Lörinczi, Eva, Helliwell, Matthew, Finch, Alina, Stansfeld, Phillip J., Davies, Noel W., Mahaut-Smith, Martyn, Muskett, Frederick W. and Mitcheson, John S. (2016) Calmodulin regulates human ether à Go-Go 1 (hEAG1) potassium channels through interactions of the eag domain with the cyclic nucleotide binding homology domain. Journal of Biological Chemistry, 291 (34). pp. 17907-17918. doi:10.1074/jbc.M116.733576 ISSN 0021-9258.
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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. Glu-600 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.
| Item Type: | Journal Article |
|---|---|
| Divisions: | Faculty of Science, Engineering and Medicine > Science > Life Sciences (2010- ) |
| Journal or Publication Title: | Journal of Biological Chemistry |
| Publisher: | American Society for Biochemistry and Molecular Biology |
| ISSN: | 0021-9258 |
| Official Date: | 20 June 2016 |
| Dates: | Date Event 20 June 2016 Published 19 August 2016 Available |
| Volume: | 291 |
| Number: | 34 |
| Page Range: | pp. 17907-17918 |
| DOI: | 10.1074/jbc.M116.733576 |
| Status: | Peer Reviewed |
| Publication Status: | Published |
| Access rights to Published version: | Open Access (Creative Commons open licence) |
| URI: | https://wrap.warwick.ac.uk/126695/ |
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