title: Dynamic Short Hydrogen Bonds in Histidine Tetrad of Full-Length M2 Proton Channel Reveal Tetrameric Structural Heterogeneity and Functional Mechanism.
abstract: The tetrameric M2 protein from influenza A conducts protons into the virus upon acid activation of its His37 tetrad and is a proven drug target. Here, in studies of full-length M2 protein solubilized in native-like liquid-crystalline lipid bilayers, a pH titration monitored by solid-state nuclear magnetic resonance revealed a clustering of the first three His37 pKas (6.3, 6.3, and 5.5). When the +2 state of the tetrad accepts a third proton from the externally exposed portion of the channel pore and releases a proton to the internally exposed pore, successful proton conductance is achieved, but more frequently the tetrad accepts and returns the proton to the externally exposed pore, resulting in a futile cycle. Both dynamics and conformational heterogeneity of the His37 tetrad featuring short hydrogen bonds between imidazolium-imidazole pairs are characterized, and the heterogeneity appears to reflect oligomeric helix packing and the extent of transmembrane helical bending around Gly34.
authors.affiliation: Department of Chemistry and Biochemistry, Florida State University, Tallahassee, FL 32306, USA.
authors.forename: Yimin
authors.initials: Y
authors.lastname: Miao
authors.affiliation: National High Magnetic Field Laboratory, Florida State University, Tallahassee, FL 32310, USA.
authors.forename: Riqiang
authors.initials: R
authors.lastname: Fu
authors.affiliation: Institute of Molecular Biophysics, Florida State University, Tallahassee, FL 32306, USA; Department of Physics, Florida State University, Tallahassee, FL 32306, USA.
authors.forename: Huan-Xiang
authors.initials: HX
authors.lastname: Zhou
authors.affiliation: Department of Chemistry and Biochemistry, Florida State University, Tallahassee, FL 32306, USA; National High Magnetic Field Laboratory, Florida State University, Tallahassee, FL 32310, USA; Institute of Molecular Biophysics, Florida State University, Tallahassee, FL 32306, USA. Electronic address: cross@magnet.fsu.edu.
authors.forename: Timothy A
authors.initials: TA
authors.lastname: Cross
mesh_terms: D000595:Amino Acid Sequence; D006639:Histidine / Q000737:chemistry; D006860:Hydrogen Bonding; D007093:Imidazoles / Q000737:chemistry; D008969:Molecular Sequence Data; D055503:Protein Multimerization; D011522:Protons; D014763:Viral Matrix Proteins / Q000737:chemistry* / Q000378:metabolism; D000086082:Viroporin Proteins
chemical_list: D006639:Histidine; D007093:Imidazoles; D011522:Protons; D014763:Viral Matrix Proteins; C488937:M2 protein, Influenza A virus; D000086082:Viroporin Proteins