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- EMDB-25816: Structure of Xenopus KCNQ1-CaM -

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Basic information

Entry
Database: EMDB / ID: EMD-25816
TitleStructure of Xenopus KCNQ1-CaM
Map data
Sample
  • Complex: Potassium voltage-gated channel subfamily KQT member 1 in complex with calmodulin
    • Protein or peptide: Potassium voltage-gated channel subfamily KQT member 1
    • Protein or peptide: Calmodulin-1
  • Ligand: CALCIUM ION
Keywordsion channel / TRANSPORT PROTEIN
Function / homology
Function and homology information


regulation of gastric acid secretion / membrane repolarization / delayed rectifier potassium channel activity / outward rectifier potassium channel activity / CaM pathway / intestinal absorption / Cam-PDE 1 activation / Sodium/Calcium exchangers / Calmodulin induced events / Reduction of cytosolic Ca++ levels ...regulation of gastric acid secretion / membrane repolarization / delayed rectifier potassium channel activity / outward rectifier potassium channel activity / CaM pathway / intestinal absorption / Cam-PDE 1 activation / Sodium/Calcium exchangers / Calmodulin induced events / Reduction of cytosolic Ca++ levels / CREB1 phosphorylation through the activation of CaMKII/CaMKK/CaMKIV cascasde / Activation of Ca-permeable Kainate Receptor / Loss of phosphorylation of MECP2 at T308 / monoatomic ion channel complex / CREB1 phosphorylation through the activation of Adenylate Cyclase / PKA activation / negative regulation of high voltage-gated calcium channel activity / CaMK IV-mediated phosphorylation of CREB / positive regulation of cyclic-nucleotide phosphodiesterase activity / Glycogen breakdown (glycogenolysis) / organelle localization by membrane tethering / negative regulation of calcium ion export across plasma membrane / CLEC7A (Dectin-1) induces NFAT activation / regulation of cardiac muscle cell action potential / mitochondrion-endoplasmic reticulum membrane tethering / autophagosome membrane docking / Activation of RAC1 downstream of NMDARs / renal absorption / positive regulation of ryanodine-sensitive calcium-release channel activity / regulation of cell communication by electrical coupling involved in cardiac conduction / Negative regulation of NMDA receptor-mediated neuronal transmission / negative regulation of peptidyl-threonine phosphorylation / Synthesis of IP3 and IP4 in the cytosol / Unblocking of NMDA receptors, glutamate binding and activation / voltage-gated potassium channel activity / Phase 0 - rapid depolarisation / protein phosphatase activator activity / RHO GTPases activate PAKs / positive regulation of phosphoprotein phosphatase activity / Ion transport by P-type ATPases / inner ear development / Long-term potentiation / Uptake and function of anthrax toxins / Regulation of MECP2 expression and activity / Calcineurin activates NFAT / catalytic complex / DARPP-32 events / detection of calcium ion / regulation of cardiac muscle contraction / negative regulation of ryanodine-sensitive calcium-release channel activity / Smooth Muscle Contraction / calcium channel inhibitor activity / RHO GTPases activate IQGAPs / cellular response to interferon-beta / regulation of cardiac muscle contraction by regulation of the release of sequestered calcium ion / Protein methylation / eNOS activation / Activation of AMPK downstream of NMDARs / regulation of release of sequestered calcium ion into cytosol by sarcoplasmic reticulum / Tetrahydrobiopterin (BH4) synthesis, recycling, salvage and regulation / regulation of calcium-mediated signaling / positive regulation of protein dephosphorylation / Ion homeostasis / titin binding / regulation of ryanodine-sensitive calcium-release channel activity / voltage-gated potassium channel complex / positive regulation of protein autophosphorylation / sperm midpiece / calcium channel complex / substantia nigra development / phosphatidylinositol-4,5-bisphosphate binding / adenylate cyclase activator activity / Ras activation upon Ca2+ influx through NMDA receptor / regulation of heart rate / sarcomere / protein serine/threonine kinase activator activity / FCERI mediated Ca+2 mobilization / FCGR3A-mediated IL10 synthesis / VEGFR2 mediated vascular permeability / positive regulation of peptidyl-threonine phosphorylation / regulation of cytokinesis / Antigen activates B Cell Receptor (BCR) leading to generation of second messengers / VEGFR2 mediated cell proliferation / Translocation of SLC2A4 (GLUT4) to the plasma membrane / RAF activation / positive regulation of receptor signaling pathway via JAK-STAT / cytoplasmic vesicle membrane / Transcriptional activation of mitochondrial biogenesis / positive regulation of protein serine/threonine kinase activity / spindle microtubule / Stimuli-sensing channels / cellular response to type II interferon / spindle pole / response to calcium ion / RAS processing / G2/M transition of mitotic cell cycle / Signaling by RAF1 mutants / Signaling by moderate kinase activity BRAF mutants / Paradoxical activation of RAF signaling by kinase inactive BRAF / Signaling downstream of RAS mutants
Similarity search - Function
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. ...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 KQT member 1
Similarity search - Component
Biological speciesXenopus laevis (African clawed frog) / Homo sapiens (human)
Methodsingle particle reconstruction / cryo EM / Resolution: 3.84 Å
AuthorsWillegems K / Kyriakis E
Funding support Canada, 1 items
OrganizationGrant numberCountry
Canadian Institutes of Health Research (CIHR) Canada
CitationJournal: Nat Commun / Year: 2022
Title: Structural and electrophysiological basis for the modulation of KCNQ1 channel currents by ML277.
Authors: Katrien Willegems / Jodene Eldstrom / Efthimios Kyriakis / Fariba Ataei / Harutyun Sahakyan / Ying Dou / Sophia Russo / Filip Van Petegem / David Fedida /
Abstract: The KCNQ1 ion channel plays critical physiological roles in electrical excitability and K recycling in organs including the heart, brain, and gut. Loss of function is relatively common and can cause ...The KCNQ1 ion channel plays critical physiological roles in electrical excitability and K recycling in organs including the heart, brain, and gut. Loss of function is relatively common and can cause sudden arrhythmic death, sudden infant death, epilepsy and deafness. Here, we report cryogenic electron microscopic (cryo-EM) structures of Xenopus KCNQ1 bound to Ca/Calmodulin, with and without the KCNQ1 channel activator, ML277. A single binding site for ML277 was identified, localized to a pocket lined by the S4-S5 linker, S5 and S6 helices of two separate subunits. Several pocket residues are not conserved in other KCNQ isoforms, explaining specificity. MD simulations and point mutations support this binding location for ML277 in open and closed channels and reveal that prevention of inactivation is an important component of the activator effect. Our work provides direction for therapeutic intervention targeting KCNQ1 loss of function pathologies including long QT interval syndrome and seizures.
History
DepositionDec 27, 2021-
Header (metadata) releaseJul 6, 2022-
Map releaseJul 6, 2022-
UpdateFeb 28, 2024-
Current statusFeb 28, 2024Processing site: RCSB / Status: Released

