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Sci Adv. 2016 Sep 9;2(9):e1501228. doi: 10.1126/sciadv.1501228. eCollection 2016 Sep.

Structural basis for KCNE3 modulation of potassium recycling in epithelia.

Author information

1
Department of Biochemistry, Vanderbilt University, Nashville, TN 37240, USA.; Center for Structural Biology, Vanderbilt University, Nashville, TN 37240, USA.
2
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.
3
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.
4
Department of Medicine, Vanderbilt University Medical Center, Nashville, TN 37240, USA.
5
Center for Structural Biology, Vanderbilt University, Nashville, TN 37240, USA.; Department of Chemistry, Vanderbilt University, Nashville, TN 37235, USA.
6
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.
7
Department of Pharmacology, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USA.
8
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.

Abstract

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."

KEYWORDS:

KCNE3; KCNQ1; Kv7.1; NMR; Structural biology; channel; cystic fibrosis; estrogen; integrative modeling; potassium

PMID:
27626070
PMCID:
PMC5017827
DOI:
10.1126/sciadv.1501228
[Indexed for MEDLINE]
Free PMC Article

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