Histidines, Heart of the Hydrogen Ion Channel from Influenza a Virus: Toward an Understanding of Conductance and Proton Selectivity

The heart of the H⁺ conductance mechanism in the homotetrameric M2 H⁺ channel from influenza A is a set of four histidine side chains. Here, we show that protonation of the third of these imidazoles coincides with acid activation of this transmembrane channel and that, at physiological pH, the chann...

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Bibliographic Details
Published in:Proceedings of the National Academy of Sciences - PNAS 2006-05, Vol.103 (18), p.6865-6870
Main Authors: Hu, Jun, Fu, Riqiang, Nishimura, Katsuyuki, Zhang, Li, Zhou, Huan-Xiang, Busath, David D., Vijayvergiya, Viksita, Cross, Timothy A.
Format: Article
Language:English
Subjects:
Biochemistry
Biological Sciences
Biophysics
Chemical equilibrium
Dielectric properties
Dimerization
Dimers
Histidine - chemistry
Histidine - metabolism
Hydrogen
Hydrogen Bonding
Hydrogen bonds
Imidazoles
Imidazoles - chemistry
Influenza
Influenza A virus
Mathematical functions
Molecular Structure
Nuclear Magnetic Resonance, Biomolecular
Protein Structure, Quaternary
Protons
Resonance
Spectrum analysis
Titration
Viral Matrix Proteins - chemistry
Viral Matrix Proteins - metabolism
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Summary:The heart of the H⁺ conductance mechanism in the homotetrameric M2 H⁺ channel from influenza A is a set of four histidine side chains. Here, we show that protonation of the third of these imidazoles coincides with acid activation of this transmembrane channel and that, at physiological pH, the channel is closed by two imidazole-imidazolium dimers, each sharing a low-barrier hydrogen bond. This unique construct succeeds in distributing a pair of charges over four rings and many atoms in a low dielectric environment to minimize charge repulsion. These dimers form with identical$pK_{a}s$of 8.2 ± 0.2, suggesting cooperative H⁺ binding and clearly illustrating high H⁺ affinity for this channel. The protonation behavior of the histidine side chains has been characterized by using solid-state NMR spectroscopy on the M2 transmembrane domain in fully hydrated lipid bilayers where the tetrameric backbone structure is known. Furthermore, electrophysiological measurements of multichannel and single-channel experiments confirm that these protein constructs are functional.
ISSN:0027-8424
1091-6490
DOI:10.1073/pnas.0601944103