M2 protein from Influenza A: from multiple structures to biophysical and functional insights

The M2 protein from influenza A is a proton channel as a tetramer, with a single transmembrane helix from each monomer lining the pore. Val27 and Trp41 form gates at either end of the pore and His37 mediates the shuttling of protons across a central barrier between the N-terminal and C-terminal aqueous pore regions. Numerous structures of this transmembrane domain and of a longer construct that includes an amphipathic helix are now in the Protein Data Bank. Many structural differences are apparent from samples obtained in a variety of membrane mimetic environments. High-resolution structural results in lipid bilayers have provided novel insights into the functional mechanism of the unique HxxxW cluster in the M2 proton channel.

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► Characterization of M2 in lipid bilayers has revealed a native-like structure.
► The tetrameric M2 structure is a dimer of dimer conformation in the +2 charged state.
► The functionally significant amantadine and rimantadine binding sites is in the pore.
► The M2 structure from influenza A is sensitive to its membrane mimetic environment.
► A mathematical model for M2 H+ transport is consistent with much conductance data.