Colvin MT, Andreas LB, Chou JJ, Griffin RG.. Proton Association Constants of His-37 in the Influenza-A M218-60 Dimer-of-Dimers. Biochemistry. 2014 Sep 3
The membrane protein M2 from influenza-A forms a single pass transmembrane helix that assembles in lipid membrane as homo-tetramers whose primary function is to act as a proton gate for viral acidification. A single residue, histidine 37 (His 37), is known to be responsible for selectivity, and plays an integral role in the protein´s function. We report pH dependent 15N MAS NMR spectra of His 37 within the influenza-A proton conduction domain of M2, M218-60, which has been previously shown to be a fully functional construct, and recently determined to adopt a dimer of dimers structure in lipids. By extracting the ratio of [His]/[HisH+] as a function of pH we obtained two singly degenerate proton disassociation constants: 7.63 ± 0.15, and 4.52 ± 0.15, respectively, despite a possible maximum of four. We also report the 1HNε chemical shifts at pH 6.5 recorded at 60 kHz MAS in a CP based 1H-15N spectrum, which provide no evidence for a shared proton among His 37 residues when the tetramer is in the +2 state. In the neutral state His 37 is exclusively in the τ tautomer indicating that the δ nitrogen is solely protonated as a function of pH. We also found that the plot of [HisH+]/[His] as a function of pH is qualitative-ly similar to previously reported proton conduction rates indicating that proton conduction rate is proportional to the level of histidine protonation within the channel. 2D 13C-13C and 13C-15N cor-relations suggest that at low pH multiple conformations are populated as the spectra broaden and eventually disappear as the acidity is increased. A second highly resolved state at low pH was not observed.
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