Mutations in the putative dimer-dimer interfaces of the measles virus hemagglutinin head domain affect membrane...

Area of Science:

• Virology
• Structural Biology
• Molecular Biology

Background:

• Measles virus (MV) entry relies on hemagglutinin (H) and fusion (F) proteins.
• MV-H protein forms tetramers (dimer of dimers) in two distinct structural forms.
• Understanding MV-H's structural dynamics is crucial for viral entry mechanisms.

Purpose of the Study:

• To investigate the role of the MV-H head domain's dimer-dimer interface in membrane fusion.
• To determine if specific tetramer interfaces are essential for MV-H function.
• To explore the contribution of head domain tetramerization to viral entry.

Main Methods:

• Site-directed mutagenesis of the MV-H head domain dimer-dimer interface.
• Functional assays measuring MV-H-mediated membrane fusion.
• Analysis of MV-H cell surface expression, receptor binding, and F protein interaction.
• Epitope mapping of neutralizing antibodies.

Main Results:

• Mutations at the dimer-dimer interface impaired MV-H's ability to support membrane fusion.
• These mutations did not significantly affect cell surface expression, receptor binding, or F protein interaction.
• Some neutralizing antibodies targeted the form I dimer-dimer interface, not receptor-binding sites.
• The MV-H head domain can form tetramers independently, though less efficiently.

Conclusions:

• Dimer-dimer interactions within the MV-H head domain tetramer, particularly in form I, are critical for triggering membrane fusion.
• Conformational changes in MV-H head domain tetramers are implicated in the fusion process.
• While stalk and transmembrane regions contribute to tetramerization, the head domain possesses intrinsic tetramerization capability.