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- EMDB-65008: structure of human KCNQ1-KCNE1-CaM complex with PIP2 -

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Basic information

Entry
Database: EMDB / ID: EMD-65008
Titlestructure of human KCNQ1-KCNE1-CaM complex with PIP2
Map data
Sample
  • Complex: structure of human KCNQ1-KCNE1-CaM complex with PIP2
    • Protein or peptide: Potassium voltage-gated channel subfamily KQT member 1
    • Protein or peptide: Calmodulin-1
    • Protein or peptide: Potassium voltage-gated channel subfamily E member 1
  • Ligand: [(2R)-1-octadecanoyloxy-3-[oxidanyl-[(1R,2R,3S,4R,5R,6S)-2,3,6-tris(oxidanyl)-4,5-diphosphonooxy-cyclohexyl]oxy-phospho ryl]oxy-propan-2-yl] (8Z)-icosa-5,8,11,14-tetraenoate
  • Ligand: CALCIUM ION
Keywordspotassium channel complex / membrane protein
Function / homology
Function and homology information


vestibular nucleus development / negative regulation of protein targeting to membrane / secretory granule organization / gastrin-induced gastric acid secretion / corticosterone secretion / voltage-gated potassium channel activity involved in atrial cardiac muscle cell action potential repolarization / basolateral part of cell / lumenal side of membrane / negative regulation of voltage-gated potassium channel activity / rhythmic behavior ...vestibular nucleus development / negative regulation of protein targeting to membrane / secretory granule organization / gastrin-induced gastric acid secretion / corticosterone secretion / voltage-gated potassium channel activity involved in atrial cardiac muscle cell action potential repolarization / basolateral part of cell / lumenal side of membrane / negative regulation of voltage-gated potassium channel activity / rhythmic behavior / regulation of gastric acid secretion / stomach development / iodide transport / voltage-gated potassium channel activity involved in cardiac muscle cell action potential repolarization / regulation of potassium ion transport / Phase 3 - rapid repolarisation / membrane repolarization during atrial cardiac muscle cell action potential / membrane repolarization during action potential / telethonin binding / Phase 2 - plateau phase / regulation of atrial cardiac muscle cell membrane repolarization / intracellular chloride ion homeostasis / membrane repolarization during ventricular cardiac muscle cell action potential / membrane repolarization during cardiac muscle cell action potential / negative regulation of delayed rectifier potassium channel activity / potassium ion export across plasma membrane / renal sodium ion absorption / voltage-gated potassium channel activity involved in ventricular cardiac muscle cell action potential repolarization / atrial cardiac muscle cell action potential / membrane repolarization / auditory receptor cell development / regulation of membrane repolarization / protein phosphatase 1 binding / detection of mechanical stimulus involved in sensory perception of sound / delayed rectifier potassium channel activity / ventricular cardiac muscle cell action potential / Voltage gated Potassium channels / potassium ion homeostasis / positive regulation of potassium ion transmembrane transport / regulation of ventricular cardiac muscle cell membrane repolarization / non-motile cilium assembly / cardiac muscle cell action potential involved in contraction / outward rectifier potassium channel activity / cardiac muscle cell contraction / regulation of potassium ion transmembrane transport / epithelial cell maturation / CaM pathway / Cam-PDE 1 activation / Sodium/Calcium exchangers / intestinal absorption / Calmodulin induced events / Reduction of cytosolic Ca++ levels / Activation of Ca-permeable Kainate Receptor / CREB1 phosphorylation through the activation of CaMKII/CaMKK/CaMKIV cascasde / Loss of phosphorylation of MECP2 at T308 / CREB1 phosphorylation through the activation of Adenylate Cyclase / inner ear morphogenesis / CaMK IV-mediated phosphorylation of CREB / PKA activation / negative regulation of high voltage-gated calcium channel activity / Glycogen breakdown (glycogenolysis) / CLEC7A (Dectin-1) induces NFAT activation / Activation of RAC1 downstream of NMDARs / negative regulation of ryanodine-sensitive calcium-release channel activity / organelle localization by membrane tethering / mitochondrion-endoplasmic reticulum membrane tethering / adrenergic receptor signaling pathway / autophagosome membrane docking / negative regulation of calcium ion export across plasma membrane / regulation of cardiac muscle cell action potential / renal absorption / presynaptic endocytosis / regulation of heart contraction / ciliary base / protein kinase A regulatory subunit binding / Synthesis of IP3 and IP4 in the cytosol / regulation of cell communication by electrical coupling involved in cardiac conduction / protein kinase A catalytic subunit binding / Phase 0 - rapid depolarisation / calcineurin-mediated signaling / Negative regulation of NMDA receptor-mediated neuronal transmission / potassium ion import across plasma membrane / Unblocking of NMDA receptors, glutamate binding and activation / RHO GTPases activate PAKs / inner ear development / regulation of heart rate by cardiac conduction / Ion transport by P-type ATPases / Uptake and function of anthrax toxins / regulation of ryanodine-sensitive calcium-release channel activity / action potential / Long-term potentiation / protein phosphatase activator activity / Calcineurin activates NFAT / Regulation of MECP2 expression and activity / cochlea development / social behavior / DARPP-32 events / catalytic complex / monoatomic ion channel complex / Smooth Muscle Contraction
Similarity search - Function
Potassium voltage-gated channel subfamily E member 1 / Potassium channel, voltage-dependent, beta subunit, KCNE / Slow voltage-gated potassium channel / Potassium channel, voltage dependent, KCNQ1 / Potassium channel, voltage dependent, KCNQ / Potassium channel, voltage dependent, KCNQ, C-terminal / KCNQ voltage-gated potassium channel / Voltage-dependent channel domain superfamily / : / EF-hand domain pair ...Potassium voltage-gated channel subfamily E member 1 / Potassium channel, voltage-dependent, beta subunit, KCNE / Slow voltage-gated potassium channel / Potassium channel, voltage dependent, KCNQ1 / Potassium channel, voltage dependent, KCNQ / Potassium channel, voltage dependent, KCNQ, C-terminal / KCNQ voltage-gated potassium channel / Voltage-dependent channel domain superfamily / : / EF-hand domain pair / EF-hand, calcium binding motif / EF-Hand 1, calcium-binding site / EF-hand calcium-binding domain. / EF-hand calcium-binding domain profile. / EF-hand domain / Ion transport domain / Ion transport protein / EF-hand domain pair
Similarity search - Domain/homology
Calmodulin-1 / Potassium voltage-gated channel subfamily E member 1 / Potassium voltage-gated channel subfamily KQT member 1
Similarity search - Component
Biological speciesHomo sapiens (human)
Methodsingle particle reconstruction / cryo EM / Resolution: 3.9 Å
AuthorsCui C / Kermani A / Cui J / Sun J
Funding support United States, Sweden, 6 items
OrganizationGrant numberCountry
National Institutes of Health/National Heart, Lung, and Blood Institute (NIH/NHLBI)R00HL143037 United States
United States - Israel Binational Science Foundation (BSF)2019159 United States
National Institutes of Health/National Heart, Lung, and Blood Institute (NIH/NHLBI)R01 HL155398 United States
National Institutes of Health/National Heart, Lung, and Blood Institute (NIH/NHLBI)R01 HL166628 United States
Swedish Research Council2022-04305 Sweden
Swedish Research Council2022-06725 Sweden
CitationJournal: Cell Res / Year: 2025
Title: Mechanisms of KCNQ1 gating modulation by KCNE1/3 for cell-specific function.
Authors: Chenxi Cui / Lu Zhao / Ali A Kermani / Shuzong Du / Tanadet Pipatpolkai / Meiqin Jiang / Sagar Chittori / Yong Zi Tan / Jingyi Shi / Lucie Delemotte / Jianmin Cui / Ji Sun /
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 ...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.
History
DepositionJun 9, 2025-
Header (metadata) releaseAug 20, 2025-
Map releaseAug 20, 2025-
UpdateAug 20, 2025-
Current statusAug 20, 2025Processing site: PDBj / Status: Released

