A Model of Human Potassium Channel KCNQ1 Modulation by Accessory Protein KCNE3

Human potassium channel KCNQ1 is expressed in several tissues including inner ear, heart muscle, lung, intestine, and stomach, each requiring a unique current profile for proper function. To tune its current output, KCNQ1 complexes with several accessory proteins from the KCNE family. Each KCNE family member modulates KCNQ1 differently: KCNE1 causes the channel to delay opening and become more conductive in the open state, KCNE3 causes the channel to be constitutively open and more conductive, and KCNE4 causes the channel to close. To extend previous efforts to characterize the spectrum of KCNQ1 structure and modulation, we used a hybrid experimental-computational approach to model the KCNQ1-KCNE3 complex. Our strategy was to determine the NMR structure of KCNE3 alone in lipid-mimicking bicelles, build a homology model of KCNQ1, generate in vivo restraints using electrophysiology, and dock the structure of KCNE3 onto the homology model of KCNQ1 using electrophysiology-based restraints to validate and refine the resulting models.The results from this method will be presented.