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Structure visualization

Supplemental images

emd_25816.png

Downloads & links

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Map

FileDownload / File: emd_25816.map.gz / Format: CCP4 / Size: 209.3 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
Voxel sizeX=Y=Z: 0.73 Å
Density
Contour LevelBy AUTHOR: 0.0617
Minimum - Maximum-0.23868155 - 0.51756716
Average (Standard dev.)0.007734223 (±0.017269583)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions380380380
Spacing380380380
CellA=B=C: 277.4 Å
α=β=γ: 90.0 °

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Supplemental data

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Sample components

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Entire : Potassium voltage-gated channel subfamily KQT member 1 in complex...

EntireName: Potassium voltage-gated channel subfamily KQT member 1 in complex with calmodulin
Components
  • Complex: Potassium voltage-gated channel subfamily KQT member 1 in complex with calmodulin
    • Protein or peptide: Potassium voltage-gated channel subfamily KQT member 1
    • Protein or peptide: Calmodulin-1
  • Ligand: CALCIUM ION

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Supramolecule #1: Potassium voltage-gated channel subfamily KQT member 1 in complex...

SupramoleculeName: Potassium voltage-gated channel subfamily KQT member 1 in complex with calmodulin
type: complex / ID: 1 / Parent: 0 / Macromolecule list: #1-#2
Source (natural)Organism: Xenopus laevis (African clawed frog)
Molecular weightTheoretical: 317.56 KDa

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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 / Number of copies: 4 / Enantiomer: LEVO
Source (natural)Organism: Xenopus laevis (African clawed frog)
Molecular weightTheoretical: 62.663398 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString: MATDPPRPTI NLDPRVSIYS GRRPLLSRTN IQGRVYNFLE RPTGWKCFVY HFTVFLIVLI CLIFSVLSTI QQYNNLATET LFWMEIVLV VFFGAEYVVR LWSAGCRSKY VGVWGRLRFA RKPISVIDLI VVVASVIVLC VGSNGQVFAT SAIRGIRFLQ I LRMLHVDR ...String:
MATDPPRPTI NLDPRVSIYS GRRPLLSRTN IQGRVYNFLE RPTGWKCFVY HFTVFLIVLI CLIFSVLSTI QQYNNLATET LFWMEIVLV VFFGAEYVVR LWSAGCRSKY VGVWGRLRFA RKPISVIDLI VVVASVIVLC VGSNGQVFAT SAIRGIRFLQ I LRMLHVDR QGGTWRLLGS VVFIHRQELI TTLYIGFLGL IFSSYFVYLA EKDAIDSSGE YQFGSYADAL WWGVVTVTTI GY GDKVPQT WIGKTIASCF SVFAISFFAL PAGILGSGFA LKVQQKQRQK HFNRQIPAAA SLIQTAWRCY AAENPDSATW KIY IRKQSR NHHLMSPSPK PKKSAMVKKK KIRTERDEGS TDKMLNIPHI TYDHVADDRK NDGYSVESYE NTVRKPFGFL DPST GPFIR TSSFTDDLDM EGDTLLTPIT HISELKEHHR AAIKVIRRMQ YFVAKKKFQQ ARKPYDVRDV IEQYSQGHLN LMVRI KELQ RRLDQSLGKP SLFLSVSDKV KDKGINTIGS RLNRVEDKVT QMDHKLNLIT DMLHHLLTNQ QSNS

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: CALCIUM ION

MacromoleculeName: CALCIUM ION / type: ligand / ID: 3 / Number of copies: 12 / 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

Concentration2 mg/mL
BufferpH: 7.2
Component:
ConcentrationFormulaName
150.0 mMKClpotassium chloride
20.0 mM4-(2-hydroxyethyl)-1-piperazineethanesulfonic acid
0.5 mMCaCl2Calcium chloride
2.0 mMDithiothreitol
0.05 %n-Dodecyl-B-D-maltoside
0.005 %Cholesteryl hemisuccinate
GridModel: Quantifoil R1.2/1.3 / Material: COPPER / Mesh: 400 / Pretreatment - Type: GLOW DISCHARGE / Pretreatment - Time: 25 sec.
VitrificationCryogen name: ETHANE / Chamber humidity: 98 % / Chamber temperature: 277.15 K / Instrument: FEI VITROBOT MARK IV

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Electron microscopy

MicroscopeFEI TITAN KRIOS
Image recordingFilm or detector model: FEI FALCON IV (4k x 4k) / Detector mode: COUNTING / Number grids imaged: 1 / Number real images: 19997 / Average electron dose: 50.0 e/Å2
Electron beamAcceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron opticsIllumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELD / Nominal defocus max: 4.9 µm / Nominal defocus min: 0.36 µm
Sample stageSpecimen holder model: FEI TITAN KRIOS AUTOGRID HOLDER / Cooling holder cryogen: NITROGEN
Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company

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Image processing

Particle selectionNumber selected: 1830000
Startup modelType of model: NONE
Final reconstructionApplied symmetry - Point group: C4 (4 fold cyclic) / Resolution.type: BY AUTHOR / Resolution: 3.84 Å / Resolution method: FSC 0.143 CUT-OFF / Software - Name: cryoSPARC (ver. 3.3.1) / Number images used: 71241
Initial angle assignmentType: MAXIMUM LIKELIHOOD / Software - Name: cryoSPARC (ver. 3.3.1)
Final angle assignmentType: MAXIMUM LIKELIHOOD / Software - Name: cryoSPARC (ver. 3.3.1)
FSC plot (resolution estimation)

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