Structural basis for KCNE3 modulation of potassium recycling in epithelia.
The single-span membrane protein KCNE3 modulates a variety of voltage-gated ion channels in diverse biological contexts. In epithelial cells, KCNE3 regulates the function of the KCNQ1 potassium ion (K(+)) channel to enable K(+) recycling coupled to transepithelial chloride ion (Cl(-)) secretion, a physiologically critical cellular transport process in various organs and whose malfunction causes diseases, such as cystic fibrosis (CF), cholera, and pulmonary edema. Structural, computational, biochemical, and electrophysiological studies lead to an atomically explicit integrative structural model of the KCNE3-KCNQ1 complex that explains how KCNE3 induces the constitutive activation of KCNQ1 channel activity, a crucial component in K(+) recycling. Central to this mechanism are direct interactions of KCNE3 residues at both ends of its transmembrane domain with residues on the intra- and extracellular ends of the KCNQ1 voltage-sensing domain S4 helix. These interactions appear to stabilize the activated "up" state configuration of S4, a prerequisite for full opening of the KCNQ1 channel gate. In addition, the integrative structural model was used to guide electrophysiological studies that illuminate the molecular basis for how estrogen exacerbates CF lung disease in female patients, a phenomenon known as the "CF gender gap."
Department of Biochemistry, Vanderbilt University, Nashville, TN 37240, USA.; Center for Structural Biology, Vanderbilt University, Nashville, TN 37240, USA.
Brett M
0000-0001-6215-0803
BM
Kroncke
Department of Biochemistry, Vanderbilt University, Nashville, TN 37240, USA.; Center for Structural Biology, Vanderbilt University, Nashville, TN 37240, USA.; School of Molecular Sciences, Arizona State University, Tempe, AZ 85287, USA.; Biodesign Institute, Arizona State University, Tempe, AZ 85287, USA.; Center for Personalized Diagnostics, Arizona State University, Tempe, AZ 85287, USA.
Wade D
WD
Van Horn
Department of Biochemistry, Vanderbilt University, Nashville, TN 37240, USA.; Center for Structural Biology, Vanderbilt University, Nashville, TN 37240, USA.
Jarrod
0000-0003-0895-2922
J
Smith
Department of Biochemistry, Vanderbilt University, Nashville, TN 37240, USA.; Center for Structural Biology, Vanderbilt University, Nashville, TN 37240, USA.; Experimental Therapeutics Centre, Agency for Science Technology and Research, Singapore, Singapore.
CongBao
0000-0002-9886-9374
C
Kang
Department of Medicine, Vanderbilt University Medical Center, Nashville, TN 37240, USA.
Richard C
RC
Welch
Department of Biochemistry, Vanderbilt University, Nashville, TN 37240, USA.; Center for Structural Biology, Vanderbilt University, Nashville, TN 37240, USA.
Yuanli
0000-0002-5078-8049
Y
Song
Center for Structural Biology, Vanderbilt University, Nashville, TN 37240, USA.; Department of Chemistry, Vanderbilt University, Nashville, TN 37235, USA.
David P
0000-0002-4946-3263
DP
Nannemann
Department of Biochemistry, Vanderbilt University, Nashville, TN 37240, USA.; Center for Structural Biology, Vanderbilt University, Nashville, TN 37240, USA.
Keenan C
0000-0002-2885-2964
KC
Taylor
School of Molecular Sciences, Arizona State University, Tempe, AZ 85287, USA.; Biodesign Institute, Arizona State University, Tempe, AZ 85287, USA.; Center for Personalized Diagnostics, Arizona State University, Tempe, AZ 85287, USA.
Nicholas J
0000-0001-8098-2726
NJ
Sisco
Department of Pharmacology, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USA.
Alfred L
AL
George
Center for Structural Biology, Vanderbilt University, Nashville, TN 37240, USA.; Department of Chemistry, Vanderbilt University, Nashville, TN 37235, USA.
Jens
J
Meiler
Department of Pharmacology, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USA.
Carlos G
0000-0002-4935-1122
CG
Vanoye
Department of Biochemistry, Vanderbilt University, Nashville, TN 37240, USA.; Center for Structural Biology, Vanderbilt University, Nashville, TN 37240, USA.; Department of Medicine, Vanderbilt University Medical Center, Nashville, TN 37240, USA.
Charles R
CR
Sanders
D000818:Animals; D018118:Chloride Channels / Q000737:chemistry; D019295:Computational Biology / Q000379:methods; D003550:Cystic Fibrosis / Q000378:metabolism* / Q000473:pathology; D055724:Electrophysiological Phenomena; D004847:Epithelial Cells / Q000737:chemistry / Q000378:metabolism; D006801:Humans; D051657:KCNQ1 Potassium Channel / Q000737:chemistry* / Q000378:metabolism; D046912:Multiprotein Complexes / Q000737:chemistry* / Q000378:metabolism; D011188:Potassium / Q000737:chemistry / Q000378:metabolism; D024642:Potassium Channels, Voltage-Gated / Q000737:chemistry* / Q000378:metabolism; D000072417:Protein Domains
D018118:Chloride Channels; C418492:KCNE3 protein, human; D051657:KCNQ1 Potassium Channel; D046912:Multiprotein Complexes; D024642:Potassium Channels, Voltage-Gated; D011188:Potassium
KCNE3; KCNQ1; Kv7.1; NMR; Structural biology; channel; cystic fibrosis; estrogen; integrative modeling; potassium