Influenza AM2 Channel Oligomerization Is Sensitive to Its Chemical Environment

Area of Science:

• Virology
• Structural Biology
• Biophysics

Background:

• Viroporins are viral ion channels crucial for infection and are established antiviral drug targets.
• Influenza A matrix protein 2 (AM2) is a well-studied viroporin, previously thought to form only tetrameric structures.

Purpose of the Study:

• To investigate the oligomeric state of the full-length and transmembrane (TM) domain of AM2.
• To determine how environmental factors, including pH, detergents, and lipids, influence AM2 oligomerization.
• To measure amantadine binding to AM2 within a lipid bilayer environment.

Main Methods:

• Native mass spectrometry was employed to characterize AM2 oligomeric complexes.
• AM2 was studied in various pH and detergent conditions, as well as within nanodiscs containing different lipids.
• Amantadine binding stoichiometry was measured using nanodiscs.

Main Results:

• AM2 forms a spectrum of oligomeric complexes, deviating from the established tetramer model.
• Oligomeric states are significantly modulated by the local chemical environment, including lipids within nanodiscs.
• Nanodiscs facilitated direct measurement of amantadine binding to AM2 in a native-like lipid bilayer.

Conclusions:

• The oligomeric plasticity of AM2 is broader than previously understood, challenging existing paradigms.
• Environmental factors critically influence AM2 structure and function, suggesting new avenues for antiviral strategies.
• These findings offer novel insights into influenza virus pathology and potential drug development targets.