Research Article

Structure of the voltage-gated K+ channel Eag1 reveals an alternative voltage sensing mechanism

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Science  12 Aug 2016:
Vol. 353, Issue 6300, pp. 664-669
DOI: 10.1126/science.aaf8070

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A different gate design

The voltage-gated potassium channel Eag1 is overexpressed in tumor cells from a range of cancers, and inhibiting Eag1 reduces tumor growth. Whicher and Mackinnon determined the structure of a mammalian Eag1 bound to the inhibitor calmodulin at 3.78 Å resolution (see the Perspective by Toombes and Swartz). The organization of the voltage-sensing and pore domains differs from that of other potassium channels, indicating that the gating mechanism is distinct. The structure also shows how the channel can be closed by a ligand, independently of the position of the voltage sensor.

Science, this issue p. 664; see also p. 646

Abstract

Voltage-gated potassium (Kv) channels are gated by the movement of the transmembrane voltage sensor, which is coupled, through the helical S4-S5 linker, to the potassium pore. We determined the single-particle cryo–electron microscopy structure of mammalian Kv10.1, or Eag1, bound to the channel inhibitor calmodulin, at 3.78 angstrom resolution. Unlike previous Kv structures, the S4-S5 linker of Eag1 is a five-residue loop and the transmembrane segments are not domain swapped, which suggest an alternative mechanism of voltage-dependent gating. Additionally, the structure and position of the S4-S5 linker allow calmodulin to bind to the intracellular domains and to close the potassium pore, independent of voltage-sensor position. The structure reveals an alternative gating mechanism for Kv channels and provides a template to further understand the gating properties of Eag1 and related channels.

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