Identification of PUFA interaction sites on the cardiac potassium channel KCNQ1

Polyunsaturated fatty acids (PUFAs) affect many different ion channels, such as voltage-gated K+, Na+, and Ca2+ channels, as well as ryanodine receptors (Xiao et al., 2001; Hamilton et al., 2003; Oliver et al., 2004; Xiao et al., 2005; Ottosson et al., 2014; Farag et al., 2016; Tian et al., 2016; Liin et al., 2018; Bohannon et al., 2020). However, the molecular mechanisms behind the effects of PUFAs are not completely understood. The identity of PUFAs' specific binding pockets remains uncharacterized for many ion channels; therefore, the molecular mechanisms of Polyunsaturated fatty acids (PUFAs), but not saturated fatty acids, modulate ion channels such as the cardiac KCNQ1 channel, although the mechanism is not completely understood. Using both simulations and experiments, we find that PUFAs interact directly with the KCNQ1 channel via two different binding sites: one at the voltage sensor and one at the pore. These two amphiphilic binding pockets stabilize the negatively charged PUFA head group by electrostatic interactions with R218, R221, and K316, while the hydrophobic PUFA tail is selectively stabilized by cassettes of hydrophobic residues. The rigid saturated tail of stearic acid prevents close contacts with KCNQ1. By contrast, the mobile tail of PUFA linoleic acid can be accommodated in the crevice of the hydrophobic cassette, a defining feature of PUFA selectivity in KCNQ1. In addition, we identify Y268 as a critical PUFA anchor point underlying fatty acid selectivity. Combined, this study provides molecular models of direct interactions between PUFAs and KCNQ1 and identifies selectivity mechanisms. Long term, this understanding may open new avenues for drug development based on PUFA mechanisms.

Automated summary

PUFAs directly interact with the KCNQ1 channel via two binding sites, stabilizing the PUFA head group and tail selectively. This study provides insights into the molecular mechanisms of PUFAs on ion channels and potential avenues for drug development.