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Department of Biochemistry and Molecular Pharmacology, University of Massachusetts Medical School, Worcester, MA 01605

Correspondence to William R. Kobertz: william.kobertz{at}umassmed.edu

Type I transmembrane KCNE peptides contain a conserved C-terminal cytoplasmic domain that abuts the transmembrane segment. In KCNE1, this region is required for modulation of KCNQ1 K⁺ channels to afford the slowly activating cardiac I_Ks current. We utilized alanine/leucine scanning to determine whether this region possesses any secondary structure and to identify the KCNE1 residues that face the KCNQ1 channel complex. Helical periodicity analysis of the mutation-induced perturbations in voltage activation and deactivation kinetics of KCNQ1-KCNE1 complexes defined that the KCNE1 C terminus is -helical when split in half at a conserved proline residue. This helical rendering assigns all known long QT mutations in the KCNE1 C-terminal domain as protein facing. The identification of a secondary structure within the KCNE1 C-terminal domain provides a structural scaffold to map protein–protein interactions with the pore-forming KCNQ1 subunit as well as the cytoplasmic regulatory proteins anchored to KCNQ1–KCNE complexes.

Abbreviations used in this paper: -PI, -periodicity index; E1–E5, KCNE1–KCNE5; HA, hemagglutinin A; Q1, KCNQ1; TEVC, two-electrode voltage clamp; WT, wild-type.

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