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Role of human Hv1 channels in sperm capacitation and white blood cell respiratory burst established by a designed peptide inhibitor.

  • Author(s): Zhao, Ruiming
  • Kennedy, Kelleigh
  • De Blas, Gerardo A
  • Orta, Gerardo
  • Pavarotti, Martín A
  • Arias, Rodolfo J
  • de la Vega-Beltrán, José Luis
  • Li, Qufei
  • Dai, Hui
  • Perozo, Eduardo
  • Mayorga, Luis S
  • Darszon, Alberto
  • Goldstein, Steve AN
  • et al.
Abstract

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.

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