28IZ
Structure of the human two pore domain potassium ion channel TASK-3 L122V mutant (K2P9.1)
Summary for 28IZ
| Entry DOI | 10.2210/pdb28iz/pdb |
| EMDB information | 56538 |
| Descriptor | Potassium channel subfamily K member 9, POTASSIUM ION, CHOLESTEROL HEMISUCCINATE (3 entities in total) |
| Functional Keywords | k2p, membrane protein, potassium channel, ion channel |
| Biological source | Homo sapiens (human) |
| Total number of polymer chains | 2 |
| Total formula weight | 63665.29 |
| Authors | |
| Primary citation | Crowther, K.M.,Jouen-Tachoire, T.R.H.,Proks, P.,Hall, P.R.,Veale, E.L.,Sormann, J.,Rodstrom, K.E.J.,Muller, T.,Wortmann, S.B.,Barisic, N.,Hauser, N.,Salpietro, V.,Forsyth, R.,Williams, L.,Derrabi, N.,Bacino, C.A.,Rosenfeld, J.A.,Houlden, H.,Newstead, S.,Wright, C.F.,Fasham, J.,Mathie, A.A.,Maroofian, R.,Tucker, S.J. Equivalent gain-of-function variants in KCNK3 and KCNK9 and their contribution to distinct TASK K2P channelopathies. J.Gen.Physiol., 158:-, 2026 Cited by PubMed 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-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. PubMed: 42560358DOI: 10.1085/jgp.202613989 PDB entries with the same primary citation |
| Experimental method | ELECTRON MICROSCOPY (2.83 Å) |
Structure validation
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