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Matrix protein, M2, an acid activated drug-sensitive proton channel.  Transport involves binding to the four His-37s and transfer to water molecules on the inside of the channel (Acharya et al., 2010).  Functional properties and structure are known (Hong and Degrado 2012). The cytoplasmic tail facilitates proton conduction (Liao et al. 2015).  It is a dimer of dimers (Andreas et al. 2015).  The four TMSs flanking the channel lumen alone seem to determine the proton conduction mechanism (Liang et al. 2016). His-37 forms a planar tetrad in the configuration of the bundle accepting and translocating the incoming protons from the N terminal side, exterior of the virus, to the C terminal side, inside the virus (Kalita and Fischer 2017). The cholesterol binding site in M2 that mediates membrane scission in a cholesterol-dependent manner to cause virus budding and release has been identified (Elkins et al. 2017).Transport-related conformational changes coupled to water and H+ movements have been studied (Mandala et al. 2018). The L46P mutant confers a novel allosteric mechanism of resistance towards the influenza A virus M2 S31N proton channel blockers (Musharrafieh et al. 2019). The C-terminal domain of M2 may serve as a sensor that regulates how M2 participates in critical events in the viral infection cycle (Kim et al. 2019). The M2 proton channel protein  self-assembles into tetramers that retain the ability to bind to the drug amantadine, and the effects of phospholipid acyl chain length and cholesterol on the peptide association were investigated. Association of the helices depends on the thickness of the bilayer and cholesterol levels present in the phospholipid bilayer. The most favorable folding occurred when there was a good match between the width of the apolar region of the bilayer and the hydrophobic length of the transmembrane helix with tighter association upon inclusion of cholesterol in the lipid bilayer (Cristian et al. 2003).

M2 of influenza virus type A

Matrix protein M2 of 96 aas and 1 TMS.  Forms a proton-selective ion channel that is necessary for the efficient release of the viral genome during virus entry. After attaching to the cell surface, the virion enters the cell by endocytosis. Acidification of the endosome triggers M2 ion channel activity. The influx of protons into the virion interior is believed to disrupt interactions between the viral ribonucleoprotein (RNP), matrix protein 1 (M1), and lipid bilayers, thereby freeing the viral genome from interaction with viral proteins and enabling RNA segments to migrate to the host cell nucleus, where influenza virus RNA transcription and replication occur. Also plays a role in viral proteins secretory pathway. The cytoplasmic tail of Influenza A virus hemagglutinin and membrane lipid composition change the mode of M1 protein association with the lipid bilayer (Kordyukova et al. 2021). Universal scFv antibodies against the influenza M2 protein have been prepaired (Kumar et al. 2023).



M2 of Influenza A virus (A/flat-faced bat/Peru)

Matrix protein 2, M2, of 80 aas and 1 TMS. The influenza virus ion channel and maturation cofactor M2 is a cholesterol-binding protein and M2 may promote clustering, merger of rafts and the pinching-off (fission) of virus particles (Schroeder et al. 2005).

M2 of Influenza A virus (A/swine)

M2 protein of 95 aas and 1 TMS, AM2.  This protein shows 28% identity, 50% similarity and 10% gaps with BM2 (TC# 1.B.58.1.1) with residues 8 - 65 aligning with residues 26 - 81. AM2 forms a range of oligomeric complexes that are strongly influenced by the local chemical environment. Native mass spectrometry of AM2 in nanodiscs with different lipids showed that lipids also affected the oligomeric states of AM2. Finally, nanodiscs uniquely enabled the measurement of amantadine binding stoichiometries to AM2 in the intact lipid bilayer (Townsend et al. 2021).

  AM2 of Influenza A virus (A/herring gull/Newfoundland)

Protein of 489 aas with C-terminal region resembling the M2 protein (33% identity with no gaps).

Protein of Apis mellifera filamentous virus