Multiple interactions between cytoplasmic domains regulate slow deactivation of Kv11.1 channels

Chai Ann Ng, Kevin Phan, Adam P. Hill, Jamie I. Vandenberg*, Matthew D. Perry

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

27 Citations (Scopus)

Abstract

The intracellular domains of many ion channels are important for fine-tuning their gating kinetics. In Kv11.1 channels, the slow kinetics of channel deactivation, which are critical for their function in the heart, are largely regulated by the N-terminal N-Cap and Per-Arnt-Sim (PAS) domains, as well as the C-terminal cyclic nucleotide-binding homology (cNBH) domain. Here, we use mutant cycle analysis to probe for functional interactions between the N-Cap/PAS domains and the cNBH domain.Weidentified a specific and stable charge-charge interaction between Arg56of the PAS domain and Asp803of the cNBH domain, as well an additional interaction between the cNBH domain and the N-Cap, both of which are critical for maintaining slow deactivation kinetics. Furthermore, we found that positively charged arginine residues within the disordered region of the N-Cap interact with negatively charged residues of the C-linker domain. Although this interaction is likely more transient than the PAS-cNBD interaction, it is strong enough to stabilize the open conformation of the channel and thus slow deactivation. These findings provide novel insights into the slow deactivation mechanism of Kv11.1 channels.

Original languageEnglish
Pages (from-to)25822-25832
Number of pages11
JournalJournal of Biological Chemistry
Volume289
Issue number37
DOIs
Publication statusPublished - 12 Sep 2014
Externally publishedYes

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