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Structure visualization

Supplemental images

emd_65008.png

Downloads & links

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Map

FileDownload / File: emd_65008.map.gz / Format: CCP4 / Size: 52.7 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
Projections & slices

Image control

Size
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AxesZ (Sec.)Y (Row.)X (Col.)
1.3 Å/pix.
x 240 pix.
= 311.28 Å		1.3 Å/pix.
x 240 pix.
= 311.28 Å		1.3 Å/pix.
x 240 pix.
= 311.28 Å

Surface

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Images are generated by Spider.

Voxel sizeX=Y=Z: 1.297 Å
Density

Histogram

Histogram (log scale)
Contour LevelBy AUTHOR: 0.025
Minimum - Maximum-0.055780742 - 0.14144768
Average (Standard dev.)0.00044756444 (±0.0044063902)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions240240240
Spacing240240240
CellA=B=C: 311.28 Å
α=β=γ: 90.0 °

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Supplemental data

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Mask #1

Fileemd_65008_msk_1.map
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Half map: #2

Fileemd_65008_half_map_1.map
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Half map: #1

Fileemd_65008_half_map_2.map
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Sample components

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Entire : structure of human KCNQ1-KCNE1-CaM complex with PIP2

EntireName: structure of human KCNQ1-KCNE1-CaM complex with PIP2
Components
  • Complex: structure of human KCNQ1-KCNE1-CaM complex with PIP2
    • Protein or peptide: Potassium voltage-gated channel subfamily KQT member 1
    • Protein or peptide: Calmodulin-1
    • Protein or peptide: Potassium voltage-gated channel subfamily E member 1
  • Ligand: [(2R)-1-octadecanoyloxy-3-[oxidanyl-[(1R,2R,3S,4R,5R,6S)-2,3,6-tris(oxidanyl)-4,5-diphosphonooxy-cyclohexyl]oxy-phospho ryl]oxy-propan-2-yl] (8Z)-icosa-5,8,11,14-tetraenoate
  • Ligand: CALCIUM ION

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Supramolecule #1: structure of human KCNQ1-KCNE1-CaM complex with PIP2

SupramoleculeName: structure of human KCNQ1-KCNE1-CaM complex with PIP2 / type: complex / ID: 1 / Parent: 0 / Macromolecule list: #1-#3
Source (natural)Organism: Homo sapiens (human)

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Macromolecule #1: Potassium voltage-gated channel subfamily KQT member 1

MacromoleculeName: Potassium voltage-gated channel subfamily KQT member 1
type: protein_or_peptide / ID: 1 / Details: 76-620, mutation I145C / Number of copies: 4 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 62.07627 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString: MASDLGPRPP VSLDPRVSIY STRRPVLART HVQGRVYNFL ERPTGWKCFV YHFAVFLIVL VCLIFSVLST CEQYAALATG TLFWMEIVL VVFFGTEYVV RLWSAGCRSK YVGLWGRLRF ARKPISIIDL IVVVASMVVL CVGSKGQVFA TSAIRGIRFL Q ILRMLHVD ...String:
MASDLGPRPP VSLDPRVSIY STRRPVLART HVQGRVYNFL ERPTGWKCFV YHFAVFLIVL VCLIFSVLST CEQYAALATG TLFWMEIVL VVFFGTEYVV RLWSAGCRSK YVGLWGRLRF ARKPISIIDL IVVVASMVVL CVGSKGQVFA TSAIRGIRFL Q ILRMLHVD RQGGTWRLLG SVVFIHRQEL ITTLYIGFLG LIFSSYFVYL AEKDAVNESG RVEFGSYADA LWWGVVTVTT IG YGDKVPQ TWVGKTIASC FSVFAISFFA LPAGILGSGF ALKVQQKQRQ KHFNRQIPAA ASLIQTAWRC YAAENPDSST WKI YIRKAP RSHTLLSPSP KPKKSVVVKK KKFKLDKDNG VTPGEKMLTV PHITCDPPEE RRLDHFSVDG YDSSVRKSPT LLEV SMPHF MRTNSFAEDL DLEGETLLTP ITHISQLREH HRATIKVIRR MQYFVAKKKF QQARKPYDVR DVIEQYSQGH LNLMV RIKE LQRRLDQSIG KPSLFISVSE KSKDRGSNTI GARLNRVEDK VTQLDQRLAL ITDMLHQLLS LH

