Authors: Yu Hong Wang Min Jiang Xu Lin Xu KaiLing Hsu Mei Zhang GeaNy Tseng
Publish Date: 2010/12/09
Volume: 239, Issue: 3, Pages: 137-156
Abstract
Cardiac slow delayed rectifier IKs channel complex consists of KCNQ1 channel and KCNE1 auxiliary subunits The extracellular juxtamembranous region of KCNE1 is an unstructured loop that contacts multiple KCNQ1 positions in a gatingstatedependent manner Congenital arrhythmiarelated mutations have been identified in the extracellular S1–S2 linker of KCNQ1 These mutations manifest abnormal phenotypes only when coexpressed with KCNE1 pointing to the importance of proper KCNQ1/KCNE1 interactions here in IKs channel function We investigate the interactions between the KCNE1 loop positions 36–47 and KCNQ1 S1–S2 linker positions 140–148 by means of disulfide trapping and voltage clamp techniques During transitions among the restingstate conformations KCNE1 positions 36–43 make contacts with KCNQ1 positions 144 145 and 147 in a parallel fashion During conformational changes in the activated state KCNE1 position 40 can make contacts with all three KCNQ1 positions while the neighboring KCNE1 positions 36 38 39 and 41 can make contact with KCNQ1 position 147 Furthermore KCNQ1 positions 143 and 146 are highimpact positions that cannot tolerate cysteine substitution To maintain the proper IKs channel function position 143 requires a small side chain with a hydroxyl group and position 146 requires a negatively charged side chain These data and the proposed molecular motions provide insights into the mechanisms by which mutations in the extracellular juxtamembranous region of the IKs channel impair its function
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