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The influenza m2 cytoplasmic tail changes the proton-exchange equilibria and the backbone conformation of the transmembrane histidine residue to facilitate proton conduction



The influenza m2 cytoplasmic tail changes the proton-exchange equilibria and the backbone conformation of the transmembrane histidine residue to facilitate proton conduction



Journal of the American Chemical Society 137(18): 6067-6077



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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Accession: 059081259

Download citation: RISBibTeXText

PMID: 25892574

DOI: 10.1021/jacs.5b02510


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