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- EMDB-51160: Structure of the human two pore domain potassium ion channel TASK... -

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Basic information

Entry
Database: EMDB / ID: EMD-51160
TitleStructure of the human two pore domain potassium ion channel TASK-1 (K2P3.1)
Map dataB factor sharpened map
Sample
  • Complex: K2P3.1 homodimer
    • Protein or peptide: Potassium channel subfamily K member 3
  • Ligand: CHOLESTEROL HEMISUCCINATE
  • Ligand: POTASSIUM ION
KeywordsK2P / membrane protein / potassium channel / ion channel
Function / homology
Function and homology information


open rectifier potassium channel activity / detection of hypoxic conditions in blood by carotid body chemoreceptor signaling / regulation of action potential firing rate / TWIK-releated acid-sensitive K+ channel (TASK) / Phase 4 - resting membrane potential / potassium ion leak channel activity / regulation of resting membrane potential / cellular response to acidic pH / outward rectifier potassium channel activity / S100 protein binding ...open rectifier potassium channel activity / detection of hypoxic conditions in blood by carotid body chemoreceptor signaling / regulation of action potential firing rate / TWIK-releated acid-sensitive K+ channel (TASK) / Phase 4 - resting membrane potential / potassium ion leak channel activity / regulation of resting membrane potential / cellular response to acidic pH / outward rectifier potassium channel activity / S100 protein binding / negative regulation of cytosolic calcium ion concentration / cellular response to zinc ion / sodium channel activity / monoatomic ion channel activity / cochlea development / potassium channel activity / potassium ion transmembrane transport / potassium ion transport / monoatomic ion transmembrane transport / cellular response to hypoxia / chemical synaptic transmission / response to xenobiotic stimulus / protein heterodimerization activity / synapse / metal ion binding / plasma membrane
Similarity search - Function
Potassium channel subfamily K member 3 / Two pore domain potassium channel, TASK family / Two pore domain potassium channel / Potassium channel domain / Ion channel
Similarity search - Domain/homology
Potassium channel subfamily K member 3
Similarity search - Component
Biological speciesHomo sapiens (human)
Methodsingle particle reconstruction / cryo EM / Resolution: 3.13 Å
AuthorsRodstrom KEJ / Hall PH / Tucker SJ
Funding support United Kingdom, 3 items
OrganizationGrant numberCountry
Biotechnology and Biological Sciences Research Council (BBSRC)BB/T002018/1 United Kingdom
Biotechnology and Biological Sciences Research Council (BBSRC)BB/S008608/1 United Kingdom
Medical Research Council (MRC, United Kingdom)MR/W017741/1 United Kingdom
CitationJournal: Structure / Year: 2025
Title: Structures of TASK-1 and TASK-3 K2P channels provide insight into their gating and dysfunction in disease.
Authors: Peter Rory Hall / Thibault Jouen-Tachoire / Marcus Schewe / Peter Proks / Thomas Baukrowitz / Elisabeth P Carpenter / Simon Newstead / Karin E J Rödström / Stephen J Tucker /
Abstract: TASK-1 and TASK-3 are pH-sensitive two-pore domain (K2P/KCNK) K channels. Their functional roles make them promising targets for treatment of multiple disorders including sleep apnea, pain, and ...TASK-1 and TASK-3 are pH-sensitive two-pore domain (K2P/KCNK) K channels. Their functional roles make them promising targets for treatment of multiple disorders including sleep apnea, pain, and atrial fibrillation. Mutations in these channels are also associated with neurodevelopmental and hypertensive disorders. A previous crystal structure of TASK-1 revealed a lower "X-gate" as a hotspot for missense gain-of-function (GoF) mutations associated with DDSA (developmental delay with sleep apnea). However, the mechanisms of gating in TASK channels are still not fully understood. Here, we resolve structures for both human TASK-1 and TASK-3 by cryoelectron microscopy (cryo-EM), as well as a recurrent TASK-3 variant (G236R) associated with KCNK9 imprinting syndrome (KIS) (formerly known as Birk-Barel syndrome). Combined with functional studies of the X-gating mechanism, we provide evidence for how a highly conserved gating mechanism becomes defective in disease, and also provide further insight into the pathway of conformational changes that underlie the pH-dependent inhibition of TASK channel activity.
History
DepositionJul 25, 2024-
Header (metadata) releaseDec 18, 2024-
Map releaseDec 18, 2024-
UpdateJan 15, 2025-
Current statusJan 15, 2025Processing site: PDBe / Status: Released

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Structure visualization

Supplemental images

emd_51160.png

Downloads & links

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Map

FileDownload / File: emd_51160.map.gz / Format: CCP4 / Size: 64 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
AnnotationB factor sharpened map
Projections & slices

Image control

Size
Brightness
Contrast
Others
AxesZ (Sec.)Y (Row.)X (Col.)
0.83 Å/pix.
x 256 pix.
= 212.992 Å		0.83 Å/pix.
x 256 pix.
= 212.992 Å		0.83 Å/pix.
x 256 pix.
= 212.992 Å

Surface

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Images are generated by Spider.

