KCNE1 Binds to the KCNQ1 Pore to Regulate Potassium Channel Activity

Abstract

Potassium channels control the resting membrane potential and excitability of biological tissues. Many voltage-gated potassium channels are controlled through interactions with accessory subunits of the KCNE family through mechanisms still not known. Gating of mammalian channel KCNQ1 is dramatically regulated by KCNE subunits. We have found that multiple segments of the channel pore structure bind to the accessory protein KCNE1. The sites that confer KCNE1 binding are necessary for the functional interaction, and all sites must be present in the channel together for proper regulation by the accessory subunit. Specific gating control is localized to a single site of interaction between the ion channel and accessory subunit. Thus, direct physical interaction with the ion channel pore is the basis of KCNE1 regulation of K+ channels.

Steric hindrance between S4 and S5 of the KCNQ1/KCNE1 channel hampers pore opening

“…Binding of KCNE1 may reduce the flexibility and lower the mobility 44 , so that Phe232 may have a narrower space to avoid Phe279 during depolarization. KCNE1 is known to bind to the PD 21,22 and the voltage sensor domain 23,25 . However, the precise location of KCNE1 still remains to be elucidated 26,[44][45][46] .…”

“…KCNE1 has been reported to bind to the PD of KCNQ1 21,22 , but growing evidence suggests the possibility that the VSD could be an interaction site as well [23][24][25][26] . By using the substituted cysteine accessibility method (SCAM) 27,28 , two groups including ours previously showed that KCNE1 slows the reaction rate of extracellular MTS reagents with the S4 segment, indicating that KCNE1 stabilizes the downstate of the VSD 23,29 .…”

Location of KCNE1 relative to KCNQ1 in the I KS potassium channel by disulfide cross-linking of substituted cysteines

“…There is evidence for (13) and against (14, 15) the contribution of E1 to the pore wall and its accessibility from the pore. There is also evidence that E1 interacts with the pore domain, although not necessarily exposed in the pore (16,17), that the E1 TM helix (E1-TM) interacts directly with Q1 S4 helix (18), that E1 modulates Q1 through its C terminus (19-21), and that E1 interacts with the cytoplasmic Q1 S4-S5 linker (22).More recently, a site of possible Q1-E1 interaction was suggested by the association of mutations in Q1 S1 with congenital atrial fibrillation (8, 9). Either of these S1 mutants, S140G and V141M, when expressed heterologously, appears constitutively open, but only in the presence of E1 (8, 9).…”

“…There is evidence for (13) and against (14,15) the contribution of E1 to the pore wall and its accessibility from the pore. There is also evidence that E1 interacts with the pore domain, although not necessarily exposed in the pore (16,17), that the E1 TM helix (E1-TM) interacts directly with Q1 S4 helix (18), that E1 modulates Q1 through its C terminus (19)(20)(21), and that E1 interacts with the cytoplasmic Q1 S4-S5 linker (22).…”

The cardiac I Ks channel, complex indeed

“…Efforts to locate the KCNE1 protein in the KCNQ1 channel complex have relied on biochemical methods because no crystal structure exists for KCNQ1 in the presence or absence of KCNE1. Early work showed that KCNE1 interacts directly with the S6 pore-forming helix of KCNQ1 (11). An emergent consensus based on homology modeling and disulfide crosslinking studies suggests that KCNE1 sits between the voltage-sensing domain and pore domain of adjacent KCNQ1 subunits (Fig.…”