Structures of TASK-1 and TASK-3 K2P channels provide insight into their gating and dysfunction in disease

Peter Rory Hall; Thibault Jouen-Tachoire; Marcus Schewe; Peter Proks; Thomas Baukrowitz; Elisabeth P Carpenter; Simon Newstead; Karin E J Rödström; Stephen J Tucker

doi:10.1016/j.str.2024.11.005

Structures of TASK-1 and TASK-3 K2P channels provide insight into their gating and dysfunction in disease

Structure. 2025 Jan 2;33(1):115-122.e4. doi: 10.1016/j.str.2024.11.005. Epub 2024 Dec 4.

Authors

Peter Rory Hall¹, Thibault Jouen-Tachoire², Marcus Schewe³, Peter Proks⁴, Thomas Baukrowitz³, Elisabeth P Carpenter⁵, Simon Newstead⁶, Karin E J Rödström⁷, Stephen J Tucker⁸

Affiliations

¹ Department of Biochemistry, University of Oxford, Oxford, UK; Clarendon Laboratory, Department of Physics, University of Oxford, Oxford, UK; Scripps Institute, San Diego, CA, USA; Kavli Institute for Nanoscience Discovery, University of Oxford, Oxford, UK.
² Clarendon Laboratory, Department of Physics, University of Oxford, Oxford, UK; Department of Pharmacology, University of Oxford, Oxford, UK; OXION Initiative in Ion Channels and Disease, University of Oxford, Oxford, UK.
³ Institute of Physiology, Kiel University, Kiel, Germany.
⁴ Clarendon Laboratory, Department of Physics, University of Oxford, Oxford, UK; Kavli Institute for Nanoscience Discovery, University of Oxford, Oxford, UK.
⁵ Centre for Medicines Discovery, University of Oxford, Oxford, UK.
⁶ Department of Biochemistry, University of Oxford, Oxford, UK; OXION Initiative in Ion Channels and Disease, University of Oxford, Oxford, UK; Kavli Institute for Nanoscience Discovery, University of Oxford, Oxford, UK.
⁷ Department of Biochemistry, University of Oxford, Oxford, UK; Clarendon Laboratory, Department of Physics, University of Oxford, Oxford, UK; Kavli Institute for Nanoscience Discovery, University of Oxford, Oxford, UK. Electronic address: karin.rodstrom@bioch.ox.ac.uk.
⁸ Clarendon Laboratory, Department of Physics, University of Oxford, Oxford, UK; OXION Initiative in Ion Channels and Disease, University of Oxford, Oxford, UK; Kavli Institute for Nanoscience Discovery, University of Oxford, Oxford, UK. Electronic address: stephen.tucker@physics.ox.ac.uk.

PMID: 39637865
DOI: 10.1016/j.str.2024.11.005

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 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.

Keywords: Birk Barel Syndrome; K2P channel; KCNK3; KCNK9; TASK channels; channelopathy; cryoEM.

MeSH terms

Cryoelectron Microscopy*
HEK293 Cells
Humans
Ion Channel Gating*
Models, Molecular
Mutation, Missense
Nerve Tissue Proteins* / chemistry
Nerve Tissue Proteins* / genetics
Nerve Tissue Proteins* / metabolism
Potassium Channels, Tandem Pore Domain* / chemistry
Potassium Channels, Tandem Pore Domain* / genetics
Potassium Channels, Tandem Pore Domain* / metabolism
Shal Potassium Channels

Substances

Potassium Channels, Tandem Pore Domain
KCNK9 protein, human
Nerve Tissue Proteins
potassium channel subfamily K member 3
KCND3 protein, human
Shal Potassium Channels