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Insight into the Mechanism of the Influenza A Proton Channel from a Structure in a Lipid Bilayer
Mukesh Sharma,1,2
Myunggi Yi,3,4
Hao Dong,3,4
Huajun Qin,1
Emily Peterson,5
David D. Busath,5
Huan-Xiang Zhou,3,4,*
Timothy A. Cross1,2,4,*
Abstract:
The M2 protein from the influenza A virus, an acid-activatedproton-selective channel, has been the subject of numerous conductance,structural, and computational studies. However, little is knownat the atomic level about the heart of the functional mechanismfor this tetrameric protein, a His37-Trp41 cluster. We reportthe structure of the M2 conductance domain (residues 22 to 62)in a lipid bilayer, which displays the defining features ofthe native protein that have not been attainable from structuressolubilized by detergents. We propose that the tetrameric His37-Trp41cluster guides protons through the channel by forming and breakinghydrogen bonds between adjacent pairs of histidines and throughspecific interactions of the histidines with the tryptophangate. This mechanism explains the main observations on M2 protonconductance.
1 Department of Chemistry and Biochemistry, Florida State University, Tallahassee, FL 32306, USA. 2 National High Magnetic Field Laboratory, Florida State University, Tallahassee, FL 32310, USA. 3 Department of Physics, Florida State University, Tallahassee, FL 32306, USA. 4 Institute of Molecular Biophysics, Florida State University, Tallahassee, FL 32306, USA. 5 Department of Physiology and Developmental Biology, Brigham Young University, Provo, UT 84602, USA.
* To whom correspondence should be addressed. E-mail: hzhou4{at}fsu.edu (H.-X.Z.); cross{at}magnet.fsu.edu (T.A.C.)
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