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Biochemistry
2010 Nov 30;4947:10061-71. doi: 10.1021/bi101229m.
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A pH-dependent conformational ensemble mediates proton transport through the influenza A/M2 protein.
Polishchuk AL
,
Lear JD
,
Ma C
,
Lamb RA
,
Pinto LH
,
Degrado WF
.
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The influenza A/M2 protein exhibits inwardly rectifying, pH-activated proton transport that saturates at low pH. A comparison of high-resolution structures of the transmembrane domain at high and low pH suggests that pH-dependent conformational changes may facilitate proton conduction by alternately changing the accessibility of the N-terminal and C-terminal regions of the channel as a proton transits through the transmembrane domain. Here, we show that M2 functionally reconstituted in liposomes populates at least three different conformational states over a physiologically relevant pH range, with transition midpoints that are consistent with previously reported His37 pK(a) values. We then develop and test two similar, quantitative mechanistic models of proton transport, where protonation shifts the equilibrium between structural states having different proton affinities and solvent accessibilities. The models account well for a collection of experimental data sets over a wide range of pH values and voltages and require only a small number of adjustable parameters to accurately describe the data. While the kinetic models do not require any specific conformation for the protein, they nevertheless are consistent with a large body of structural information based on high-resolution nuclear magnetic resonance and crystallographic structures, optical spectroscopy, and molecular dynamics calculations.
Acharya,
Structure and mechanism of proton transport through the transmembrane tetrameric M2 protein bundle of the influenza A virus.
2010, Pubmed,
Xenbase
Acharya,
Structure and mechanism of proton transport through the transmembrane tetrameric M2 protein bundle of the influenza A virus.
2010,
Pubmed
,
Xenbase
Balannik,
Functional studies and modeling of pore-lining residue mutants of the influenza a virus M2 ion channel.
2010,
Pubmed
,
Xenbase
Bright,
Adamantane resistance among influenza A viruses isolated early during the 2005-2006 influenza season in the United States.
2006,
Pubmed
Cady,
Structure of the amantadine binding site of influenza M2 proton channels in lipid bilayers.
2010,
Pubmed
Chen,
The influenza virus M2 protein cytoplasmic tail interacts with the M1 protein and influences virus assembly at the site of virus budding.
2008,
Pubmed
Chizhmakov,
Differences in conductance of M2 proton channels of two influenza viruses at low and high pH.
2003,
Pubmed
Chizhmakov,
Selective proton permeability and pH regulation of the influenza virus M2 channel expressed in mouse erythroleukaemia cells.
1996,
Pubmed
Czabotar,
Studies of structural changes in the M2 proton channel of influenza A virus by tryptophan fluorescence.
2004,
Pubmed
DAVIES,
ANTIVIRAL ACTIVITY OF 1-ADAMANTANAMINE (AMANTADINE).
1964,
Pubmed
Decoursey,
Voltage-gated proton channels and other proton transfer pathways.
2003,
Pubmed
Dvorin,
Conformational properties of human and rat apolipoprotein A-IV.
1985,
Pubmed
Gouaux,
Principles of selective ion transport in channels and pumps.
2005,
Pubmed
Grambas,
Maturation of influenza A virus hemagglutinin--estimates of the pH encountered during transport and its regulation by the M2 protein.
1992,
Pubmed
Holsinger,
Influenza A virus M2 ion channel protein: a structure-function analysis.
1994,
Pubmed
,
Xenbase
Hu,
Backbone structure of the amantadine-blocked trans-membrane domain M2 proton channel from Influenza A virus.
2007,
Pubmed
Hu,
Histidines, heart of the hydrogen ion channel from influenza A virus: toward an understanding of conductance and proton selectivity.
2006,
Pubmed
Khurana,
Molecular dynamics calculations suggest a conduction mechanism for the M2 proton channel from influenza A virus.
2009,
Pubmed
Kolocouris,
Design and synthesis of bioactive adamantane spiro heterocycles.
