title: Kv Channel S1-S2 Linker Working as a Binding Site of Human β-Defensin 2 for Channel Activation Modulation.
abstract: Among the three extracellular domains of the tetrameric voltage-gated K(+) (Kv) channels consisting of six membrane-spanning helical segments named S1-S6, the functional role of the S1-S2 linker still remains unclear because of the lack of a peptide ligand. In this study, the Kv1.3 channel S1-S2 linker was reported as a novel receptor site for human β-defensin 2 (hBD2). hBD2 shifts the conductance-voltage relationship curve of the human Kv1.3 channel in a positive direction by nearly 10.5 mV and increases the activation time constant for the channel. Unlike classical gating modifiers of toxin peptides from animal venoms, which generally bind to the Kv channel S3-S4 linker, hBD2 only targets residues in both the N and C termini of the S1-S2 linker to influence channel gating and inhibit channel currents. The increment and decrement of the basic residue number in a positively charged S4 sensor of Kv1.3 channel yields conductance-voltage relationship curves in the positive direction by ∼31.2 mV and 2-4 mV, which suggests that positively charged hBD2 is anchored in the channel S1-S2 linker and is modulating channel activation through electrostatic repulsion with an adjacent S4 helix. Together, these findings reveal a novel peptide ligand that binds with the Kv channel S1-S2 linker to modulate channel activation. These findings also highlight the functional importance of the Kv channel S1-S2 linker in ligand recognition and modification of channel activation.
authors.affiliation: State Key Laboratory of Virology, College of Life Sciences, Wuhan University, Wuhan 430072, China.
authors.forename: Jing
authors.initials: J
authors.lastname: Feng
authors.affiliation: State Key Laboratory of Virology, College of Life Sciences, Wuhan University, Wuhan 430072, China.
authors.forename: Weishan
authors.initials: W
authors.lastname: Yang
authors.affiliation: State Key Laboratory of Virology, College of Life Sciences, Wuhan University, Wuhan 430072, China.
authors.forename: Zili
authors.initials: Z
authors.lastname: Xie
authors.affiliation: State Key Laboratory of Virology, College of Life Sciences, Wuhan University, Wuhan 430072, China.
authors.forename: Fang
authors.initials: F
authors.lastname: Xiang
authors.affiliation: State Key Laboratory of Virology, College of Life Sciences, Wuhan University, Wuhan 430072, China; Center for BioDrug Research, Wuhan University, Wuhan 430072, China.
authors.forename: Zhijian
authors.initials: Z
authors.lastname: Cao
authors.affiliation: State Key Laboratory of Virology, College of Life Sciences, Wuhan University, Wuhan 430072, China; Center for BioDrug Research, Wuhan University, Wuhan 430072, China.
authors.forename: Wenxin
authors.initials: W
authors.lastname: Li
authors.affiliation: Center for the Study of Itch, Washington University Pain Center, Department of Anesthesiology, Washington University School of Medicine, St. Louis, Missouri 63110.
authors.forename: Hongzhen
authors.initials: H
authors.lastname: Hu
authors.affiliation: State Key Laboratory of Virology, College of Life Sciences, Wuhan University, Wuhan 430072, China. Electronic address: chenzy2005@126.com.
authors.forename: Zongyun
authors.initials: Z
authors.lastname: Chen
authors.affiliation: State Key Laboratory of Virology, College of Life Sciences, Wuhan University, Wuhan 430072, China; Center for BioDrug Research, Wuhan University, Wuhan 430072, China. Electronic address: ylwu@whu.edu.cn.
authors.forename: Yingliang
authors.initials: Y
authors.lastname: Wu
mesh_terms: D001665:Binding Sites; D057809:HEK293 Cells; D006801:Humans; D015640:Ion Channel Gating / Q000502:physiology*; D051664:Kv1.3 Potassium Channel / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D008564:Membrane Potentials / Q000502:physiology*; D011485:Protein Binding / Q000502:physiology; D017433:Protein Structure, Secondary; D023083:beta-Defensins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*
chemical_list: C106641:DEFB4A protein, human; D051664:Kv1.3 Potassium Channel; D023083:beta-Defensins
keywords: Kv channel, S1-S2 linker, human beta-defensin 2, electrostatic interaction, gating modifier; defensin; immunology; ligand-binding protein; toxin; voltage-dependent anion channel (VDAC)