The gate of the influenza virus M2 proton channel is formed by a single tryptophan residue

The influenza virus M-2 proton-selective ion channel is known to be essential for acidifying the interior of virions during virus uncoating in the lumen of endosomes. The M-2 protein is a homotetramer that contains four 19-residue transmembrane (TM) domains. These TM domains are multifunctional, because they contain the channel pore and also anchor the protein in membranes. The M-2 protein is gated by pH, and thus we have measured pH-gated currents, the accessibility of the pore to Cu2+, and the effect of a protein-modifying reagent for a series of TM domain mutant M-2 proteins. The results indicate that gating of the M-2 ion channel is governed by a single side chain at residue 41 of the TM domain and that this property is mediated by an indole moiety. Unlike many ion channels where the gate is formed by a whole segment of a protein, our data suggest a model of striking simplicity for the M-2 ion channel protein, with the side chain of Trp(41) blocking the pore of the M-2 channel when pH(out) is high and with this side chain leaving the pore when pH(out) is low. Thus, the Trp(41) side chain acts as the gate that opens and closes the pore.