Voxel sizeX=Y=Z: 0.832 Å
Density

Histogram

Histogram (log scale)
Contour LevelBy AUTHOR: 0.2
Minimum - Maximum-1.6802871 - 2.5686445
Average (Standard dev.)0.0012509273 (±0.042038992)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions256256256
Spacing256256256
CellA=B=C: 212.992 Å
α=β=γ: 90.0 °

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Supplemental data

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Mask #1

Fileemd_51160_msk_1.map
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Mask #2

Fileemd_51160_msk_2.map
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Half map: Half map A

Fileemd_51160_half_map_1.map
AnnotationHalf map A
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Half map: Half map B

Fileemd_51160_half_map_2.map
AnnotationHalf map B
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Sample components

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Entire : K2P3.1 homodimer

EntireName: K2P3.1 homodimer
Components
  • Complex: K2P3.1 homodimer
    • Protein or peptide: Potassium channel subfamily K member 3
  • Ligand: CHOLESTEROL HEMISUCCINATE
  • Ligand: POTASSIUM ION

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Supramolecule #1: K2P3.1 homodimer

SupramoleculeName: K2P3.1 homodimer / type: complex / ID: 1 / Parent: 0 / Macromolecule list: #1
Details: Protein generated by removal of the 10xHis and FLAG purification tags with TEV protease cleavage
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 600 KDa

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Macromolecule #1: Potassium channel subfamily K member 3

MacromoleculeName: Potassium channel subfamily K member 3 / type: protein_or_peptide / ID: 1
Details: K2P3.1 residues M1 to E259 with a TEV protease site. Fused purification tags were cleaved prior to EM sample preparation.
Number of copies: 2 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 30.117014 KDa
Recombinant expressionOrganism: Spodoptera frugiperda (fall armyworm)
SequenceString: MKRQNVRTLA LIVCTFTYLL VGAAVFDALE SEPELIERQR LELRQQELRA RYNLSQGGYE ELERVVLRLK PHKAGVQWRF AGSFYFAIT VITTIGYGHA APSTDGGKVF CMFYALLGIP LTLVMFQSLG ERINTLVRYL LHRAKKGLGM RRADVSMANM V LIGFFSCI ...String:
MKRQNVRTLA LIVCTFTYLL VGAAVFDALE SEPELIERQR LELRQQELRA RYNLSQGGYE ELERVVLRLK PHKAGVQWRF AGSFYFAIT VITTIGYGHA APSTDGGKVF CMFYALLGIP LTLVMFQSLG ERINTLVRYL LHRAKKGLGM RRADVSMANM V LIGFFSCI STLCIGAAAF SHYEHWTFFQ AYYYCFITLT TIGFGDYVAL QKDQALQTQP QYVAFSFVYI LTGLTVIGAF LN LVVLRFM TMNAEDEKRD AENLYFQ

UniProtKB: Potassium channel subfamily K member 3

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Macromolecule #2: CHOLESTEROL HEMISUCCINATE

MacromoleculeName: CHOLESTEROL HEMISUCCINATE / type: ligand / ID: 2 / Number of copies: 4 / Formula: Y01
Molecular weightTheoretical: 486.726 Da
Chemical component information

ChemComp-Y01:
CHOLESTEROL HEMISUCCINATE

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Macromolecule #3: POTASSIUM ION

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

Concentration3.6 mg/mL
BufferpH: 7.5
Details: 20 mM HEPES pH 7.5, 200 mM KCl, 0.045% w/v UDM, 0.0045% w/v CHS
GridModel: Quantifoil R1.2/1.3 / Material: COPPER / Mesh: 300 / Support film - Material: CARBON / Support film - topology: HOLEY / Pretreatment - Type: GLOW DISCHARGE / Pretreatment - Time: 120 sec.
VitrificationCryogen name: ETHANE / Chamber humidity: 100 % / Chamber temperature: 277 K / Instrument: FEI VITROBOT MARK IV / Details: Grid blotted for 3.5 seconds.
DetailsMonodisperse sample

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Electron microscopy

MicroscopeFEI TITAN KRIOS
Specialist opticsEnergy filter - Name: GIF Bioquantum / Energy filter - Slit width: 20 eV
Image recordingFilm or detector model: GATAN K3 BIOQUANTUM (6k x 4k) / Number grids imaged: 1 / Number real images: 17288 / Average electron dose: 41.17 e/Å2
Electron beamAcceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron opticsIllumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELD / Nominal defocus max: 2.5 µm / Nominal defocus min: 1.25 µm / Nominal magnification: 105000
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

Startup modelType of model: NONE / Details: Ab-initio
Final reconstructionApplied symmetry - Point group: C2 (2 fold cyclic) / Resolution.type: BY AUTHOR / Resolution: 3.13 Å / Resolution method: FSC 0.143 CUT-OFF / Software - Name: cryoSPARC (ver. 4.4.1) / Number images used: 117627
Initial angle assignmentType: MAXIMUM LIKELIHOOD / Software - Name: cryoSPARC (ver. 4.4.0)
Final angle assignmentType: MAXIMUM LIKELIHOOD / Software - Name: cryoSPARC (ver. 4.4.1)
FSC plot (resolution estimation)

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Atomic model buiding 1

Initial modelPDB ID:

6rv2


Chain - Source name: PDB / Chain - Initial model type: experimental model
RefinementSpace: REAL / Protocol: FLEXIBLE FIT
Output model

PDB-9g9x:
Structure of the human two pore domain potassium ion channel TASK-1 (K2P3.1)

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