title: Asp44 stabilizes the Trp41 gate of the M2 proton channel of influenza A virus.
abstract: Channel gating and proton conductance of the influenza A virus M2 channel result from complex pH-dependent interactions involving the pore-lining residues His37, Trp41, and Asp44. Protons diffusing from the outside of the virus protonate His37, which opens the Trp41 gate and allows one or more protons to move into the virus interior. The Trp41 gate gives rise to a strong asymmetry in the conductance, favoring rapid proton flux only when the outside is at acid pH. Here, we show that the proton currents recorded for mutants of Asp44, including D44N found in the A/FPV/Rostock/34 strain, lose this asymmetry. Moreover, NMR and MD simulations show that the mutations induce a conformational change similar to that induced by protonation of His37 at low pH, and decrease the structural stability of the hydrophobic seal associated with the Trp41 gate. Thus, Asp44 is able to determine two important properties of the M2 proton channel.
authors.affiliation: Department of Neurobiology, Northwestern University, Evanston, IL 60208-3500, USA; Department of Molecular Biosciences, Northwestern University, Evanston, IL 60208-3500, USA.
authors.forename: Chunlong
authors.initials: C
authors.lastname: Ma
authors.forename: Giacomo
authors.initials: G
authors.lastname: Fiorin
authors.forename: Vincenzo
authors.initials: V
authors.lastname: Carnevale
authors.forename: Jun
authors.initials: J
authors.lastname: Wang
authors.forename: Robert A
authors.initials: RA
authors.lastname: Lamb
authors.forename: Michael L
authors.initials: ML
authors.lastname: Klein
authors.forename: Yibing
authors.initials: Y
authors.lastname: Wu
authors.forename: Lawrence H
authors.initials: LH
authors.lastname: Pinto
authors.forename: William F
authors.initials: WF
authors.lastname: DeGrado
mesh_terms: D020816:Amino Acid Motifs; D000595:Amino Acid Sequence; D019943:Amino Acid Substitution; D000818:Animals; D001224:Aspartic Acid / Q000737:chemistry; D002478:Cells, Cultured; D006863:Hydrogen-Ion Concentration; D009980:Influenza A virus; D008564:Membrane Potentials; D056004:Molecular Dynamics Simulation; D008969:Molecular Sequence Data; D019906:Nuclear Magnetic Resonance, Biomolecular; D009865:Oocytes / Q000502:physiology; D018408:Patch-Clamp Techniques; D055550:Protein Stability; D017434:Protein Structure, Tertiary; D014364:Tryptophan / Q000737:chemistry; D014763:Viral Matrix Proteins / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D014982:Xenopus laevis; D000086082:Viroporin Proteins
chemical_list: D001224:Aspartic Acid; D014364:Tryptophan; D014763:Viral Matrix Proteins; C488937:M2 protein, Influenza A virus; D000086082:Viroporin Proteins