Structural basis for KCNE3 modulation of potassium recycling in epithelia

Brett M. Kroncke, Wade Van Horn, Jarrod Smith, Cong Bao Kang, Richard C. Welch, Yuanli Song, David P. Nannemann, Keenan C. Taylor, Nicholas J. Sisco, Alfred L. George, Jens Meiler, Carlos G. Vanoye, Charles R. Sanders

Research output: Contribution to journalArticle

13 Citations (Scopus)

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.

Original languageEnglish (US)
Article numbere1501228
JournalScience advances
Volume2
Issue number9
DOIs
StatePublished - Sep 1 2016

Fingerprint

Cystic Fibrosis
Potassium
Epithelium
Structural Models
Recycling
Cholera
Potassium Channels
Pulmonary Edema
Ion Channels
Lung Diseases
Chlorides
Estrogens
Membrane Proteins
Epithelial Cells
Ions

ASJC Scopus subject areas

  • Medicine(all)

Cite this

Kroncke, B. M., Van Horn, W., Smith, J., Kang, C. B., Welch, R. C., Song, Y., ... Sanders, C. R. (2016). Structural basis for KCNE3 modulation of potassium recycling in epithelia. Science advances, 2(9), [e1501228]. https://doi.org/10.1126/sciadv.1501228

Structural basis for KCNE3 modulation of potassium recycling in epithelia. / Kroncke, Brett M.; Van Horn, Wade; Smith, Jarrod; Kang, Cong Bao; Welch, Richard C.; Song, Yuanli; Nannemann, David P.; Taylor, Keenan C.; Sisco, Nicholas J.; George, Alfred L.; Meiler, Jens; Vanoye, Carlos G.; Sanders, Charles R.

In: Science advances, Vol. 2, No. 9, e1501228, 01.09.2016.

Research output: Contribution to journalArticle

Kroncke, BM, Van Horn, W, Smith, J, Kang, CB, Welch, RC, Song, Y, Nannemann, DP, Taylor, KC, Sisco, NJ, George, AL, Meiler, J, Vanoye, CG & Sanders, CR 2016, 'Structural basis for KCNE3 modulation of potassium recycling in epithelia', Science advances, vol. 2, no. 9, e1501228. https://doi.org/10.1126/sciadv.1501228
Kroncke, Brett M. ; Van Horn, Wade ; Smith, Jarrod ; Kang, Cong Bao ; Welch, Richard C. ; Song, Yuanli ; Nannemann, David P. ; Taylor, Keenan C. ; Sisco, Nicholas J. ; George, Alfred L. ; Meiler, Jens ; Vanoye, Carlos G. ; Sanders, Charles R. / Structural basis for KCNE3 modulation of potassium recycling in epithelia. In: Science advances. 2016 ; Vol. 2, No. 9.
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