title: Histidines, heart of the hydrogen ion channel from influenza A virus: toward an understanding of conductance and proton selectivity.
abstract: The heart of the H+ conductance mechanism in the homotetrameric M2 H+ channel from influenza A is a set of four histidine side chains. Here, we show that protonation of the third of these imidazoles coincides with acid activation of this transmembrane channel and that, at physiological pH, the channel is closed by two imidazole-imidazolium dimers, each sharing a low-barrier hydrogen bond. This unique construct succeeds in distributing a pair of charges over four rings and many atoms in a low dielectric environment to minimize charge repulsion. These dimers form with identical pKas of 8.2 +/- 0.2, suggesting cooperative H+ binding and clearly illustrating high H+ affinity for this channel. The protonation behavior of the histidine side chains has been characterized by using solid-state NMR spectroscopy on the M2 transmembrane domain in fully hydrated lipid bilayers where the tetrameric backbone structure is known. Furthermore, electrophysiological measurements of multichannel and single-channel experiments confirm that these protein constructs are functional.
authors.affiliation: Department of Chemistry and Biochemistry, Florida State University, Tallahassee, FL 32310, USA.
authors.forename: Jun
authors.initials: J
authors.lastname: Hu
authors.forename: Riqiang
authors.initials: R
authors.lastname: Fu
authors.forename: Katsuyuki
authors.initials: K
authors.lastname: Nishimura
authors.forename: Li
authors.initials: L
authors.lastname: Zhang
authors.forename: Huan-Xiang
authors.initials: HX
authors.lastname: Zhou
authors.forename: David D
authors.initials: DD
authors.lastname: Busath
authors.forename: Viksita
authors.initials: V
authors.lastname: Vijayvergiya
authors.forename: Timothy A
authors.initials: TA
authors.lastname: Cross
mesh_terms: D019281:Dimerization; D006639:Histidine / Q000737:chemistry / Q000378:metabolism*; D006860:Hydrogen Bonding; D007093:Imidazoles / Q000737:chemistry; D015394:Molecular Structure; D019906:Nuclear Magnetic Resonance, Biomolecular; D020836:Protein Structure, Quaternary; D011522:Protons; D014763:Viral Matrix Proteins / Q000737:chemistry* / Q000378:metabolism; D000086082:Viroporin Proteins
chemical_list: D006639:Histidine; D007093:Imidazoles; D011522:Protons; D014763:Viral Matrix Proteins; C488937:M2 protein, Influenza A virus; D000086082:Viroporin Proteins