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KCNE4 domains required for inhibition of KCNQ1
Author(s) -
Manderfield Lauren J.,
Daniels Melissa A.,
Vanoye Carlos G.,
George Jr Alfred L.
Publication year - 2009
Publication title -
the journal of physiology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.802
H-Index - 240
eISSN - 1469-7793
pISSN - 0022-3751
DOI - 10.1113/jphysiol.2008.161281
Subject(s) - transmembrane domain , tripeptide , transmembrane protein , chemistry , biology , microbiology and biotechnology , c terminus , potassium channel , biochemistry , amino acid , biophysics , receptor
Voltage‐gated potassium (K v ) channels are modulated in distinct ways by members of the KCNE family of single transmembrane domain accessory subunits. KCNE4 has a dramatic inhibitory effect on KCNQ1 that differs substantially from the activating effects of KCNE1 and KCNE3. The structural features of KCNE4 that enable this behaviour are unknown. We exploited chimeras of KCNE1, KCNE3 and KCNE4 to identify specific domains responsible for the inhibitory effects on heterologously expressed KCNQ1. Previous structure–function analysis of KCNE1 and KCNE3 identified a critical tripeptide motif within the transmembrane domain that accounts for the differences in KCNQ1 modulation evoked by these two KCNE proteins. Swapping the transmembrane tripeptide motif of KCNE4 with the corresponding amino acid sequence of KCNE1 did not influence the behaviour of either protein. Similarly, exchanging the tripeptide regions of KCNE3 and KCNE4 further demonstrated that this transmembrane motif does not explain the activity of KCNE4. Using a more systematic approach, we demonstrated that the KCNE4 C‐terminus was critical for KCNQ1 modulation. Replacement of the KCNE1 or KCNE3 C‐termini with that of KCNE4 created chimeric proteins that strongly inhibited KCNQ1. Additional evidence supported a cooperative role of the KCNE4 transmembrane domain. Although the C‐terminus was necessary for KCNE4 activity, we demonstrated that a surrogate transmembrane domain derived from the cytokine receptor CD8 did not enable inhibition of KCNQ1, indicating that the KCNE4 C‐terminus alone was not sufficient for KCNQ1 modulation. We further demonstrated that the KCNE4 C‐terminus interacts with KCNQ1. Our data reveal important structure–function relationships for KCNE4 that help advance our understanding of potassium channel modulation by KCNE proteins.