| Structural highlights
Disease
KCNQ1_HUMAN Defects in KCNQ1 are the cause of long QT syndrome type 1 (LQT1) [MIM:192500; also known as Romano-Ward syndrome (RWS). Long QT syndromes are heart disorders characterized by a prolonged QT interval on the ECG and polymorphic ventricular arrhythmias. They cause syncope and sudden death in response to exercise or emotional stress. LQT1 inheritance is an autosomal dominant.[1] [2] [3] [4] [5] [6] [7] [:][8] [9] [10] [11] [12] [13] [14] [15] [16] [17] [18] [19] [20] [21] [22] [23] [24] [25] [26] [27] Defects in KCNQ1 are the cause of Jervell and Lange-Nielsen syndrome type 1 (JLNS1) [MIM:220400. JLNS1 is an autosomal recessive disorder characterized by congenital deafness, prolongation of the QT interval, syncopal attacks due to ventricular arrhythmias, and a high risk of sudden death.[28] [29] [30] Defects in KCNQ1 are the cause of familial atrial fibrillation type 3 (ATFB3) [MIM:607554. Atrial fibrillation is a common disorder of cardiac rhythm that is hereditary in a small subgroup of patients. It is characterized by disorganized atrial electrical activity and ineffective atrial contraction promoting blood stasis in the atria and reduces ventricular filling. It can result in palpitations, syncope, thromboembolic stroke, and congestive heart failure.[31] Defects in KCNQ1 are the cause of short QT syndrome type 2 (SQT2) [MIM:609621. Short QT syndromes are heart disorders characterized by idiopathic persistently and uniformly short QT interval on ECG in the absence of structural heart disease in affected individuals. They cause syncope and sudden death.[32]
Function
KCNQ1_HUMAN Probably important in cardiac repolarization. Associates with KCNE1 (MinK) to form the I(Ks) cardiac potassium current. Elicits a rapidly activating, potassium-selective outward current. Muscarinic agonist oxotremorine-M strongly suppresses KCNQ1/KCNE1 current in CHO cells in which cloned KCNQ1/KCNE1 channels were coexpressed with M1 muscarinic receptors. May associate also with KCNE3 (MiRP2) to form the potassium channel that is important for cyclic AMP-stimulated intestinal secretion of chloride ions, which is reduced in cystic fibrosis and pathologically stimulated in cholera and other forms of secretory diarrhea.
Publication Abstract from PubMed
The KCNQ1 + KCNE1 potassium channel complex produces the slow delayed rectifier current (I(Ks)) critical for cardiac repolarization. Loss-of-function mutations in KCNQ1 and KCNE1 cause long QT syndrome (LQTS) types 1 and 5 (LQT1/LQT5), accounting for over one-third of clinical LQTS cases. Despite prior structural work on KCNQ1 and KCNQ1 + KCNE3, the structural basis of KCNQ1 + KCNE1 remains unresolved. Using cryo-electron microscopy and electrophysiology, we determined high-resolution (2.5-3.4 A) structures of human KCNQ1(APO), and KCNQ1 + KCNE1 in both closed and open states. KCNE1 occupies a pivotal position at the interface of three KCNQ1 subunits, inducing six helix-to-loop transitions in KCNQ1 transmembrane segments. Three of them occur at both ends of the S4-S5 linker, maintaining a loop conformation during I(Ks) gating, while the other three, in S6 and helix A, undergo dynamic helix-loop transitions during I(Ks) gating. These structural rearrangements: (1) stabilize the closed pore and the conformation of the intermediate state voltage-sensing domain, thereby determining channel gating, ion permeation, and single-channel conductance; (2) enable a dual-PIP2 modulation mechanism, where one PIP2 occupies the canonical site, while the second PIP2 bridges the S4-S5 linker, KCNE1, and the adjacent S6', stabilizing channel opening; (3) create a fenestration capable of binding compounds specific for KCNQ1 + KCNE1 (e.g., AC-1). Together, these findings reveal a previously unrecognized large-scale secondary structural transition during ion channel gating that fine-tunes I(Ks) function and provides a foundation for developing targeted LQTS therapy.
Secondary structure transitions and dual PIP2 binding define cardiac KCNQ1-KCNE1 channel gating.,Zhong L, Lin X, Cheng X, Wan S, Hua Y, Nan W, Hu B, Peng X, Zhou Z, Zhang Q, Yang H, Noe F, Yan Z, Jiang D, Zhang H, Liu F, Xiao C, Zhou Z, Mou Y, Yu H, Ma L, Huang C, Wong VKW, Chung SK, Shen B, Jiang ZH, Neher E, Zhu W, Zhang J, Hou P Cell Res. 2025 Nov;35(11):887-899. doi: 10.1038/s41422-025-01182-9. Epub 2025 Oct , 2. PMID:41034624[33]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
References
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- ↑ Zhong L, Lin X, Cheng X, Wan S, Hua Y, Nan W, Hu B, Peng X, Zhou Z, Zhang Q, Yang H, Noé F, Yan Z, Jiang D, Zhang H, Liu F, Xiao C, Zhou Z, Mou Y, Yu H, Ma L, Huang C, Wong VKW, Chung SK, Shen B, Jiang ZH, Neher E, Zhu W, Zhang J, Hou P. Secondary structure transitions and dual PIP2 binding define cardiac KCNQ1-KCNE1 channel gating. Cell Res. 2025 Nov;35(11):887-899. PMID:41034624 doi:10.1038/s41422-025-01182-9
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