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Functional studies reveal the similarities and differences between AM2 and BM2 proton channels from influenza viruses
1BIO5 Institute, The University of Arizona, Tucson, AZ 85721, United States.
Abstract:
AM2 and BM2 proton channels are attractive antiviral drug targets due to their essential roles during influenza virus replication. Although both AM2 and BM2 are proton-selective ion channels, they share little sequence similarity except for the HXXXW sequence, which suggests that their proton conductance properties might differ. To test this hypothesis, we applied two-electrode voltage clamp electrophysiological assays to study the specific conductance, leakage current, channel activation, and inhibition of AM2 and BM2 proton channels. It was found that BM2 channel has a higher specific conductance than AM2 channel at pH5.5. Unlike AM2 channel, whose proton conductance is asymmetric (from viral exterior to interior), BM2 channel is capable of conducting proton in both directions. Moreover, BM2 requires a more acidic pH for channel activation than AM2, as revealed by its lower pKa values. Finally, both AM2 and BM2 can be inhibited by Cu(II) and Cu(I). Overall, the results from this side-by-side comparison of AM2 and BM2 channels reveal the structure-function relationships of these two viroporins, and such information might be important for the designing of novel ion channels.
Insights
Influenza virus AM2 and BM2 proton channels exhibit distinct conductance properties and activation requirements. This comparative study reveals crucial structure-function insights for developing new antiviral drugs targeting these viroporins.
Area of Science:
- Virology
- Biophysics
- Drug Discovery
Background:
- AM2 and BM2 are essential proton channels for influenza virus replication.
- These viroporins share limited sequence homology, suggesting functional differences.
Purpose of the Study:
- To comparatively analyze the biophysical properties of AM2 and BM2 proton channels.
- To investigate their conductance, activation, and inhibition characteristics.
Main Methods:
- Two-electrode voltage clamp electrophysiology was employed.
- Specific conductance, leakage current, channel activation, and inhibition were measured.
Main Results:
- BM2 channel exhibits higher specific conductance than AM2.
- BM2 conducts protons bidirectionally, while AM2 is asymmetric.
- BM2 requires more acidic pH for activation (lower pKa) compared to AM2.
- Both channels are inhibited by Cu(II) and Cu(I).
Conclusions:
- Significant functional differences exist between AM2 and BM2 proton channels.
- Understanding these structure-function relationships is vital for designing novel antiviral agents targeting viroporins.
