Kv7.1 α-subunit assembles with the KCNE1 auxiliary subunit to form the cardiac IKS K+ channel. Mutations in these subunit genes produce the long QT syndrome, a life-threatening ventricular arrhythmia. Here we studied the static interactions and the voltage-dependent molecular rearrangements of the intra-cellular domains of the IKS channel complex. The IKS subunits were tagged with ECFP and/or EYFP and expressed in Xenopus oocytes. Simultaneous spectral analysis of the fluorescence resonance energy transfer (FRET) were combined with TEVC recordings of K+ currents. In the channel closed state, a strong constitutive FRET signal between the C-termini of Kv7.1 and KCNE1 was observed. This static FRET signal was increased by 2-fold with a C-terminal truncation of Kv7.1 (Δ622-676). In addition, a marked FRET signal was observed between C-terminally CFP/YFP labeled Kv7.1 subunits, and between the N- and C-termini of double tagged α-subunits. Upon channel opening at +30 mV, concomitantly with IKS K+ currents recording, a voltage-dependent FRET elevation was detected between the C-termini of Kv7.1 and KCNE1 and between the N- and C-termini of the doubly-tagged Kv7.1. Notably, both K+ currents and dynamic FRET changes were abolished by coexpressing the KCNE1 LQT5 mutant D76N along with Kv7.1. Direct interactions between the C-termini of Kv7.1 and KCNE1 were further explored by the use of purified recombinant peptides in a series of in-vitro pull-down experiments. These experiments indicated that the KCNE1 C-terminus physically interacts with the coiled-coil helix-C of the tetramerization domain. Thus, we suggest that the tetramerization domain of Kv7.1 possesses an additional function as an intra-cellular docking site for KCNE1. Moreover, we demonstrate that channel gating is propagated to the C-termini of both subunits, and accompanied by a spatial rearrangement of the channel complex.