitroxide spin labeling of cysteine-substituted peptide variants.
  • Analytical equilibrium ultracentrifugation to study solution structure.
  • Electron paramagnetic resonance (EPR) to assess membrane binding to lipid vesicles.
  • Site-directed mutagenesis to probe coiled-coil stability and membrane affinity.

Main Results:

  • The 38-residue peptide exists primarily as a tetramer in solution, unlike the gp160 protein.
  • EPR showed peptides bind to negatively charged lipid vesicles, adopting a monomeric structure parallel to the membrane surface.
  • Mutations at the core 'a' position destabilized the coiled coil and reduced membrane-binding affinity.

Conclusions:

  • The gp41 heptad repeat functions in two ways: forming a coiled coil and presenting a hydrophobic face for membrane binding.
  • Destabilization of the coiled coil correlates with decreased membrane binding.
  • These findings support a model where the heptad repeat brings viral and cellular membranes together to facilitate fusion.

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