2007,
Pubmed
Ladokhin,
How to measure and analyze tryptophan fluorescence in membranes properly, and why bother?
2000,
Pubmed
Lear,
Proton conduction through the M2 protein of the influenza A virus; a quantitative, mechanistic analysis of experimental data.
2003,
Pubmed
Levitt,
Interpretation of biological ion channel flux data--reaction-rate versus continuum theory.
1986,
Pubmed
Li,
Solid-state NMR characterization of conformational plasticity within the transmembrane domain of the influenza A M2 proton channel.
2007,
Pubmed
Lin,
Definitive assignment of proton selectivity and attoampere unitary current to the M2 ion channel protein of influenza A virus.
2001,
Pubmed
Ma,
Identification of the functional core of the influenza A virus A/M2 proton-selective ion channel.
2009,
Pubmed
,
Xenbase
MacKinnon,
Potassium channels.
2003,
Pubmed
Miller,
ClC chloride channels viewed through a transporter lens.
2006,
Pubmed
Moffat,
Proton transport through influenza A virus M2 protein reconstituted in vesicles.
2008,
Pubmed
Mould,
Mechanism for proton conduction of the M(2) ion channel of influenza A virus.
2000,
Pubmed
,
Xenbase
Nguyen,
pH-induced conformational change of the influenza M2 protein C-terminal domain.
2008,
Pubmed
,
Xenbase
Nishimura,
The closed state of a H+ channel helical bundle combining precise orientational and distance restraints from solid state NMR.
2002,
Pubmed
Ohigashi,
An amantadine-sensitive chimeric BM2 ion channel of influenza B virus has implications for the mechanism of drug inhibition.
2009,
Pubmed
Pielak,
Mechanism of drug inhibition and drug resistance of influenza A M2 channel.
2009,
Pubmed
Pinto,
A functionally defined model for the M2 proton channel of influenza A virus suggests a mechanism for its ion selectivity.
1997,
Pubmed
,
Xenbase
Pinto,
The M2 proton channels of influenza A and B viruses.
2006,
Pubmed
Pinto,
Influenza virus M2 protein has ion channel activity.
1992,
Pubmed
,
Xenbase
Sansom,
The influenza A virus M2 channel: a molecular modeling and simulation study.
1997,
Pubmed
Schnell,
Structure and mechanism of the M2 proton channel of influenza A virus.
2008,
Pubmed
Schroeder,
Functional reconstitution in lipid vesicles of influenza virus M2 protein expressed by baculovirus: evidence for proton transfer activity.
1994,
Pubmed
Shimbo,
Ion selectivity and activation of the M2 ion channel of influenza virus.
1996,
Pubmed
,
Xenbase
Skehel,
Receptor binding and membrane fusion in virus entry: the influenza hemagglutinin.
2000,
Pubmed
Stouffer,
Structural basis for the function and inhibition of an influenza virus proton channel.
2008,
Pubmed
Tang,
The gate of the influenza virus M2 proton channel is formed by a single tryptophan residue.
2002,
Pubmed
,
Xenbase
Wang,
Activation of the M2 ion channel of influenza virus: a role for the transmembrane domain histidine residue.
1995,
Pubmed
,
Xenbase
Wang,
Direct measurement of the influenza A virus M2 protein ion channel activity in mammalian cells.
1994,
Pubmed
Wang,
Ion channel activity of influenza A virus M2 protein: characterization of the amantadine block.
1993,
Pubmed
,
Xenbase
Wang,
Discovery of spiro-piperidine inhibitors and their modulation of the dynamics of the M2 proton channel from influenza A virus.
2009,
Pubmed
,
Xenbase
Yi,
Conformational heterogeneity of the M2 proton channel and a structural model for channel activation.
2009,
Pubmed
Zhirnov,
Solubilization of matrix protein M1/M from virions occurs at different pH for orthomyxo- and paramyxoviruses.
1990,
Pubmed
Zhou,
Diffusion-Influenced Transport of Ions across a Transmembrane Channel with an Internal Binding Site.
2010,
Pubmed
