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Key points

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    The voltage-gated H+ channel assembles as a dimer by the cytoplasmic coiled-coil domain.
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    This study focuses on understanding the structural characteristics and functional significance of dimerization.
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    Monomeric, trimeric and tetrameric channels can be engineered by changing the assembly state of the coiled coil by mutation, and interestingly, they show functional currents.
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    However, only the native dimeric form shows successful cooperative gating, which is of physiological importance in the phagosomal production of reactive oxygen species.
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    These results help us to understand better why the native form of the channel is a dimer from a standpoint of molecular structure and physiological function.

Abstract  The voltage-gated H+ channel functions as a dimer, a configuration that is different from standard tetrameric voltage-gated channels. Each channel protomer has its own permeation pathway. The C-terminal coiled-coil domain has been shown to be necessary for both dimerization and cooperative gating in the two channel protomers. Here we report the gating cooperativity in trimeric and tetrameric Hv channels engineered by altering the hydrophobic core sequence of the coiled-coil assembly domain. Trimeric and tetrameric channels exhibited more rapid and less sigmoidal kinetics of activation of H+ permeation than dimeric channels, suggesting that some channel protomers in trimers and tetramers failed to produce gating cooperativity observed in wild-type dimers. Multimerization of trimer and tetramer channels were confirmed by the biochemical analysis of proteins, including crystallography. These findings indicate that the voltage-gated H+ channel is optimally designed as a dimeric channel on a solid foundation of the sequence pattern of the coiled-coil core, with efficient cooperative gating that ensures sustained and steep voltage-dependent H+ conductance in blood cells.