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Mechanisms of KCNQ1 gating modulation by KCNE1/3 for cell-specific function

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Abstract

KCNQ1 potassium channels are essential for physiological processes such as cardiac rhythm and intestinal chloride secretion. KCNE family subunits (KCNE1–5) associate with KCNQ1, conferring distinct properties across various tissues. KCNQ1 activation requires membrane depolarization and phosphatidylinositol 4,5-bisphosphate (PIP2) whose cellular levels are controlled by Gαq-coupled GPCR activation. While modulation of KCNQ1’s voltage-dependent activation by KCNE1/3 is well-characterized, their effects on PIP2-dependent gating of KCNQ1 via GPCR signaling remain less understood. Here we resolved structures of KCNQ1–KCNE1 and reassessed the reported KCNQ1–KCNE3 structures with and without PIP2. We revealed that KCNQ1–KCNE1/3 complexes feature two PIP2-binding sites, with KCNE1/3 contributing to a previously overlooked, uncharacterized site involving residues critical for coupling voltage sensor and pore domains. Via this site, KCNE1 and KCNE3 distinctly modulate the PIP2-dependent gating, in addition to the voltage sensitivity, of KCNQ1. Consequently, KCNE3 converts KCNQ1 into a voltage-insensitive PIP2-gated channel governed by GPCR signaling to maintain ion homeostasis in non-excitable cells. KCNE1, by significantly enhancing KCNQ1’s PIP2 affinity and resistance to GPCR regulation, forms predominantly voltage-gated channels with KCNQ1 for conducting the slow-delayed rectifier current in excitable cardiac cells. Our study highlights how KCNE1/3 modulates KCNQ1 gating in different cellular contexts, providing insights into tissue-specifically targeting multi-functional channels.

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Fig. 1: Structural and functional characterization of KCNQ1 and KCNQ1–KCNEs.
Fig. 2: PIP2-binding sites in the KCNQ1–KCNE1 complex.
Fig. 3: PIP2-binding sites in KCNQ1 and KCNQ1–KCNE complexes.
Fig. 4: Sensitivity of KCNQ1 and KCNQ1–KCNE complexes to GqPCR pathway.
Fig. 5: Working model of the cell-specific regulation of KCNQ1.

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Data availability

Plasmids generated in this study are available upon request. All tpr files associated with MD simulations in this study are available through the link at Zenodo (https://zenodo.org/records/14632060). The cryo-EM maps of KCNQ1( + PIP2) and KCNQ1–KCNE1 ( + /–PIP2) have been deposited in the Electron Microscopy Data Bank under the accession codes: EMD-65013 (KCNQ1 with PIP2, bent), EMD-65014 (KCNQ1 with PIP2, straight), EMD-64997 (KCNQ1–KCNE1, bent) and EMD-65008 (KCNQ1–KCNE1 with PIP2, straight). The corresponding coordinates have been deposited in the Protein Data Bank under the accession codes: 9VEN, 9VEO, 9VEC, and 9VEI.

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Acknowledgements

We thank the staff at the cryo-EM facility at St Jude Children’s Research Hospital for help with data collection, Ines Chen for constructive feedback on manuscript writing and members from Sun lab, including Xiao Chen, Patricia Hixson and Hanwen Zhu for helpful discussions and support. This research is funded by American Lebanese Syrian Associated Charities (ALSAC), President Young Professorship (PYP) from National University of Singapore, MOE Tier 1 grant A-8002958-00-00 and NIH R00HL143037 (to J.S.); US-Israel BSF research grant 2019159, NIH R01 HL155398 and R01 HL166628 (to J.C.); the Knut and Alice Wallenberg Foundation, the Science for Life Laboratory, the Swedish eScience Research Center and Swedish Research Council grants VR 2019-02433 and 2022-04305 (to L.D.); the National Academic Infrastructure for Supercomputing in Sweden (NAISS) and the Swedish Research Council through grant agreement no. 2022-06725 (to L.D.) funded the MD simulations; Ministry of Education Tier 1 and 2 grants A-8000037-00-00, A-8002962-00-00, T2EP30222-0042, National University of Singapore PYP A-0008405-00-00, A-0008405-01-00 and National Research Foundation Fellowship grant NRFF15-2023-0005 (to Y.Z.T.).

Author information

Author notes

  1. Tanadet Pipatpolkai

    Present address: Division of Physics and Applied Physics, Nanyang Technological University, Singapore, Singapore

  2. These authors contributed equally: Chenxi Cui, Lu Zhao, Ali A. Kermani, Shuzong Du.

Authors and Affiliations

  1. Department of Biological Sciences, National University of Singapore, Singapore, Singapore

    Chenxi Cui, Meiqin Jiang, Yong Zi Tan & Ji Sun

  2. Biomedical Engineering at Washington University in St. Louis, St. Louis, MO, USA

    Lu Zhao, Shuzong Du, Jingyi Shi & Jianmin Cui

  3. Department of Structural Biology, St Jude Children’s Research Hospital, Memphis, TN, USA

    Ali A. Kermani & Sagar Chittori

  4. Department of Applied Physics, KTH Royal Institute of Technology, Stockholm, Sweden

    Tanadet Pipatpolkai & Lucie Delemotte

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Contributions

J.S. and J.C. conceived, designed and supervised the study. A.A.K. and S.C. collected cryo-EM data. C.C. and A.A.K. performed cryo-EM data processing and analyzed the structures under the supervision of J.S. C.C., A.A.K. and M.J. did model building. L.Z. and S.D. conducted the electrophysical experiments and related data analysis under the supervision of J.C. T.P. performed the MD simulations and analysis under supervision of L.D. Y.Z.T. and Jingyi S. provided intellectual and technical support during the project. J.S. prepared the manuscript draft with input from all authors.

Corresponding authors

Correspondence to Jianmin Cui or Ji Sun.

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The authors declare no competing interests.

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Supplementary information

Supplementary information, Fig. S1: Structural determination of KCNQ1–KCNE1 in the presence of PIP2

Supplementary information, Fig. S2: Structural determination of KCNQ1 in the presence of PIP2

Supplementary information, Fig. S3: Structural determination of KCNQ1–KCNE1 in the absence of PIP2

Supplementary information, Fig. S4: Structural comparison between KCNQ1 and KCNQ1–KCNE1/3

Supplementary information, Fig. S5: Structural comparison between KCNQ1–KCNE1 and KCNQ1–KCNE3

Supplementary information, Fig. S6: PIP2-binding sites in KCNQ1 and KCNQ1–KCNE complexes

Supplementary information, Fig. S7: Structural and functional characterization of mutations at Site 2

Supplementary information, Fig. S8: MD simulation of PIP2 binding

Supplementary information, Fig. S9: GPCR activation and KCNQ1–KCNE1 current

Supplementary information, Fig. S10: Representative traces of PLC titration and channel inhibition

Supplementary information, Table S1: Cryo-EM data collection, refinement and validation statistics

Supplementary information, Video S1: Site 2 PIP2-induced conformational change of KCNQ1 at the protomer level

Supplementary information, Video S2: Site 2 PIP2-induced conformational change of KCNQ1 at the pore region

Supplementary information, Video S3: PIP2-binding site remodeling by KCNE1

Supplementary information, Video S4: PIP2-binding site remodeling by KCNE3

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Cui, C., Zhao, L., Kermani, A.A. et al. Mechanisms of KCNQ1 gating modulation by KCNE1/3 for cell-specific function. Cell Res (2025). https://doi.org/10.1038/s41422-025-01152-1

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