| Structural highlights
Disease
[KCNE1_HUMAN] Mutations in KCNE1 cause long QT syndrome type 5 (LQT5) [MIM:613695].
Congenital long QT syndrome is electrocardiographically characterized by a prolonged QT interval and polymorphic ventricular arrhythmias (torsade de pointes). These cardiac arrhythmias may result in recurrent syncope, seizure, or sudden death. [1]
Mutations in KCNE1 are the cause of Jervell and Lange-Nielsen syndrome type 2 (JLNS2)[MIM:612347].
The Jervell and Lange-Nielsen syndrome 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. [2]
These mutations inhibit the ability of KCNE1 to form fully functional IKs channels. Mutation that disrupts the N5 sequon of KCNE1 protein hinders its glycosylation,
leading to the formation of channels that are unable of proper cell surface expression due to defect in anterograde trafficking. [3] [4] [5] [6] [7] [8] [9] [10][11]
Function
KCNE1 and KVLQT1 protein products coassemble to form the cardiac I(Ks) channel. [12] Through the formation of heteromeric channel complexes, KCNE1 is central to the control of the heart rate and rhythm. [13]
Evolutionary Conservation
Check, as determined by ConSurfDB. You may read the explanation of the method and the full data available from ConSurf.
Publication Abstract from PubMed
KCNE1 is a single-span membrane protein that modulates the voltage-gated potassium channel KCNQ1 (K V7.1) by slowing activation and enhancing channel conductance to generate the slow delayed rectifier current ( I Ks) that is critical for the repolarization phase of the cardiac action potential. Perturbation of channel function by inherited mutations in KCNE1 or KCNQ1 results in increased susceptibility to cardiac arrhythmias and sudden death with or without accompanying deafness. Here, we present the three-dimensional structure of KCNE1. The transmembrane domain (TMD) of KCNE1 is a curved alpha-helix and is flanked by intra- and extracellular domains comprised of alpha-helices joined by flexible linkers. Experimentally restrained docking of the KCNE1 TMD to a closed state model of KCNQ1 suggests that KCNE1 slows channel activation by sitting on and restricting the movement of the S4-S5 linker that connects the voltage sensor to the pore domain. We postulate that this is an adhesive interaction that must be disrupted before the channel can be opened in response to membrane depolarization. Docking to open KCNQ1 indicates that the extracellular end of the KCNE1 TMD forms an interface with an intersubunit cleft in the channel that is associated with most known gain-of-function disease mutations. Binding of KCNE1 to this "gain-of-function cleft" may explain how it increases conductance and stabilizes the open state. These working models for the KCNE1-KCNQ1 complexes may be used to formulate testable hypotheses for the molecular bases of disease phenotypes associated with the dozens of known inherited mutations in KCNE1 and KCNQ1.
Structure of KCNE1 and implications for how it modulates the KCNQ1 potassium channel.,Kang C, Tian C, Sonnichsen FD, Smith JA, Meiler J, George AL Jr, Vanoye CG, Kim HJ, Sanders CR Biochemistry. 2008 Aug 5;47(31):7999-8006. Epub 2008 Jul 9. PMID:18611041[14]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
References
- ↑ Jongbloed RJ, Wilde AA, Geelen JL, Doevendans P, Schaap C, Van Langen I, van Tintelen JP, Cobben JM, Beaufort-Krol GC, Geraedts JP, Smeets HJ. Novel KCNQ1 and HERG missense mutations in Dutch long-QT families. Hum Mutat. 1999;13(4):301-10. PMID:10220144 doi:<301::AID-HUMU7>3.0.CO;2-V 10.1002/(SICI)1098-1004(1999)13:4<301::AID-HUMU7>3.0.CO;2-V
