A distinct three-helix centipede toxin SSD609 inhibits Iks channels by interacting with the KCNE1 auxiliary subunit

TL;DR

A new centipede toxin called SSD609 inhibits potassium currents in heart cells by interacting with a specific protein, KCNE1.

Contribution

SSD609 is the first polypeptide toxin shown to target the KCNE1 auxiliary subunit of ion channels.

Findings

SSD609 inhibits Iks currents in guinea pig cardiomyocytes and KCNQ1/KCNE1 currents in CHO cells.

SSD609 has a unique three-helix structure stabilized by a novel disulfide bonding pattern.

The negatively charged Glu19 residue in KCNE1 is critical for SSD609 interaction.

Abstract

KCNE1 is a single-span transmembrane auxiliary protein that modulates the voltage-gated potassium channel KCNQ1. The KCNQ1/KCNE1 complex in cardiomyocytes exhibited slow activated potassium (Iks) currents. Recently, a novel 47-residue polypeptide toxin SSD609 was purified from Scolopendra subspinipes dehaani venom and showed Iks current inhibition. Here, chemically synthesized SSD609 was shown to exert Iks inhibition in extracted guinea pig cardiomyocytes and KCNQ1/KCNE1 current attenuation in CHO cells. The K+ current attenuation of SSD609 showed decent selectivity among different auxiliary subunits. Solution nuclear magnetic resonance analysis of SSD609 revealed a distinctive three-helix conformation that was stabilized by a new disulfide bonding pattern as well as segregated surface charge distribution. Structure-activity studies demonstrated that negatively charged Glu19 in the amphipathic extracellular helix of KCNE1 was the key residue that interacted with SSD609. The distinctive three-helix centipede toxin SSD609 is known to be the first polypeptide toxin acting on channel auxiliary subunit KCNE1, which suggests a new type of pharmacological regulation for ion channels in cardiomyocytes.

Figures