Click here to close
Hello! We notice that you are using Internet Explorer, which is not supported by Xenbase and may cause the site to display incorrectly.
We suggest using a current version of Chrome,
FireFox, or Safari.
The interplay of functional tuning, drug resistance, and thermodynamic stability in the evolution of the M2 proton channel from the influenza A virus.
Stouffer AL
,
Ma C
,
Cristian L
,
Ohigashi Y
,
Lamb RA
,
Lear JD
,
Pinto LH
,
DeGrado WF
.
???displayArticle.abstract???
We explore the interplay between amino acid sequence, thermodynamic stability, and functional fitness in the M2 proton channel of influenza A virus. Electrophysiological measurements show that drug-resistant mutations have minimal effects on M2's specific activity, and suggest that resistance is achieved by altering a binding site within the pore rather than a less direct allosteric mechanism. In parallel, we measure the effects of these mutations on the free energy of assembling the homotetrameric transmembrane pore from monomeric helices in micelles and bilayers. Although there is no simple correlation between the evolutionary fitness of the mutants and their stability, all variants formed more stable tetramers in bilayers, and the least-fit mutants showed the smallest increase in stability upon moving from a micelle to a bilayer environment. We speculate that the folding landscape of a micelle is rougher than that of a bilayer, and more accommodating of conformational variations in nonoptimized mutants.
Abed,
Generation and characterization of recombinant influenza A (H1N1) viruses harboring amantadine resistance mutations.
2005, Pubmed
Abed,
Generation and characterization of recombinant influenza A (H1N1) viruses harboring amantadine resistance mutations.
2005,
Pubmed
Betakova,
Influence of residue 44 on the activity of the M2 proton channel of influenza A virus.
2005,
Pubmed
Beumer,
Whole-mount immunohistochemistry on Xenopus embryos using far-red fluorescent dyes.
1995,
Pubmed
,
Xenbase
Bowie,
Membrane proteins: a new method enters the fold.
2004,
Pubmed
Bowie,
Stabilizing membrane proteins.
2001,
Pubmed
Bright,
Incidence of adamantane resistance among influenza A (H3N2) viruses isolated worldwide from 1994 to 2005: a cause for concern.
2005,
Pubmed
Bright,
Adamantane resistance among influenza A viruses isolated early during the 2005-2006 influenza season in the United States.
2006,
Pubmed
Chen,
Proton transport behavior through the influenza A M2 channel: insights from molecular simulation.
2007,
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
Choma,
Asparagine-mediated self-association of a model transmembrane helix.
2000,
Pubmed
Ciampor,
Regulation of pH by the M2 protein of influenza A viruses.
1992,
Pubmed
Cristian,
Determination of membrane protein stability via thermodynamic coupling of folding to thiol-disulfide interchange.
2003,
Pubmed
Cristian,
Use of thiol-disulfide equilibria to measure the energetics of assembly of transmembrane helices in phospholipid bilayers.
2003,
Pubmed
Czabotar,
Studies of structural changes in the M2 proton channel of influenza A virus by tryptophan fluorescence.
2004,
Pubmed
Deyde,
Surveillance of resistance to adamantanes among influenza A(H3N2) and A(H1N1) viruses isolated worldwide.
2007,
Pubmed
Fernández,
Lipid-protein interactions in DHPC micelles containing the integral membrane protein OmpX investigated by NMR spectroscopy.
2002,
Pubmed
Fisher,
Detergents modulate dimerization, but not helicity, of the glycophorin A transmembrane domain.
1999,
Pubmed
Fleming,
Specificity in transmembrane helix-helix interactions can define a hierarchy of stability for sequence variants.
2001,
Pubmed
Fleming,
Thermodynamics of glycophorin A transmembrane helix dimerization in C14 betaine micelles.
2004,
Pubmed
Fleming,
The effect of point mutations on the free energy of transmembrane alpha-helix dimerization.
1997,
Pubmed
Gandhi,
Cu(II) inhibition of the proton translocation machinery of the influenza A virus M2 protein.
1999,
Pubmed
,
Xenbase
Grambas,
Influence of amantadine resistance mutations on the pH regulatory function of the M2 protein of influenza A viruses.
1992,
Pubmed
Gratkowski,
Polar side chains drive the association of model transmembrane peptides.