UniProtKB: Potassium voltage-gated channel subfamily KQT member 1

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Macromolecule #2: Calmodulin-1

MacromoleculeName: Calmodulin-1 / type: protein_or_peptide / ID: 2 / Number of copies: 4 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 16.852545 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString:
MADQLTEEQI AEFKEAFSLF DKDGDGTITT KELGTVMRSL GQNPTEAELQ DMINEVDADG NGTIDFPEFL TMMARKMKDT DSEEEIREA FRVFDKDGNG YISAAELRHV MTNLGEKLTD EEVDEMIREA DIDGDGQVNY EEFVQMMTAK

UniProtKB: Calmodulin-1

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Macromolecule #3: Potassium voltage-gated channel subfamily E member 1

MacromoleculeName: Potassium voltage-gated channel subfamily E member 1 / type: protein_or_peptide / ID: 3 / Details: mutation K41C / Number of copies: 4 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 14.664686 KDa
Recombinant expressionOrganism: Homo (humans)
SequenceString:
MILSNTTAVT PFLTKLWQET VQQGGNMSGL ARRSPRSSDG CLEALYVLMV LGFFGFFTLG IMLSYIRSKK LEHSNDPFNV YIESDAWQE KDKAYVQARV LESYRSCYVV ENHLAIEQPN THLPETKPSP

UniProtKB: Potassium voltage-gated channel subfamily E member 1

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Macromolecule #4: [(2R)-1-octadecanoyloxy-3-[oxidanyl-[(1R,2R,3S,4R,5R,6S)-2,3,6-tr...

MacromoleculeName: [(2R)-1-octadecanoyloxy-3-[oxidanyl-[(1R,2R,3S,4R,5R,6S)-2,3,6-tris(oxidanyl)-4,5-diphosphonooxy-cyclohexyl]oxy-phospho ryl]oxy-propan-2-yl] (8Z)-icosa-5,8,11,14-tetraenoate
type: ligand / ID: 4 / Number of copies: 8 / Formula: PT5
Molecular weightTheoretical: 1.047088 KDa

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Macromolecule #5: CALCIUM ION

MacromoleculeName: CALCIUM ION / type: ligand / ID: 5 / Number of copies: 8 / Formula: CA
Molecular weightTheoretical: 40.078 Da

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Experimental details

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Structure determination

Methodcryo EM
Processingsingle particle reconstruction
Aggregation stateparticle

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Sample preparation

BufferpH: 7.4
VitrificationCryogen name: ETHANE

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Electron microscopy

MicroscopeTFS KRIOS
Image recordingFilm or detector model: GATAN K3 BIOCONTINUUM (6k x 4k) / Average electron dose: 52.47 e/Å2
Electron beamAcceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron opticsIllumination mode: OTHER / Imaging mode: BRIGHT FIELD / Nominal defocus max: 2.0 µm / Nominal defocus min: 0.5 µm
Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company

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Image processing

CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
Startup modelType of model: INSILICO MODEL
Final reconstructionApplied symmetry - Point group: C4 (4 fold cyclic) / Resolution.type: BY AUTHOR / Resolution: 3.9 Å / Resolution method: FSC 0.143 CUT-OFF / Software - Name: RELION / Number images used: 110909
Initial angle assignmentType: RANDOM ASSIGNMENT
Final angle assignmentType: ANGULAR RECONSTITUTION
FSC plot (resolution estimation)

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