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- EMDB-7538: Cryo-EM structure of the human SK4/calmodulin channel complex in ... -

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Basic information

Entry
Database: EMDB / ID: EMD-7538
TitleCryo-EM structure of the human SK4/calmodulin channel complex in the Ca2+ bound state I
Map datahuman SK4/calmodulin channel complex in the Ca2+ bound state I: sharpened, filtered map
Sample
  • Complex: human SK4/calmodulin channel complex
    • Protein or peptide: Intermediate conductance calcium-activated potassium channel protein 4
    • Protein or peptide: Calmodulin-1
  • Ligand: POTASSIUM IONPotassium
  • Ligand: (2S)-3-(hexadecanoyloxy)-2-[(9Z)-octadec-9-enoyloxy]propyl 2-(trimethylammonio)ethyl phosphate
  • Ligand: DODECYL-BETA-D-MALTOSIDE
  • Ligand: CALCIUM IONCalcium
Keywordsion channel / neuroscience / calmodulin / MEMBRANE PROTEIN
Function / homology
Function and homology information


intermediate conductance calcium-activated potassium channel activity / small conductance calcium-activated potassium channel activity / saliva secretion / Ca2+ activated K+ channels / calcium-activated potassium channel activity / stabilization of membrane potential / positive regulation of potassium ion transmembrane transport / cell volume homeostasis / CaM pathway / Cam-PDE 1 activation ...intermediate conductance calcium-activated potassium channel activity / small conductance calcium-activated potassium channel activity / saliva secretion / Ca2+ activated K+ channels / calcium-activated potassium channel activity / stabilization of membrane potential / positive regulation of potassium ion transmembrane transport / cell volume homeostasis / CaM pathway / Cam-PDE 1 activation / Sodium/Calcium exchangers / phospholipid translocation / 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 / PKA activation / negative regulation of high voltage-gated calcium channel activity / CaMK IV-mediated phosphorylation of CREB / Glycogen breakdown (glycogenolysis) / negative regulation of calcium ion export across plasma membrane / organelle localization by membrane tethering / Activation of RAC1 downstream of NMDARs / regulation of cardiac muscle cell action potential / mitochondrion-endoplasmic reticulum membrane tethering / CLEC7A (Dectin-1) induces NFAT activation / autophagosome membrane docking / immune system process / positive regulation of T cell receptor signaling pathway / positive regulation of ryanodine-sensitive calcium-release channel activity / Negative regulation of NMDA receptor-mediated neuronal transmission / regulation of cell communication by electrical coupling involved in cardiac conduction / Unblocking of NMDA receptors, glutamate binding and activation / negative regulation of peptidyl-threonine phosphorylation / Synthesis of IP3 and IP4 in the cytosol / Phase 0 - rapid depolarisation / protein phosphatase activator activity / RHO GTPases activate PAKs / positive regulation of cyclic-nucleotide phosphodiesterase activity / potassium channel activity / positive regulation of phosphoprotein phosphatase activity / Long-term potentiation / Ion transport by P-type ATPases / Uptake and function of anthrax toxins / Calcineurin activates NFAT / Regulation of MECP2 expression and activity / catalytic complex / DARPP-32 events / detection of calcium ion / negative regulation of ryanodine-sensitive calcium-release channel activity / Smooth Muscle Contraction / RHO GTPases activate IQGAPs / regulation of cardiac muscle contraction / calcium channel inhibitor activity / cellular response to interferon-beta / regulation of cardiac muscle contraction by regulation of the release of sequestered calcium ion / Protein methylation / voltage-gated potassium channel complex / Activation of AMPK downstream of NMDARs / eNOS activation / regulation of release of sequestered calcium ion into cytosol by sarcoplasmic reticulum / regulation of calcium-mediated signaling / positive regulation of protein dephosphorylation / titin binding / regulation of ryanodine-sensitive calcium-release channel activity / Tetrahydrobiopterin (BH4) synthesis, recycling, salvage and regulation / Ion homeostasis / positive regulation of protein autophosphorylation / potassium ion transmembrane transport / sperm midpiece / calcium channel complex / substantia nigra development / adenylate cyclase activator activity / Ras activation upon Ca2+ influx through NMDA receptor / regulation of heart rate / protein serine/threonine kinase activator activity / sarcomere / FCERI mediated Ca+2 mobilization / FCGR3A-mediated IL10 synthesis / VEGFR2 mediated vascular permeability / positive regulation of peptidyl-threonine phosphorylation / Antigen activates B Cell Receptor (BCR) leading to generation of second messengers / VEGFR2 mediated cell proliferation / regulation of cytokinesis / Translocation of SLC2A4 (GLUT4) to the plasma membrane / spindle microtubule / establishment of localization in cell / positive regulation of protein secretion / RAF activation / positive regulation of receptor signaling pathway via JAK-STAT / defense response / positive regulation of protein serine/threonine kinase activity / Transcriptional activation of mitochondrial biogenesis / potassium ion transport / Stimuli-sensing channels / spindle pole / cellular response to type II interferon / response to calcium ion
Similarity search - Function
Calmodulin-binding domain / Potassium channel, calcium-activated, SK / SK, calmodulin-binding domain superfamily / Calmodulin binding domain / Calcium-activated SK potassium channel / Calmodulin binding domain / Potassium channel domain / Ion channel / EF-hand domain pair / EF-hand, calcium binding motif ...Calmodulin-binding domain / Potassium channel, calcium-activated, SK / SK, calmodulin-binding domain superfamily / Calmodulin binding domain / Calcium-activated SK potassium channel / Calmodulin binding domain / Potassium channel domain / Ion channel / 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 / EF-hand domain pair
Similarity search - Domain/homology
Intermediate conductance calcium-activated potassium channel protein 4 / Calmodulin-1
Similarity search - Component
Biological speciesHomo sapiens (human)
Methodsingle particle reconstruction / cryo EM / Resolution: 3.5 Å
AuthorsLee CH / MacKinnon R
Funding support United States, 2 items
OrganizationGrant numberCountry
National Institutes of Health/National Human Genome Research Institute (NIH/NHGRI)GM43949 United States
Howard Hughes Medical Institute (HHMI) United States
CitationJournal: Science / Year: 2018
Title: Activation mechanism of a human SK-calmodulin channel complex elucidated by cryo-EM structures.
Authors: Chia-Hsueh Lee / Roderick MacKinnon /
Abstract: Small-conductance Ca-activated K (SK) channels mediate neuron excitability and are associated with synaptic transmission and plasticity. They also regulate immune responses and the size of blood ...Small-conductance Ca-activated K (SK) channels mediate neuron excitability and are associated with synaptic transmission and plasticity. They also regulate immune responses and the size of blood cells. Activation of SK channels requires calmodulin (CaM), but how CaM binds and opens SK channels has been unclear. Here we report cryo-electron microscopy (cryo-EM) structures of a human SK4-CaM channel complex in closed and activated states at 3.4- and 3.5-angstrom resolution, respectively. Four CaM molecules bind to one channel tetramer. Each lobe of CaM serves a distinct function: The C-lobe binds to the channel constitutively, whereas the N-lobe interacts with the S4-S5 linker in a Ca-dependent manner. The S4-S5 linker, which contains two distinct helices, undergoes conformational changes upon CaM binding to open the channel pore. These structures reveal the gating mechanism of SK channels and provide a basis for understanding SK channel pharmacology.
History
DepositionMar 8, 2018-
Header (metadata) releaseMay 2, 2018-
Map releaseMay 2, 2018-
UpdateMar 13, 2024-
Current statusMar 13, 2024Processing site: RCSB / Status: Released

