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- EMDB-56538: Structure of the human two pore domain potassium ion channel TASK... -

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Basic information

Entry
Database: EMDB / ID: EMD-56538
TitleStructure of the human two pore domain potassium ion channel TASK-3 L122V mutant (K2P9.1)
Map data
Sample
  • Complex: K2P9.1 L122V homodimer
    • Protein or peptide: Potassium channel subfamily K member 9
  • Ligand: POTASSIUM ION
  • Ligand: CHOLESTEROL HEMISUCCINATE
KeywordsK2P / membrane protein / potassium channel / ion channel
Function / homology
Function and homology information


negative regulation of aldosterone secretion / TWIK-releated acid-sensitive K+ channel (TASK) / regulation of action potential firing rate / Phase 4 - resting membrane potential / regulation of resting membrane potential / potassium ion leak channel activity / outward rectifier potassium channel activity / sodium channel activity / potassium ion import across plasma membrane / potassium ion transport ...negative regulation of aldosterone secretion / TWIK-releated acid-sensitive K+ channel (TASK) / regulation of action potential firing rate / Phase 4 - resting membrane potential / regulation of resting membrane potential / potassium ion leak channel activity / outward rectifier potassium channel activity / sodium channel activity / potassium ion import across plasma membrane / potassium ion transport / potassium channel activity / cellular response to acidic pH / visual perception / synaptic vesicle / mitochondrial inner membrane / protein heterodimerization activity / dendrite / metal ion binding / identical protein binding / plasma membrane
Similarity search - Function
Potassium channel subfamily K member 9 / 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 9
Similarity search - Component
Biological speciesHomo sapiens (human)
Methodsingle particle reconstruction / cryo EM / Resolution: 2.83 Å
AuthorsHall PR / Rodstrom KEJ / 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: J Gen Physiol / Year: 2026
Title: Equivalent gain-of-function variants in KCNK3 and KCNK9 and their contribution to distinct TASK K2P channelopathies.
Authors: Kate M Crowther / Thibault R H Jouen-Tachoire / Peter Proks / Peter Rory Hall / Emma L Veale / Janina Sörmann / Karin E J Rödström / Thomas Müller / Saskia B Wortmann / Nina Barisic / ...Authors: Kate M Crowther / Thibault R H Jouen-Tachoire / Peter Proks / Peter Rory Hall / Emma L Veale / Janina Sörmann / Karin E J Rödström / Thomas Müller / Saskia B Wortmann / Nina Barisic / Natalie Hauser / Vincenzo Salpietro / RaeLynn Forsyth / Linford Williams / Nora Derrabi / Carlos A Bacino / Jill A Rosenfeld / Henry Houlden / Simon Newstead / Caroline F Wright / James Fasham / Alistair A Mathie / Reza Maroofian / Stephen J Tucker /
Abstract: Gain-of-function (GoF) missense variants in the two-pore domain (K2P) K+ channel TASK-1 (KCNK3) result in developmental delay with sleep apnea (DDSA), a neurodevelopmental channelopathy, while loss- ...Gain-of-function (GoF) missense variants in the two-pore domain (K2P) K+ channel TASK-1 (KCNK3) result in developmental delay with sleep apnea (DDSA), a neurodevelopmental channelopathy, while loss-of-function (LoF) variants cause pulmonary arterial hypertension. However, for the related TASK-3 channel (KCNK9), both LoF and GoF variants underlie a distinct neurodevelopmental disorder, KCNK9 imprinting syndrome (KIS). The relationship between genotype and phenotype in these disorders is further complicated because TASK-1 and TASK-3 can co-assemble into heteromeric channels with distinct functional properties. Here, we report additional patients with missense variants in KCNK3 and KCNK9 and investigate the effect of four novel genetic variants on the functional properties of homomeric and heteromeric TASK channels. Interestingly, two of these new pathogenic GoF variants (R131H and L122V) are found in both TASK-1 and TASK-3 and have equivalent functional effects on heteromeric TASK-1/TASK-3 channel activity, yet result in different clinical phenotypes. We have also determined a cryo-EM structure for the pathogenic L122V mutant TASK-3 channel, which suggests that subtle changes in gating and permeation within the inner cavity are responsible for its activatory effect. Overall, these results highlight the dominant role that homomeric TASK channels likely play in defining their associated channelopathies as well as the complexity of interpreting K+ channel dysfunction in pathophysiology.
History
DepositionFeb 2, 2026-
Header (metadata) releaseAug 19, 2026-
Map releaseAug 19, 2026-
UpdateAug 19, 2026-
Current statusAug 19, 2026Processing site: PDBe / Status: Released

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Structure visualization

Supplemental images

emd_56538.png

Downloads & links

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Map

FileDownload / File: emd_56538.map.gz / Format: CCP4 / Size: 64 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
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

Projections

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Slices (2/3)

Images are generated by Spider.

