title: Structure and mechanism of proton transport through the transmembrane tetrameric M2 protein bundle of the influenza A virus.
abstract: The M2 proton channel from influenza A virus is an essential protein that mediates transport of protons across the viral envelope. This protein has a single transmembrane helix, which tetramerizes into the active channel. At the heart of the conduction mechanism is the exchange of protons between the His37 imidazole moieties of M2 and waters confined to the M2 bundle interior. Protons are conducted as the total charge of the four His37 side chains passes through 2(+) and 3(+) with a pK(a) near 6. A 1.65 A resolution X-ray structure of the transmembrane protein (residues 25-46), crystallized at pH 6.5, reveals a pore that is lined by alternating layers of sidechains and well-ordered water clusters, which offer a pathway for proton conduction. The His37 residues form a box-like structure, bounded on either side by water clusters with well-ordered oxygen atoms at close distance. The conformation of the protein, which is intermediate between structures previously solved at higher and lower pH, suggests a mechanism by which conformational changes might facilitate asymmetric diffusion through the channel in the presence of a proton gradient. Moreover, protons diffusing through the channel need not be localized to a single His37 imidazole, but instead may be delocalized over the entire His-box and associated water clusters. Thus, the new crystal structure provides a possible unification of the discrete site versus continuum conduction models.
authors.affiliation: Department of Biochemistry and Biophysics, School of Medicine, University of Pennsylvania, Philadelphia, PA 19104-6059.
authors.forename: Rudresh
authors.initials: R
authors.lastname: Acharya
authors.forename: Vincenzo
authors.initials: V
authors.lastname: Carnevale
authors.forename: Giacomo
authors.initials: G
authors.lastname: Fiorin
authors.forename: Benjamin G
authors.initials: BG
authors.lastname: Levine
authors.forename: Alexei L
authors.initials: AL
authors.lastname: Polishchuk
authors.forename: Victoria
authors.initials: V
authors.lastname: Balannik
authors.forename: Ilan
authors.initials: I
authors.lastname: Samish
authors.forename: Robert A
authors.initials: RA
authors.lastname: Lamb
authors.forename: Lawrence H
authors.initials: LH
authors.lastname: Pinto
authors.forename: William F
authors.initials: WF
authors.lastname: DeGrado
authors.forename: Michael L
authors.initials: ML
authors.lastname: Klein
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D055592:Biophysical Phenomena; D018360:Crystallography, X-Ray; D005260:Female; D006639:Histidine / Q000737:chemistry; D006863:Hydrogen-Ion Concentration; D066298:In Vitro Techniques; D009980:Influenza A virus / Q000235:genetics / Q000378:metabolism*; D007473:Ion Channels / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D017136:Ion Transport; D008958:Models, Molecular; D008969:Molecular Sequence Data; D016297:Mutagenesis, Site-Directed; D050505:Mutant Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D009865:Oocytes / Q000378:metabolism; D011487:Protein Conformation; D055503:Protein Multimerization; D055550:Protein Stability; D011522:Protons; D011994:Recombinant Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D014763:Viral Matrix Proteins / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D014981:Xenopus; D000086082:Viroporin Proteins
chemical_list: D006639:Histidine; D007473:Ion Channels; D050505:Mutant Proteins; D011522:Protons; D011994:Recombinant Proteins; D014763:Viral Matrix Proteins; C488937:M2 protein, Influenza A virus; D000086082:Viroporin Proteins