Structural, Biochemical, and Functional Characterization of the Cyclic Nucleotide Binding Homology Domain from the Mouse EAG1 Potassium Channel.

Abstract : KCNH channels are voltage-gated potassium channels with important physiological functions. In these channels, a C-terminal cytoplasmic region, known as the cyclic nucleotide binding homology (CNB-homology) domain displays strong sequence similarity to cyclic nucleotide binding (CNB) domains. However, the isolated domain does not bind cyclic nucleotides. Here, we report the X-ray structure of the CNB-homology domain from the mouse EAG1 channel. Through comparison with the recently determined structure of the CNB-homology domain from the zebrafish ELK (eag-like K(+)) channel and the CNB domains from the MlotiK1 and HCN (hyperpolarization-activated cyclic nucleotide-gated) potassium channels, we establish the structural features of CNB-homology domains that explain the low affinity for cyclic nucleotides. Our structure establishes that the "self-liganded" conformation, where two residues of the C-terminus of the domain are bound in an equivalent position to cyclic nucleotides in CNB domains, is a conserved feature of CNB-homology domains. Importantly, we provide biochemical evidence that suggests that there is also an unliganded conformation where the C-terminus of the domain peels away from its bound position. A functional characterization of this unliganded conformation reveals a role of the CNB-homology domain in channel gating.
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https://hal.archives-ouvertes.fr/hal-00747621
Contributor : Isabelle Frapart <>
Submitted on : Wednesday, October 31, 2012 - 5:05:41 PM
Last modification on : Friday, June 7, 2019 - 5:50:04 PM

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Maria J Marques-Carvalho, Nirakar Sahoo, Frederick W Muskett, Ricardo S Vieira-Pires, Guillaume Gabant, et al.. Structural, Biochemical, and Functional Characterization of the Cyclic Nucleotide Binding Homology Domain from the Mouse EAG1 Potassium Channel.. Journal of Molecular Biology, Elsevier, 2012, 423 (1), pp.34-46. ⟨10.1016/j.jmb.2012.06.025⟩. ⟨hal-00747621⟩

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