Voxel sizeX=Y=Z: 0.832 Å
Density

Histogram

Histogram (log scale)
Contour LevelBy AUTHOR: 0.283
Minimum - Maximum-1.3328905 - 1.9761496
Average (Standard dev.)0.0011971721 (±0.04713504)
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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Half map: #2

Fileemd_56538_half_map_1.map
Projections & Slices
AxesZYX

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Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Half map: #1

Fileemd_56538_half_map_2.map
Projections & Slices
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Histogram (log scale)

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Sample components

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Entire : K2P9.1 L122V homodimer

EntireName: K2P9.1 L122V homodimer
Components
  • Complex: K2P9.1 L122V homodimer
    • Protein or peptide: Potassium channel subfamily K member 9
  • Ligand: POTASSIUM ION
  • Ligand: CHOLESTEROL HEMISUCCINATE

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Supramolecule #1: K2P9.1 L122V homodimer

SupramoleculeName: K2P9.1 L122V homodimer / type: complex / ID: 1 / Parent: 0 / Macromolecule list: #1
Details: Protein generated by removal of the 10xHis and FLAG purification tags with 3C protease cleavage
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 63.58 KDa

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Macromolecule #1: Potassium channel subfamily K member 9

MacromoleculeName: Potassium channel subfamily K member 9 / type: protein_or_peptide / ID: 1
Details: M1 to D259 containing L122V mutation, with a HRV 3C 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: 30.294273 KDa
Recombinant expressionOrganism: Spodoptera frugiperda (fall armyworm)
SequenceString: MKRQNVRTLS LIVCTFTYLL VGAAVFDALE SDHEMREEEK LKAEEIRIKG KYNISSEDYR QLELVILQSE PHRAGVQWKF AGSFYFAIT VITTIGYGHA APGTDAGKAF CMFYAVLGIP LTVVMFQSLG ERMNTFVRYL LKRIKKCCGM RNTDVSMENM V TVGFFSCM ...String:
MKRQNVRTLS LIVCTFTYLL VGAAVFDALE SDHEMREEEK LKAEEIRIKG KYNISSEDYR QLELVILQSE PHRAGVQWKF AGSFYFAIT VITTIGYGHA APGTDAGKAF CMFYAVLGIP LTVVMFQSLG ERMNTFVRYL LKRIKKCCGM RNTDVSMENM V TVGFFSCM GTLCIGAAAF SQCEEWSFFH AYYYCFITLT TIGFGDYVAL QTKGALQKKP LYVAFSFMYI LVGLTVIGAF LN LVVLRFL TMNSEDERRD AEAELEVLFQ

UniProtKB: Potassium channel subfamily K member 9

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Macromolecule #2: POTASSIUM ION

MacromoleculeName: POTASSIUM ION / type: ligand / ID: 2 / Number of copies: 4 / Formula: K
Molecular weightTheoretical: 39.098 Da

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Macromolecule #3: CHOLESTEROL HEMISUCCINATE

MacromoleculeName: CHOLESTEROL HEMISUCCINATE / type: ligand / ID: 3 / Number of copies: 6 / Formula: Y01
Molecular weightTheoretical: 486.726 Da
Chemical component information

ChemComp-Y01:
CHOLESTEROL HEMISUCCINATE

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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

Concentration4 mg/mL
BufferpH: 7.5
Details: 20 mM HEPES pH 7.5, 200 mM KCl, 0.12% w/v DM, 0.012% w/v CHS
GridModel: Au-flat 1.2/1.3 / Material: GOLD / Mesh: 300 / Support film - Material: GOLD / 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 approximately 4 seconds.
DetailsMonodisperse sample

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Electron microscopy

MicroscopeTFS 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: 13035 / Average electron dose: 43.9 e/Å2
Electron beamAcceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron opticsIllumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELD / Nominal defocus max: 2.7 µm / Nominal defocus min: 1.2 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

Particle selectionNumber selected: 8381007
CTF correctionSoftware - Name: cryoSPARC (ver. 4.5.3) / Type: PHASE FLIPPING AND AMPLITUDE CORRECTION
Startup modelType of model: NONE / Details: Ab-initio
Final reconstructionApplied symmetry - Point group: C2 (2 fold cyclic) / Resolution.type: BY AUTHOR / Resolution: 2.83 Å / Resolution method: FSC 0.143 CUT-OFF / Software - Name: cryoSPARC (ver. 4.6.2) / Number images used: 211355
Initial angle assignmentType: MAXIMUM LIKELIHOOD / Software - Name: cryoSPARC (ver. 4.5.3)
Final angle assignmentType: MAXIMUM LIKELIHOOD / Software - Name: cryoSPARC (ver. 4.6.2)
FSC plot (resolution estimation)

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Atomic model buiding 1

Initial modelPDB ID:

9g9v


Chain - Source name: PDB / Chain - Initial model type: experimental model
DetailsInitial fitting was done using Coot and refinement was conducted with PHENIX.
RefinementSpace: REAL / Protocol: FLEXIBLE FIT / Overall B value: 60.32
Output model

PDB-28iz:
Structure of the human two pore domain potassium ion channel TASK-3 L122V mutant (K2P9.1)

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