title: How pH opens a H+ channel: the gating mechanism of influenza A M2.
abstract: The tetrameric M2 protein from influenza A is one of the simplest pH-gated H+ channels known, offering the potential of structurally characterizing its gating mechanism. Since the only ionizable groups in the pore are four histidines, we investigated the stability and dynamics of all six possible protonation states of the protein by using molecular dynamics. We show that while all channel protonation states are surprisingly stable, only systems with two or more charged histidines are appreciably conductive. The structural switch, from a uniprotonated to a biprotonated channel, causes an electrostatic repulsion between the charged histidines that pushes the helices apart. This results in the formation of a continuous water file that conducts protons via a H+ wire. pKa calculations place this transition at a pH of 5.6, in remarkable agreement with the experimental value. Since the conversion from uniprotonation to biprotonation occurs during endosome acidification, this explains how M2 is activated in vivo.
authors.affiliation: Department of Biological Chemistry, The Alexander Silberman Institute of Life Sciences, The Hebrew University of Jerusalem, Edmond J. Safra Campus, Givat-Ram, Jerusalem, 91904, Israel.
authors.forename: Itamar
authors.initials: I
authors.lastname: Kass
authors.forename: Isaiah T
authors.initials: IT
authors.lastname: Arkin
mesh_terms: D006639:Histidine / Q000737:chemistry; D006863:Hydrogen-Ion Concentration; D015640:Ion Channel Gating; D007473:Ion Channels / Q000737:chemistry* / Q000378:metabolism; D008566:Membranes / Q000737:chemistry; D011487:Protein Conformation; D011522:Protons; D014763:Viral Matrix Proteins / Q000737:chemistry* / Q000378:metabolism; D014867:Water / Q000737:chemistry / Q000378:metabolism; D000086082:Viroporin Proteins
chemical_list: D006639:Histidine; D007473:Ion Channels; D011522:Protons; D014763:Viral Matrix Proteins; D014867:Water; C488937:M2 protein, Influenza A virus; D000086082:Viroporin Proteins