2001,
Pubmed
Hayden,
Antiviral resistance in influenza viruses--implications for management and pandemic response.
2006,
Pubmed
Hilty,
Membrane protein-lipid interactions in mixed micelles studied by NMR spectroscopy with the use of paramagnetic reagents.
2004,
Pubmed
Holsinger,
Influenza A virus M2 ion channel protein: a structure-function analysis.
1994,
Pubmed
,
Xenbase
Holsinger,
Influenza virus M2 integral membrane protein is a homotetramer stabilized by formation of disulfide bonds.
1991,
Pubmed
Howard,
Sequence determinants of the energetics of folding of a transmembrane four-helix-bundle protein.
2002,
Pubmed
Hu,
Backbone structure of the amantadine-blocked trans-membrane domain M2 proton channel from Influenza A virus.
2007,
Pubmed
Kitahori,
Frequency of amantadine-resistant influenza A virus isolated from 2001-02 to 2004-05 in Nara Prefecture.
2006,
Pubmed
Lear,
Position-dependence of stabilizing polar interactions of asparagine in transmembrane helical bundles.
2003,
Pubmed
Lin,
Different modes of inhibition by adamantane amine derivatives and natural polyamines of the functionally reconstituted influenza virus M2 proton channel protein.
1997,
Pubmed
Lin,
Definitive assignment of proton selectivity and attoampere unitary current to the M2 ion channel protein of influenza A virus.
2001,
Pubmed
Mould,
Permeation and activation of the M2 ion channel of influenza A virus.
2000,
Pubmed
,
Xenbase
Nishimura,
The closed state of a H+ channel helical bundle combining precise orientational and distance restraints from solid state NMR.
2002,
Pubmed
Okada,
Protonation of histidine and histidine-tryptophan interaction in the activation of the M2 ion channel from influenza a virus.
2001,
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
Russ,
TOXCAT: a measure of transmembrane helix association in a biological membrane.
1999,
Pubmed
Russ,
The GxxxG motif: a framework for transmembrane helix-helix association.
2000,
Pubmed
Salom,
pH-dependent tetramerization and amantadine binding of the transmembrane helix of M2 from the influenza A virus.
2000,
Pubmed
Schnell,
Structure and mechanism of the M2 proton channel of influenza A virus.
2008,
Pubmed
Senes,
Statistical analysis of amino acid patterns in transmembrane helices: the GxxxG motif occurs frequently and in association with beta-branched residues at neighboring positions.
2000,
Pubmed
Senes,
Folding of helical membrane proteins: the role of polar, GxxxG-like and proline motifs.
2004,
Pubmed
Shimbo,
Ion selectivity and activation of the M2 ion channel of influenza virus.
1996,
Pubmed
,
Xenbase
Simonsen,
The genesis and spread of reassortment human influenza A/H3N2 viruses conferring adamantane resistance.
2007,
Pubmed
Steinhauer,
Amantadine selection of a mutant influenza virus containing an acid-stable hemagglutinin glycoprotein: evidence for virus-specific regulation of the pH of glycoprotein transport vesicles.
1991,
Pubmed
Stouffer,
Sequence determinants of a transmembrane proton channel: an inverse relationship between stability and function.
2005,
Pubmed
Stouffer,
Structural basis for the function and inhibition of an influenza virus proton channel.
2008,
Pubmed
Suzuki,
Emergence of amantadine-resistant influenza A viruses: epidemiological study.
2003,
Pubmed
Tamm,
Folding and assembly of beta-barrel membrane proteins.
2004,
Pubmed
Tang,
The gate of the influenza virus M2 proton channel is formed by a single tryptophan residue.
2002,
Pubmed
,
Xenbase
Venkataraman,
Chemical rescue of histidine selectivity filter mutants of the M2 ion channel of influenza A virus.
2005,
Pubmed
,
Xenbase
Wang,
Ion channel activity of influenza A virus M2 protein: characterization of the amantadine block.
1993,
Pubmed
,
Xenbase
Wang,
Activation of the M2 ion channel of influenza virus: a role for the transmembrane domain histidine residue.
1995,
Pubmed
,
Xenbase
Wu,
A computational study of the closed and open states of the influenza a M2 proton channel.
2005,
Pubmed
