9g9x
Structure of the human two pore domain potassium ion channel TASK-1 (K2P3.1)
Structural highlights
DiseaseKCNK3_HUMAN Heritable pulmonary arterial hypertension. The disease is caused by mutations affecting the gene represented in this entry. FunctionKCNK3_HUMAN pH-dependent, voltage-insensitive, background potassium channel protein. Rectification direction results from potassium ion concentration on either side of the membrane. Acts as an outward rectifier when external potassium concentration is low. When external potassium concentration is high, current is inward.[1] [2] Publication Abstract from PubMedTASK-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. Structures of TASK-1 and TASK-3 K2P channels provide insight into their gating and dysfunction in disease.,Hall PR, Jouen-Tachoire T, Schewe M, Proks P, Baukrowitz T, Carpenter EP, Newstead S, Rodstrom KEJ, Tucker SJ Structure. 2024 Nov 27:S0969-2126(24)00495-7. doi: 10.1016/j.str.2024.11.005. PMID:39637865[3] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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