Structural Basis of a Kv7.1 Potassium Channel Gating Module: Studies of the Intracellular C-Terminal Domain in Complex with Calmodulin

Dana Sachyani, Meidan Dvir, Roi Strulovich, Giancarlo Tria, William Tobelaim, Asher Peretz, Olaf Pongs, Dmitri Svergun, Bernard Attali, Joel A. Hirsch*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

Abstract

Kv7 channels tune neuronal and cardiomyocyte excitability. In addition to the channel membrane domain, they also have a unique intracellular C-terminal (CT) domain, bound constitutively to calmodulin (CaM). This CT domain regulates gating and tetramerization. We investigated the structure of the membrane proximal CT module in complex with CaM by X-ray crystallography. The results show how the CaM intimately hugs a two-helical bundle, explaining many channelopathic mutations. Structure-based mutagenesis of this module in the context of concatemeric tetramer channels and functional analysis along with in vitro data lead us to propose that one CaM binds to one individual protomer, without crosslinking subunits and that this configuration is required for proper channel expression and function. Molecular modeling of the CT/CaM complex in conjunction with small-angle X-ray scattering suggests that the membrane proximal region, having a rigid lever arm, is a critical gating regulator.

Original languageEnglish
Pages (from-to)1582-1594
Number of pages13
JournalStructure
Volume22
Issue number11
DOIs
StatePublished - 4 Nov 2014

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