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The opening of the two pores of the Hv1 voltage-gated proton channel is tuned by cooperativity


In voltage-gated sodium, potassium and calcium channels, the functions of ion conduction and voltage sensing are performed by two distinct structural units: the pore domain and the voltage-sensing domain (VSD). In the hydrogen voltage-gated channel 1 (Hv1), the VSD, unusually, performs both functions. Hv1 was recently found to dimerize and to form channels made of two pores. However, the channels were also found to function when dimerization was prevented, raising a question about the functional role of dimerization. Here we show that the two subunits of the human Hv1 dimer influence one another during gating, with positive cooperativity shaping the response to voltage of the two pores. We also find that the two voltage sensors undergo conformational changes that precede pore opening and that these conformational changes are allosterically coupled between the two subunits. Our results point to an important role for dimerization in the modulation of Hv1 activity.

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Figure 1: Gating perturbation of one Hv1 subunit spreads to the neighboring subunits.
Figure 2: Cooperative gating in Hv1 linked dimers made of 153C and WT subunits.
Figure 3: Cooperative gating in Hv1 dimers made of MS and ZS subunits.
Figure 4: Quantification of cooperativity in Hv1.
Figure 5: Hv1 voltage-sensor coupling detected by voltage-clamp fluorometry.
Figure 6: Proposed basic gating mechanism for the Hv1 channel.


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We are grateful to S. Wiese and W. McFadden for valuable technical assistance. We thank D.E. Clapham (Children's Hospital Boston) for the cDNA of the human Hv1 channel and Y. Okamura (Okazaki Center for Integrative Biosciences) for the cDNA of Ci-VSP. We thank J.E. Hall and S.H. White for helpful discussion. This work was supported by the US National Institutes of Health (grant R01NS035549 to E.Y.I.), by the American Heart Association WSA (grant 09BGIA2160044 to F.T.) and by a postdoctoral fellowship from the American Heart Association to M.H.U.

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Correspondence to Ehud Y Isacoff.

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Tombola, F., Ulbrich, M., Kohout, S. et al. The opening of the two pores of the Hv1 voltage-gated proton channel is tuned by cooperativity. Nat Struct Mol Biol 17, 44–50 (2010).

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