KCNE1 Structure and Interaction with KCNQ1 Channel

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DESCRIPTION (provided by applicant): Voltage-gated potassium ion channels are essential for the function of the auditory, nervous, and cardiac systems and are potential targets for therapeutic agents. Some K channels are assembled as heteromultimeric complexes of pore-forming (alpha) and accessory or modulatory (beta) subunits. Among the beta subunits is KCNE1 (minK), which belongs to the KCNE family of single membrane-spanning proteins that modulate the activity of several K+ channels, including KCNQ1. In the heart KCNQ1 co- assembles with KCNE1 to form a channel complex that generates the slowly activating cardiac potassium current, an important determinant of myocardial repolarization. In the cochlea, this same channel complex enables secretion of K+ into endolymph and is critical for hearing. The relevance of KCNE1 for proper channel function is underscored by mutations in KCNE1 that can cause deafness and congenital long QT syndrome (LOTS). Here, the first stage of a long term project is proposed to unravel the molecular basis for various phenotypes of deafness and congenital LOTS. The specific aims focus upon KCNE1, related family members, and its disease-linked mutant forms. The high resolution structures and motional dynamics of KCNE1 and related mutants/family members will be characterized in model membranes using solution NMR spectroscopy. Structural information will shed light upon how the beta subunits modulate potassium channel function under both physiological and pathophysiological conditions. In concert, we will also conduct electrophysiological and biochemical studies of KCNQVs modulation by KCNE family members and related disease mutant forms in order to test structurally-inspired hypotheses and models for how these proteins interact.