- ↑ JERVELL A, LANGE-NIELSEN F. Congenital deaf-mutism, functional heart disease with prolongation of the Q-T interval and sudden death. Am Heart J. 1957 Jul;54(1):59-68. PMID:13435203
- ↑ Schulze-Bahr E, Wang Q, Wedekind H, Haverkamp W, Chen Q, Sun Y, Rubie C, Hordt M, Towbin JA, Borggrefe M, Assmann G, Qu X, Somberg JC, Breithardt G, Oberti C, Funke H. KCNE1 mutations cause jervell and Lange-Nielsen syndrome. Nat Genet. 1997 Nov;17(3):267-8. doi: 10.1038/ng1197-267. PMID:9354783 doi:http://dx.doi.org/10.1038/ng1197-267
- ↑ Tyson J, Tranebjaerg L, Bellman S, Wren C, Taylor JF, Bathen J, Aslaksen B, Sorland SJ, Lund O, Malcolm S, Pembrey M, Bhattacharya S, Bitner-Glindzicz M. IsK and KvLQT1: mutation in either of the two subunits of the slow component of the delayed rectifier potassium channel can cause Jervell and Lange-Nielsen syndrome. Hum Mol Genet. 1997 Nov;6(12):2179-85. PMID:9328483
- ↑ Bas T, Gao GY, Lvov A, Chandrasekhar KD, Gilmore R, Kobertz WR. Post-translational N-glycosylation of type I transmembrane KCNE1 peptides: implications for membrane protein biogenesis and disease. J Biol Chem. 2011 Aug 12;286(32):28150-9. doi: 10.1074/jbc.M111.235168. Epub 2011, Jun 15. PMID:21676880 doi:http://dx.doi.org/10.1074/jbc.M111.235168
- ↑ Splawski I, Tristani-Firouzi M, Lehmann MH, Sanguinetti MC, Keating MT. Mutations in the hminK gene cause long QT syndrome and suppress IKs function. Nat Genet. 1997 Nov;17(3):338-40. doi: 10.1038/ng1197-338. PMID:9354802 doi:http://dx.doi.org/10.1038/ng1197-338
- ↑ Duggal P, Vesely MR, Wattanasirichaigoon D, Villafane J, Kaushik V, Beggs AH. Mutation of the gene for IsK associated with both Jervell and Lange-Nielsen and Romano-Ward forms of Long-QT syndrome. Circulation. 1998 Jan 20;97(2):142-6. PMID:9445165
- ↑ Splawski I, Shen J, Timothy KW, Lehmann MH, Priori S, Robinson JL, Moss AJ, Schwartz PJ, Towbin JA, Vincent GM, Keating MT. Spectrum of mutations in long-QT syndrome genes. KVLQT1, HERG, SCN5A, KCNE1, and KCNE2. Circulation. 2000 Sep 5;102(10):1178-85. PMID:10973849
- ↑ Schulze-Bahr E, Schwarz M, Hauenschild S, Wedekind H, Funke H, Haverkamp W, Breithardt G, Pongs O, Isbrandt D. A novel long-QT 5 gene mutation in the C-terminus (V109I) is associated with a mild phenotype. J Mol Med. 2001 Sep;79(9):504-9. PMID:11692163 doi:http://dx.doi.org/10.1007/s001090100249
- ↑ Kapplinger JD, Tester DJ, Salisbury BA, Carr JL, Harris-Kerr C, Pollevick GD, Wilde AA, Ackerman MJ. Spectrum and prevalence of mutations from the first 2,500 consecutive unrelated patients referred for the FAMILION long QT syndrome genetic test. Heart Rhythm. 2009 Sep;6(9):1297-303. doi: 10.1016/j.hrthm.2009.05.021. Epub 2009, Jun 23. PMID:19716085 doi:http://dx.doi.org/10.1016/j.hrthm.2009.05.021
- ↑ . PMID:216315890657
- ↑ Sanguinetti MC, Curran ME, Zou A, Shen J, Spector PS, Atkinson DL, Keating MT. Coassembly of K(V)LQT1 and minK (IsK) proteins to form cardiac I(Ks) potassium channel. Nature. 1996 Nov 7;384(6604):80-3. doi: 10.1038/384080a0. PMID:8900283 doi:http://dx.doi.org/10.1038/384080a0
- ↑ McDonald TV, Yu Z, Ming Z, Palma E, Meyers MB, Wang KW, Goldstein SA, Fishman GI. A minK-HERG complex regulates the cardiac potassium current I(Kr). Nature. 1997 Jul 17;388(6639):289-92. PMID:9230439 doi:http://dx.doi.org/10.1038/40882
- ↑ Kang C, Tian C, Sonnichsen FD, Smith JA, Meiler J, George AL Jr, Vanoye CG, Kim HJ, Sanders CR. Structure of KCNE1 and implications for how it modulates the KCNQ1 potassium channel. Biochemistry. 2008 Aug 5;47(31):7999-8006. Epub 2008 Jul 9. PMID:18611041 doi:http://dx.doi.org/10.1021/bi800875q
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