Trends in Biochemical Sciences
Research FocusThe voltage-sensor structure in a voltage-gated channel
Section snippets
The nerve impulse and voltage-dependent channels
In the generation of a nerve impulse, the membrane potential of the axon undergoes a rapid change from its negative resting potential to a positive potential followed by a repolarization to its resting level. These changes are produced by voltage-dependent conductances described in a classical series of papers by Hodgkin and Huxley [1]. Today, we know that these conductances are the result of the contribution of billions of voltage-dependent ion channels, which are specialized membrane proteins
The crystal structures and the EPR study
Until recently, the location and movement of the gating charges was not known with any certainty because there was no crystal structure available for voltage-gated channels. The pioneering work of the MacKinnon group presented the first crystal structure of KvAP, a voltage-gated channel from the archea Aeropirum pernix [7]. The crystal was obtained in detergent and in the presence of Fab fragments, and now there is wide consensus that it is distorted and does not represent a conformation found
The location of the S4 segment and its gating charges
The S4 segment carries most of the gating charge of the voltage sensor 3, 4, therefore, its location is crucial to our understanding of how the voltage sensor might operate. In the full crystal structure of KvAP, the S4 segment is completely intracellular [7]. The MacKinnon group found this arrangement incompatible with their results [9], and repositioned it into the lipid bilayer when they proposed the paddle model (Figure 1a). The new results of Cuello et al. [8] indeed confirm that at least
The location of the S1 TM segment
An unexpected result from the EPR study of Cuello et al. [8] was the accessibility and mobility of S1 in KvAP. It is clear from their results that the S1 segment is surrounded by protein (Figure 1b). This is in contrast to the inference obtained by perturbation analysis done in eukaryotic channels, which locates S1 in the periphery of the channel that is making contact with the lipid bilayer 14, 15. Note that the residues that are tolerant of being replaced by tryptophan are also poorly
Concluding remarks and outlook
The arrangement of the TM segments of voltage-gated channels, which was not determined by the crystal structures of KvAP, have now been better defined by EPR studies on the same channel, at least for the open-inactivated state of the channel. Important conclusions are (i) that S1, S2, S3 and S4 are helical TM segments, (ii) that the loops are solvent-exposed, and (iii) that the charges carried by S4 are not exposed to the lipids (Figure 1b). Contrary to what was recently stated [10], the center
Acknowledgements
Many thanks to Benoit Roux and Ana M. Correa for helpful comments on the article. Supported by NIH grant GM30376.
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