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Title: Calmodulin regulates human ether à go-go 1 (hEAG1) potassium channels through interactions of the eag-domain with the cyclic nucleotide binding homology domain
Authors: Lörinczi, Eva
Helliwell, Matthew
Finch, Alina
Stansfeld, Phillip J.
Davies, Noel
Mahaut-Smith, Martyn
Muskett, Frederick W.
Mitcheson, John S.
First Published: 20-Jun-2016
Publisher: American Society for Biochemistry and Molecular Biology
Citation: Journal of Biological Chemistry, 2016, 291 (34), pp. 17907-17918
Abstract: The ether à go-go family of voltage-gated potassium channels is structurally distinct. The N-terminus contains an eag domain (eagD) that contains a Per-Arnt-Sim (PAS) domain that is preceded by a conserved sequence of 25-27 amino acids known as the PAS-cap. The C-terminus contains a region with homology to cyclic nucleotide binding domains (cNBHD), which is directly linked to the channel pore. The human EAG1 (hEAG1) channel is remarkably sensitive to inhibition by intracellular calcium (Ca²⁺ᵢ) through binding of Ca²⁺-calmodulin to three sites adjacent to the eagD and cNBHD. Here, we show that the eagD and cNBHD interact to modulate Ca²⁺-calmodulin as well as voltage-dependent gating. Sustained elevation of Ca²⁺ᵢ resulted in an initial profound inhibition of hEAG1 currents, which was followed by a phase when current amplitudes partially recovered, but activation gating was slowed and shifted to depolarized potentials. Deletion of either the eagD or cNBHD abolished the inhibition by Ca²⁺ᵢ. However, deletion of just the PAS-cap resulted in a >15-fold potentiation in response to elevated Ca²⁺ᵢ. Mutations of residues at the interface between the eagD and cNBHD have been linked to human cancer. E600 on the cNBHD, when substituted with residues with a larger volume, resulted in hEAG1 currents that were profoundly potentiated by Ca²⁺ᵢ in a manner similar to the ΔPAS-cap mutant. These findings provide the first evidence that eagD and cNBHD interactions are regulating Ca²⁺-dependent gating and indicate that the binding of the PAS-cap with the cNBHD is required for the closure of the channels upon CaM binding.
DOI Link: 10.1074/jbc.M116.733576
ISSN: 0021-9258
eISSN: 1083-351X
Version: Publisher Version
Status: Peer-reviewed
Type: Journal Article
Rights: Copyright © 2016, The American Society for Biochemistry and Molecular Biology. This is an open-access article distributed under the terms of the Creative Commons Attribution License ( ), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Appears in Collections:Published Articles, Dept. of Molecular and Cell Biology

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