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  • 标题:Role of human Hv1 channels in sperm capacitation and white blood cell respiratory burst established by a designed peptide inhibitor
  • 作者:Ruiming Zhao ; Kelleigh Kennedy ; Gerardo A. De Blas
  • 期刊名称:Proceedings of the National Academy of Sciences
  • 印刷版ISSN:0027-8424
  • 电子版ISSN:1091-6490
  • 出版年度:2018
  • 卷号:115
  • 期号:50
  • 页码:E11847-E11856
  • DOI:10.1073/pnas.1816189115
  • 语种:English
  • 出版社:The National Academy of Sciences of the United States of America
  • 摘要:Using a de novo peptide inhibitor, Corza6 (C6), we demonstrate that the human voltage-gated proton channel (hHv1) is the main pathway for H+ efflux that allows capacitation in sperm and permits sustained reactive oxygen species (ROS) production in white blood cells (WBCs). C6 was identified by a phage-display strategy whereby ∼1 million novel peptides were fabricated on an inhibitor cysteine knot (ICK) scaffold and sorting on purified hHv1 protein. Two C6 peptides bind to each dimeric channel, one on the S3–S4 loop of each voltage sensor domain (VSD). Binding is cooperative with an equilibrium affinity ( K d) of ∼1 nM at −50 mV. As expected for a VSD-directed toxin, C6 inhibits by shifting hHv1 activation to more positive voltages, slowing opening and speeding closure, effects that diminish with membrane depolarization.
  • 关键词:proton channel ; C6 ; ICK ; venom ; TIRF
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