Intramolecular complementation of measles virus fusion protein stability confers cell-cell fusion activity at 37 °C

Area of Science:

• Virology
• Molecular Biology
• Structural Biology

Background:

• The measles virus fusion (F) protein is essential for viral entry into host cells.
• Understanding the F protein's mechanism is crucial for developing antiviral strategies.

Purpose of the Study:

• To investigate the molecular mechanisms underlying measles virus F protein-mediated cell-cell fusion.
• To identify specific mutations affecting F protein stability and fusion activity.

Main Methods:

• Site-directed mutagenesis was used to introduce specific amino acid substitutions into the F protein.
• Cell-cell fusion assays were performed to quantify the fusion activity of mutant F proteins.
• Thermodynamic stability of the F protein was assessed under different temperature conditions.

Main Results:

• A substitution (N465H) in the stalk region (heptad repeat B) abolished F protein fusion activity.
• Five distinct mutations in the DIII domain of the head region restored fusion activity.
• The N465H mutation stabilized the F protein, requiring higher temperatures (40 °C) for fusion, while DIII mutations destabilized it, enabling fusion at lower temperatures (30 °C).
• Complementation of stability between the stalk and head domains resulted in efficient fusion at physiological temperature (37 °C).

Conclusions:

• The stability of the measles virus F protein is a critical determinant of its cell-cell fusion activity.
• Interplay between the stalk and head regions of the F protein regulates its fusion capability.
• Targeting F protein stability offers a potential strategy for controlling measles virus infection.