| Structural highlights
Disease
KCNK9_HUMAN Intellectual deficit, Birk-Barel type. Birk-Barel mental retardation dysmorphism syndrome (BIBAS) [MIM:612292: A syndrome characterized by mental retardation, hypotonia, hyperactivity, and facial dysmorphism. Note=The disease is caused by mutations affecting the gene represented in this entry.[1]
Function
KCNK9_HUMAN pH-dependent, voltage-insensitive, background potassium channel protein.[2] [3]
Publication Abstract from PubMed
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.
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[4]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
References
- ↑ Barel O, Shalev SA, Ofir R, Cohen A, Zlotogora J, Shorer Z, Mazor G, Finer G, Khateeb S, Zilberberg N, Birk OS. Maternally inherited Birk Barel mental retardation dysmorphism syndrome caused by a mutation in the genomically imprinted potassium channel KCNK9. Am J Hum Genet. 2008 Aug;83(2):193-9. PMID:18678320 doi:S0002-9297(08)00410-2
- ↑ Chapman CG, Meadows HJ, Godden RJ, Campbell DA, Duckworth M, Kelsell RE, Murdock PR, Randall AD, Rennie GI, Gloger IS. Cloning, localisation and functional expression of a novel human, cerebellum specific, two pore domain potassium channel. Brain Res Mol Brain Res. 2000 Oct 20;82(1-2):74-83. PMID:11042359
- ↑ Vega-Saenz de Miera E, Lau DH, Zhadina M, Pountney D, Coetzee WA, Rudy B. KT3.2 and KT3.3, two novel human two-pore K(+) channels closely related to TASK-1. J Neurophysiol. 2001 Jul;86(1):130-42. PMID:11431495
- ↑ Hall PR, Jouen-Tachoire T, Schewe M, Proks P, Baukrowitz T, Carpenter EP, Newstead S, Rödström KEJ, Tucker SJ. Structures of TASK-1 and TASK-3 K2P channels provide insight into their gating and dysfunction in disease. Structure. 2024 Nov 27:S0969-2126(24)00495-7. PMID:39637865 doi:10.1016/j.str.2024.11.005
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