title: Selectivity Mechanism of the Voltage-gated Proton Channel, HV1.
abstract: Voltage-gated proton channels, HV1, trigger bioluminescence in dinoflagellates, enable calcification in coccolithophores, and play multifarious roles in human health. Because the proton concentration is minuscule, exquisite selectivity for protons over other ions is critical to HV1 function. The selectivity of the open HV1 channel requires an aspartate near an arginine in the selectivity filter (SF), a narrow region that dictates proton selectivity, but the mechanism of proton selectivity is unknown. Here we use a reduced quantum model to elucidate how the Asp-Arg SF selects protons but excludes other ions. Attached to a ring scaffold, the Asp and Arg side chains formed bidentate hydrogen bonds that occlude the pore. Introducing H3O(+) protonated the SF, breaking the Asp-Arg linkage and opening the conduction pathway, whereas Na(+) or Cl(-) was trapped by the SF residue of opposite charge, leaving the linkage intact, thus preventing permeation. An Asp-Lys SF behaved like the Asp-Arg one and was experimentally verified to be proton-selective, as predicted. Hence, interacting acidic and basic residues form favorable AspH(0)-H2O(0)-Arg(+) interactions with hydronium but unfavorable Asp(-)-X(-)/X(+)-Arg(+) interactions with anions/cations. This proposed mechanism may apply to other proton-selective molecules engaged in bioenergetics, homeostasis, and signaling.
authors.affiliation: 1] Institute of Biomedical Sciences, Academia Sinica, Taipei 115, Taiwan [2] Faculty of Chemistry and Pharmacy, Sofia University, Sofia 1164, Bulgaria.
authors.forename: Todor
authors.initials: T
authors.lastname: Dudev
authors.affiliation: Institute of Complex Systems (ICS-4 Zelluläre Biophysik), Forschungszentrum Jülich, Jülich, NRW, Germany.
authors.forename: Boris
authors.initials: B
authors.lastname: Musset
authors.affiliation: Department of Molecular Biophysics and Physiology, Rush University, Chicago, IL 60612, USA.
authors.forename: Deri
authors.initials: D
authors.lastname: Morgan
authors.affiliation: Department of Molecular Biophysics and Physiology, Rush University, Chicago, IL 60612, USA.
authors.forename: Vladimir V
authors.initials: VV
authors.lastname: Cherny
authors.affiliation: Department of Biology and Physics, Kennesaw State University, Kennesaw, GA 30144, USA.
authors.forename: Susan M E
authors.initials: SM
authors.lastname: Smith
authors.affiliation: 1] Institute of Biomedical Sciences, Academia Sinica, Taipei 115, Taiwan [2] Chemical Biology and Molecular Biophysics Program, Taiwan International Graduate Program, Academia Sinica, Nankang, Taipei 11529, Taiwan.
authors.forename: Karine
authors.initials: K
authors.lastname: Mazmanian
authors.affiliation: Department of Molecular Biophysics and Physiology, Rush University, Chicago, IL 60612, USA.
authors.forename: Thomas E
authors.initials: TE
authors.lastname: DeCoursey
authors.affiliation: 1] Institute of Biomedical Sciences, Academia Sinica, Taipei 115, Taiwan [2] Department of Chemistry, National Tsing Hua University, Hsinchu 300, Taiwan.
authors.forename: Carmay
authors.initials: C
authors.lastname: Lim
mesh_terms: D001120:Arginine / Q000737:chemistry / Q000378:metabolism; D001224:Aspartic Acid / Q000737:chemistry / Q000378:metabolism; D006801:Humans; D007473:Ion Channels / Q000737:chemistry / Q000502:physiology*; D007477:Ions; D008958:Models, Molecular; D008968:Molecular Conformation; D009154:Mutation; D011485:Protein Binding; D011522:Protons; D014316:Tritium / Q000378:metabolism; D014867:Water / Q000378:metabolism
chemical_list: C510235:HVCN1 protein, human; D007473:Ion Channels; D007477:Ions; D011522:Protons; D014867:Water; D014316:Tritium; C033961:tritium oxide; D001224:Aspartic Acid; D001120:Arginine