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Variable sensitivity to substitutions in the N-terminal heptad repeat of Mason-Pfizer monkey virus transmembrane

Chisu Song1, Eric Hunter

  • 1Department of Microbiology and Center for AIDS Research, University of Alabama at Birmingham, 845 19th Street S., Birmingham, AL 35294, USA.

Journal of Virology
|June 28, 2003
PubMed

Insights

The N-terminal heptad repeat of Mason-Pfizer monkey virus envelope protein is critical for membrane fusion. Central hydrophobic residues are key for Env function, with charge substitutions significantly impacting viral infectivity.

Area of Science:

  • Virology
  • Molecular Biology
  • Structural Biology

Background:

  • The Mason-Pfizer monkey virus (MPMV) transmembrane envelope protein (Env) is essential for viral entry.
  • Heptad repeats within the Env protein are predicted to mediate membrane fusion through conformational changes.
  • Understanding the role of specific residues in these heptad repeats is crucial for deciphering the viral fusion mechanism.

Purpose of the Study:

  • To investigate the functional significance of the N-terminal heptad repeat in MPMV Env-mediated membrane fusion.
  • To determine the sensitivity of specific residues within the heptad repeat to various amino acid substitutions (alanine, serine, glutamic acid).
  • To analyze the impact of these mutations on viral infectivity and Env function.

Main Methods:

  • Site-directed mutagenesis was used to introduce alanine, serine, or glutamic acid substitutions at positions 436, 443, 450, and 457 of the MPMV Env protein.
  • Novel assay systems utilizing Tat protein and the GHOST cell line were developed to quantify Env-mediated fusion and viral infectivity.
  • Analysis of glycoprotein complex synthesis, processing, and plasma membrane transport was performed.

Main Results:

  • No significant interference with glycoprotein complex synthesis, processing, or transport was observed for single amino acid changes.
  • Nine out of 12 nonconservative mutations in the targeted heptad repeat residues completely abolished fusion activity and virus infectivity.
  • Mutations at central positions (443 and 450) were most detrimental, with even single alanine substitutions dramatically reducing fusogenicity.

Conclusions:

  • The N-terminal heptad repeat of MPMV Env plays a critical role in mediating membrane fusion.
  • Central hydrophobic residues within this heptad repeat are essential for Env function.
  • All positions within the heptad repeat exhibit sensitivity to charge substitutions, highlighting their importance in the fusion process.

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