The voltage-dependent potassium channel Kv1.3, playing crucial roles in leukocytes, physically interacts with KCNE4. This assembly inhibits the K+ currents by retaining the channel within intracellular compartments. Thus KCNE subunits are novel regulators of K+ channels in the immune system. Although the canonical interactions of KCNE with Kv7 channels are under intensive investigation, the molecular determinants governing this new and relevant association for the immune system physiology are unknown. Our results suggest that the tertiary structure of the C-terminal domain of Kv1.3 is necessary and sufficient for such interaction. However, this element is apparently not involved in modulating Kv1.3 gating. Furthermore, the KCNE4-dependent intracellular retention of the channel, which negatively affects the physiological role of Kv1.3, is mediated by two independent and additive mechanisms. First, KCNE4 masks the YMVIEE signature at the C-terminus of Kv1.3 that is crucial for the surface targeting of the channel; second, we identify a potent endoplasmic reticulum retention motif in KCNE4 that further limits cell surface expression. Our results define specific molecular determinants that play crucial roles in the physiological function of Kv1.3 in leukocytes.
- Received April 30, 2016.
- Accepted September 29, 2016.
- © 2016. Published by The Company of Biologists Ltd