ArticleJournal of the American Chemical Society2015
The influenza m2 cytoplasmic tail changes the proton-exchange equilibria and the backbone conformation of the transmembrane histidine residue to facilitate proton conduction.
Article in Journal of the American Chemical Society, 2015. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 41 papers.
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41 citing papers in PubMed, 57 citations in OpenAlex.
- Roles of the M2 protein of influenza A virus.Virus genes · 2026Review
- Structural Transition from Closed to Open for the Influenza A M2 Proton Channel as Observed by Proton-Detected Solid-State NMR.Journal of the American Chemical Society · 2025Article
- Molecular biophysics and inhibition mechanism of influenza virus A M2 viroporin by adamantane-based drugs - Challenges in designing antiviral agents.Journal of structural biology: X · 2025Article
- Oligomeric State and Drug Binding of the SARS-CoV-2 Envelope Protein Are Sensitive to the Ectodomain.Journal of the American Chemical Society · 2024Article
- Structure and dynamics of the proton-selective histidine and the gating tryptophan in an inward rectifying hybrid influenza B and A virus M2 proton channel.Physical chemistry chemical physics : PCCP · 2024Article
- The Potential of Cyclodextrins as Inhibitors for the BM2 Protein: An In Silico Investigation.Molecules (Basel, Switzerland) · 2024Article
- Rapid Determination of the Topology of Oligomeric α-Helical Membrane Proteins by Water- and Lipid-Edited Methyl NMR.The journal of physical chemistry. B · 2023Article
- Cooperativity in regulation of membrane protein function: phenomenological analysis of the effects of pH and phospholipids.Biophysical reviews · 2023Review
- Cholesterol and M2 Rendezvous in Budding and Scission of Influenza A Virus.Sub-cellular biochemistry · 2023Article
- Multiscale Simulation of an Influenza A M2 Channel Mutant Reveals Key Features of Its Markedly Different Proton Transport Behavior.Journal of the American Chemical Society · 2022Article
- Water orientation and dynamics in the closed and open influenza B virus M2 proton channels.Communications biology · 2021Article
- Native Chemical Ligation of Highly Hydrophobic Peptides in Ionic Liquid-Containing Media.The Journal of organic chemistry · 2021Article
- From Acid Activation Mechanisms of Proton Conduction to Design of Inhibitors of the M2 Proton Channel of Influenza A Virus.Frontiers in molecular biosciences · 2021Review
- Increased Dissociation of Adamantanamines in Influenza A M2 S31N with Partial Block by Rimantadine.Biophysical journal · 2020Article
- M2 amphipathic helices facilitate pH-dependent conformational transition in influenza A virus.Proceedings of the National Academy of Sciences of the United States of America · 2020Article
- The distal cytoplasmic tail of the influenza A M2 protein dynamically extends from the membrane.Biochimica et biophysica acta. Biomembranes · 2019Article
- Proton-Induced Conformational and Hydration Dynamics in the Influenza A M2 Channel.Journal of the American Chemical Society · 2019Article
- X-ray Crystal Structure of the Influenza A M2 Proton Channel S31N Mutant in Two Conformational States: An Open and Shut Case.Journal of the American Chemical Society · 2019Article
- Viroporins in the Influenza Virus.Cells · 2019Review
- Elucidating Relayed Proton Transfer through a His-Trp-His Triad of a Transmembrane Proton Channel by Solid-State NMR.Journal of molecular biology · 2019Article
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4 authors at 1 institution in 1 country.
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Abstract
The influenza M2 protein forms an acid-activated tetrameric proton channel important for the virus lifecycle. Residue His37 in the transmembrane domain is responsible for channel activation and proton selectivity. While the structure and dynamics of His37 have been well studied in TM peptide constructs, it has not been investigated in the presence of the full cytoplasmic domain, which increases the proton conductivity by 2-fold compared to the TM peptide. We report here (13)C and (15)N chemical shifts of His37 in the cytoplasmic-containing M2(21-97) and show that cationic histidines are already present at neutral pH, in contrast to the TM peptide, indicating that the cytoplasmic domain shifts the protonation equilibria. Quantification of the imidazole (15)N intensities yielded two resolved proton dissociation constants (pKa's) of 7.1 and 5.4, which differ from the TM result but resemble the M2(18-60) result, suggesting cooperative proton binding. The average His37 pKa is higher for M2(21-97) than for the shorter constructs. We attribute this higher pKa to direct and indirect effects of the cytoplasmic domain, which is rich in acidic residues. 2D (13)C-(13)C correlation spectra reveal seven His37 Cα-Cβ cross peaks at different pH, some of which are unique to the cytoplasmic-containing M2 and correspond to more ideal α-helical conformations. Based on the pH at which these chemical shifts appear and their side chain structures, we assign these conformations to His37 in differently charged tetramers. Thus, the cytoplasmic domain facilitates proton conduction through the transmembrane pore by modifying the His37-water proton exchange equilibria and the His37 backbone conformational distribution.
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