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Structure visualization

Movie
  • Surface view with section colored by density value
  • Surface level: 0.019
  • Imaged by UCSF Chimera
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  • Surface view colored by cylindrical radius
  • Surface level: 0.019
  • Imaged by UCSF Chimera
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  • Surface view with fitted model
  • Atomic models: PDB-6cnn
  • Surface level: 0.019
  • Imaged by UCSF Chimera
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Movie viewer
Structure viewerEM map:
SurfViewMolmilJmol/JSmol
Supplemental images

emd_7538.png

Downloads & links

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Map

FileDownload / File: emd_7538.map.gz / Format: CCP4 / Size: 103 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
Annotationhuman SK4/calmodulin channel complex in the Ca2+ bound state I: sharpened, filtered map
Voxel sizeX=Y=Z: 1.03 Å
Density
Contour LevelBy AUTHOR: 0.019 / Movie #1: 0.019
Minimum - Maximum-0.07681577 - 0.15338854
Average (Standard dev.)-0.0000020241432 (±0.0039230934)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions300300300
Spacing300300300
CellA=B=C: 309.0 Å
α=β=γ: 90.0 °

CCP4 map header:

modeImage stored as Reals
Å/pix. X/Y/Z1.031.031.03
M x/y/z300300300
origin x/y/z0.0000.0000.000
length x/y/z309.000309.000309.000
α/β/γ90.00090.00090.000
MAP C/R/S123
start NC/NR/NS000
NC/NR/NS300300300
D min/max/mean-0.0770.153-0.000

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Supplemental data

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Additional map: human SK4/calmodulin channel complex in the Ca2+ bound...

