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- PDB-28iz: Structure of the human two pore domain potassium ion channel TASK... -

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Basic information

Entry
Database: PDB / ID: 28iz
TitleStructure of the human two pore domain potassium ion channel TASK-3 L122V mutant (K2P9.1)
ComponentsPotassium channel subfamily K member 9
KeywordsMEMBRANE PROTEIN / K2P / 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
: / CHOLESTEROL HEMISUCCINATE / Potassium channel subfamily K member 9
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 2.83 Å
AuthorsHall, P.R. / Rodstrom, K.E.J. / Tucker, S.J.
Funding support United Kingdom, 3items
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, 2026Deposition site: PDBE / Processing site: PDBE
Revision 1.0Aug 19, 2026Provider: repository / Type: Initial release
Revision 1.0Aug 19, 2026Data content type: EM metadata / Data content type: EM metadata / Provider: repository / Type: Initial release
Revision 1.0Aug 19, 2026Data content type: FSC / Data content type: FSC / Provider: repository / Type: Initial release
Revision 1.0Aug 19, 2026Data content type: Half map / Part number: 1 / Data content type: Half map / Provider: repository / Type: Initial release
Revision 1.0Aug 19, 2026Data content type: Half map / Part number: 2 / Data content type: Half map / Provider: repository / Type: Initial release
Revision 1.0Aug 19, 2026Data content type: Image / Data content type: Image / Provider: repository / Type: Initial release
Revision 1.0Aug 19, 2026Data content type: Primary map / Data content type: Primary map / Provider: repository / Type: Initial release

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

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Assembly

Deposited unit
A: Potassium channel subfamily K member 9
B: Potassium channel subfamily K member 9
hetero molecules


Theoretical massNumber of molelcules
Total (without water)63,66512
Polymers60,5892
Non-polymers3,07710
Water00
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: electron microscopy, not applicable
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1

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Components

#1: Protein Potassium channel subfamily K member 9 / Acid-sensitive potassium channel protein TASK-3 / TWIK-related acid-sensitive K(+) channel 3 / Two ...Acid-sensitive potassium channel protein TASK-3 / TWIK-related acid-sensitive K(+) channel 3 / Two pore potassium channel KT3.2 / Two pore K(+) channel KT3.2


Mass: 30294.273 Da / Num. of mol.: 2 / Mutation: L122V
Source method: isolated from a genetically manipulated source
Details: M1 to D259 containing L122V mutation, with a HRV 3C protease site. Fused purification tags were cleaved prior to EM sample preparation.
Source: (gene. exp.) Homo sapiens (human) / Gene: KCNK9, TASK3 / Plasmid: pFB-C3C10HF-LIC / Cell line (production host): Sf9 / Production host: Spodoptera frugiperda (fall armyworm) / References: UniProt: Q9NPC2
#2: Chemical
ChemComp-K / POTASSIUM ION


Mass: 39.098 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: K
#3: Chemical
ChemComp-Y01 / CHOLESTEROL HEMISUCCINATE


Mass: 486.726 Da / Num. of mol.: 6 / Source method: obtained synthetically / Formula: C31H50O4
Has ligand of interestN
Has protein modificationN

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Experimental details

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Experiment

ExperimentMethod: ELECTRON MICROSCOPY
EM experimentAggregation state: PARTICLE / 3D reconstruction method: single particle reconstruction

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Sample preparation

ComponentName: K2P9.1 L122V homodimer / Type: COMPLEX
Details: Protein generated by removal of the 10xHis and FLAG purification tags with 3C protease cleavage
Entity ID: #1 / Source: RECOMBINANT
Molecular weightValue: 0.06358 MDa / Experimental value: NO
Source (natural)Organism: Homo sapiens (human)
Source (recombinant)Organism: Spodoptera frugiperda (fall armyworm) / Strain: Sf9
Buffer solutionpH: 7.5
Details: 20 mM HEPES pH 7.5, 200 mM KCl, 0.12% w/v DM, 0.012% w/v CHS
SpecimenConc.: 4 mg/ml / Embedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES / Details: Monodisperse sample
Specimen supportGrid material: GOLD / Grid mesh size: 300 divisions/in. / Grid type: Au-flat 1.2/1.3
VitrificationInstrument: FEI VITROBOT MARK IV / Cryogen name: ETHANE / Humidity: 100 % / Chamber temperature: 277 K / Details: Grid blotted for approximately 4 seconds

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Electron microscopy imaging

Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company
MicroscopyModel: TFS KRIOS
Electron gunElectron source: FIELD EMISSION GUN / Accelerating voltage: 300 kV / Illumination mode: FLOOD BEAM
Electron lensMode: BRIGHT FIELD / Nominal magnification: 105000 X / Nominal defocus max: 2700 nm / Nominal defocus min: 1200 nm / Alignment procedure: COMA FREE
Specimen holderCryogen: NITROGEN / Specimen holder model: FEI TITAN KRIOS AUTOGRID HOLDER
Image recordingElectron dose: 43.9 e/Å2 / Film or detector model: GATAN K3 BIOQUANTUM (6k x 4k) / Num. of grids imaged: 1 / Num. of real images: 13035
EM imaging opticsEnergyfilter name: GIF Bioquantum / Energyfilter slit width: 20 eV

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Processing

EM software
IDNameVersionCategory
1cryoSPARC4.5.3particle selection
2EPUimage acquisition
4cryoSPARC4.5.3CTF correction
7Coot0.9.8.96 ELmodel fitting
9PHENIX1.21.2_5419model refinement
10cryoSPARC4.5.3initial Euler assignment
11cryoSPARC4.6.2final Euler assignment
12cryoSPARC4.6.2classification
13cryoSPARC4.6.23D reconstruction
CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
Particle selectionNum. of particles selected: 8381007
SymmetryPoint symmetry: C2 (2 fold cyclic)
3D reconstructionResolution: 2.83 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 211355 / Symmetry type: POINT
Atomic model buildingB value: 60.32 / Protocol: FLEXIBLE FIT / Space: REAL
Details: Initial fitting was done using Coot and refinement was conducted with PHENIX.
Atomic model buildingPDB-ID: 9G9V

9g9v


Accession code: 9G9V / Source name: PDB / Type: experimental model
RefinementHighest resolution: 2.83 Å
Stereochemistry target values: REAL-SPACE (WEIGHTED MAP SUM AT ATOM CENTERS)

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