Abstract
VSOP/Hv1 is a dimeric voltage-gated H+ channel in which the gating of one subunit is reportedly coupled to that of the other subunit within the dimer. The molecular basis for the dimer formation and intersubunit coupling remains unknown, however. Here we analyzed the high-resolution (1.45 A) crystal structure of VSOP and showed that the C-terminal cytoplasmic coiled-coil architecture mediates dimer assembly and modulates channel gating via linkage to the transmembrane S4 domain. Electrophysiological analysis and circular dichroism spectroscopy revealed that the temperature-dependent activation of VSOP is regulated by the thermostability of the coiled-coil domain. Modulation of the activation kinetics by the cytoplasmic coiled-coil domain was also altered by changing the flexibility/stability of the linker between S4 and the coiled-coil. Collectively, our results indicate that VSOP activation is modified by the coiled-coil assembly through force transmission along a continuous α-helix consisting of the S4 voltage sensor helix and the coiled-coil strands.
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