Fileemd_7538_additional.map
Annotationhuman SK4/calmodulin channel complex in the Ca2+ bound state I: unsharpened, unfiltered map
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Sample components

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Entire : human SK4/calmodulin channel complex

EntireName: human SK4/calmodulin channel complex
Components
  • Complex: human SK4/calmodulin channel complex
    • Protein or peptide: Intermediate conductance calcium-activated potassium channel protein 4
    • Protein or peptide: Calmodulin-1
  • Ligand: POTASSIUM IONPotassium
  • Ligand: (2S)-3-(hexadecanoyloxy)-2-[(9Z)-octadec-9-enoyloxy]propyl 2-(trimethylammonio)ethyl phosphate
  • Ligand: DODECYL-BETA-D-MALTOSIDE
  • Ligand: CALCIUM IONCalcium

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Supramolecule #1: human SK4/calmodulin channel complex

SupramoleculeName: human SK4/calmodulin channel complex / type: complex / ID: 1 / Parent: 0 / Macromolecule list: #1-#2
Source (natural)Organism: Homo sapiens (human)

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Macromolecule #1: Intermediate conductance calcium-activated potassium channel protein 4

MacromoleculeName: Intermediate conductance calcium-activated potassium channel protein 4
type: protein_or_peptide / ID: 1 / Number of copies: 4 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 47.758496 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString: MGGDLVLGLG ALRRRKRLLE QEKSLAGWAL VLAGTGIGLM VLHAEMLWFG GCSWALYLFL VKCTISISTF LLLCLIVAFH AKEVQLFMT DNGLRDWRVA LTGRQAAQIV LELVVCGLHP APVRGPPCVQ DLGAPLTSPQ PWPGFLGQGE ALLSLAMLLR L YLVPRAVL ...String:
MGGDLVLGLG ALRRRKRLLE QEKSLAGWAL VLAGTGIGLM VLHAEMLWFG GCSWALYLFL VKCTISISTF LLLCLIVAFH AKEVQLFMT DNGLRDWRVA LTGRQAAQIV LELVVCGLHP APVRGPPCVQ DLGAPLTSPQ PWPGFLGQGE ALLSLAMLLR L YLVPRAVL LRSGVLLNAS YRSIGALNQV RFRHWFVAKL YMNTHPGRLL LGLTLGLWLT TAWVLSVAER QAVNATGHLS DT LWLIPIT FLTIGYGDVV PGTMWGKIVC LCTGVMGVCC TALLVAVVAR KLEFNKAEKH VHNFMMDIQY TKEMKESAAR VLQ EAWMFY KHTRRKESHA ARRHQRKLLA AINAFRQVRL KHRKLREQVN SMVDISKMHM ILYDLQQNLS SSHRALEKQI DTLA GKLDA LTELLSTALG PRQLPEPSQQ SK

UniProtKB: Intermediate conductance calcium-activated potassium channel protein 4

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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 ION

MacromoleculeName: POTASSIUM ION / type: ligand / ID: 3 / Number of copies: 4 / Formula: K
Molecular weightTheoretical: 39.098 Da

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Macromolecule #4: (2S)-3-(hexadecanoyloxy)-2-[(9Z)-octadec-9-enoyloxy]propyl 2-(tri...

MacromoleculeName: (2S)-3-(hexadecanoyloxy)-2-[(9Z)-octadec-9-enoyloxy]propyl 2-(trimethylammonio)ethyl phosphate
type: ligand / ID: 4 / Number of copies: 4 / Formula: POV
Molecular weightTheoretical: 760.076 Da
Chemical component information

ChemComp-POV:
(2S)-3-(hexadecanoyloxy)-2-[(9Z)-octadec-9-enoyloxy]propyl 2-(trimethylammonio)ethyl phosphate / phospholipid*YM / POPC

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Macromolecule #5: DODECYL-BETA-D-MALTOSIDE

MacromoleculeName: DODECYL-BETA-D-MALTOSIDE / type: ligand / ID: 5 / Number of copies: 8 / Formula: LMT
Molecular weightTheoretical: 510.615 Da
Chemical component information

ChemComp-LMT:
DODECYL-BETA-D-MALTOSIDE / detergent*YM

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Macromolecule #6: CALCIUM ION

MacromoleculeName: CALCIUM ION / type: ligand / ID: 6 / 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

BufferpH: 8
VitrificationCryogen name: ETHANE

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Electron microscopy

MicroscopeFEI TITAN KRIOS
Electron beamAcceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron opticsIllumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELDBright-field microscopy
Image recordingFilm or detector model: GATAN K2 SUMMIT (4k x 4k) / Average electron dose: 75.0 e/Å2
Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company

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Image processing

Startup modelType of model: OTHER
Initial angle assignmentType: PROJECTION MATCHING
Final angle assignmentType: PROJECTION MATCHING
Final reconstructionApplied symmetry - Point group: C4 (4 fold cyclic) / Resolution.type: BY AUTHOR / Resolution: 3.5 Å / Resolution method: FSC 0.143 CUT-OFF / Number images used: 91511

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