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Review
, 586 (7), 1803-10

The C-terminus of Kv7 Channels: A Multifunctional Module

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Review

The C-terminus of Kv7 Channels: A Multifunctional Module

Yoni Haitin et al. J Physiol.

Abstract

Kv7 channels (KCNQ) represent a family of voltage-gated K(+) channels which plays a prominent role in brain and cardiac excitability. Their physiological importance is underscored by the existence of mutations in human Kv7 genes, leading to severe cardiovascular and neurological disorders such as the cardiac long QT syndrome and neonatal epilepsy. Kv7 channels exhibit some structural and functional features that are distinct from other Kv channels. Notably, the Kv7 C-terminus is long compared to other K(+) channels and is endowed with characteristic structural domains, including coiled-coils, amphipatic alpha helices containing calmodulin-binding motifs and basic amino acid clusters. Here we provide a brief overview of current insights and as yet unsettled issues about the structural and functional attributes of the C-terminus of Kv7 channels. Recent data indicate that the proximal half of the Kv7 C-terminus associates with one calmodulin constitutively bound to each subunit. Epilepsy and long QT mutations located in this proximal region impair calmodulin binding and can affect channel gating, folding and trafficking. The distal half of the Kv7 C-terminus directs tetramerization, employing tandem coiled-coils. Together, the data indicate that the Kv7 C-terminal domain is a multimodular structure playing a crucial role in channel gating, assembly and trafficking as well as in scaffolding the channel complex with signalling proteins.

Figures

Figure 1
Figure 1. Structure of Kv7 channels and interaction sites on the carboxy-terminal tail
The C-termini of only two subunits are depicted for clarity. The Kv7 C-terminus exhibits conserved interaction sites with CaM at helices A and B, with PIP2, as well as specific interaction sites (red arrows) with the AKAP79/150 in Kv7.2 at helix A-linker A–B, with the AKAP-yotiao in Kv7.1 at helix D, with ankyrin-G in Kv7.2/3 and with Nedd4-2 in Kv7.1 and Kv7.2/3. Helix B is endowed with PKC phosphorylation sites. Helix A contains a tyrosine kinase phosphorylation site. In addition to a potential role in channel trafficking, the coiled-coils C and D may correspond to subunit dimerization and tetramerization modules, respectively. Neighbouring subunits would form a dimer at helix C. The helix C complex may undergo dimerization of its dimeric coiled-coil while the helix D complex is depicted as a stable, tetrameric parallel coiled-coil, as seen in the crystal structure.
Figure 2
Figure 2. Functional properties of Kv7.1 Δhelix C mutant
Representative current traces of WT KCNQ1 (A) and Kv7.1 Δhelix C mutant (deletion AAs 548–562) (B). From a holding potential of −90 mV, CHO cells were stepped for 3 s from −70 mV to +60 mV in 10 mV increments and repolarized for 1 s at −60 mV. Deletion of helix C does not result in any detectable K+ currents. Immunocytochemical imaging of COS cells expressing WT Kv7.1 (C) and Kv7.1 Δhelix C mutant (D), detected with rabbit anti-Kv7.1 antibodies. While the Kv7.1 Δhelix C mutant exhibits essentially intracellular localization with strong accumulation in the ER, the WT channel protein displays both intracellular and significant plasma membrane distribution. Images were taken using a Zeiss 510 meta confocal microscope with a 458 nm excitation argon laser line.
Figure 3
Figure 3. KCNE1 interacts with the Kv7.1 C-terminal domain
The Kv7.1 FLAG-tagged C-terminal domain (CTD) (AAs 510–620) or the full length C-terminus (C-term) (AAs 354–676) were co-expressed with KCNE1 in HEK 293T cells. After standard lysis procedure, immunoprecipitation experiments were carried out using anti-αM2 (FLAG) antibodies. KCNE1 is clearly able to co-immunoprecipitate with both Kv7.1 CTD and Kv7.1 C-term (upper panel).

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