Molecular mapping of KCNE4-dependent regulation of Kv1.3

The voltage-gated potassium channel Kv1.3 plays a crucial role in the
immune system response. In leukocytes, the channel is coexpressed with the
dominant negative regulatory subunit KCNE4, which associates with Kv1.3 to
trigger intracellular retention and accelerating C-type inactivation of
the channel. Previous research has demonstrated that the main association
between these proteins occurs through both C-termini. However, these data
fail to fully elucidate the KCNE4-dependent modulation of channel
kinetics. In the present study, we analyzed the contribution of each KCNE4
domain to the modulation of Kv1.3. Our results further confirmed that the
C-terminus of KCNE4 is the main determinant involved in the
association-triggered intracellular retention of the channel.
Additionally, interactions throughout the transmembrane region were also
observed. Both the C-terminus and, especially, the transmembrane domain of
KCNE4 accentuated the C-type inactivation of Kv1.3. Our data provide, for
the first time, the molecular effects that a KCNE peptide, such as KCNE4,
exerts on a Shaker channel, such as Kv1.3. Our results pave the
way for understanding the molecular mechanisms underlying potassium
channel modulation and suggest that KCNE4 participates in the
conformational rearrangement of the Kv1.3 architecture, altering the
C-type inactivation of the channel.