User:Milan Horňák/Sandbox 1

From Proteopedia

< User:Milan Horňák(Difference between revisions)

Current revision

NMR structure of human KCNE1 in LMPG micelles at pH 6.0 and 40 degree C

1 Structural highlights
2 Evolutionary Conservation
3 Function
4 Disease
5 References

Structural highlights

2k21 is a 1 chain structure with sequence from Human. Full experimental information is available from OCA. For a guided tour on the structure components use FirstGlance.
Gene:	KCNE1 (HUMAN)
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Evolutionary Conservation

Check, as determined by ConSurfDB. You may read the explanation of the method and the full data available from ConSurf.

Function

[KCNE1_HUMAN] KCNE1 and KVLQT1 protein products coassemble to form the slow delayed rectifier current I(Ks) . ^[1] Through the formation of heteromeric channel complexes, KCNE1 is central to the control of the heart rate and rhythm. ^[2] KCNE1 modifies the KCNQ1 potassium channel by slowing activation and enhancing channel conductance. Experiments suggest that this is carried out by restricting the movement of the S4–S5 linker of KCNQ1. This interaction must be first disrupted before the channel can be opened.

Disease

LQT5

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. ^[3] ^[4] ^[5] ^[6] ^[7] ^[8]

JLNS2

Mutations in KCNE1 are also 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. ^[9] ^[10] ^[11] ^[12]

N5Q and T7I mutants

These mutations inhibit the ability of KCNE1 to form fully functional IKs channels. Mutations that disrupt the proper glycosylation of KCNE1 (i.e. N5Q and T7I) lead to the formation of channels that are unable of proper cell surface expression due to defect in anterograde trafficking. WT subunits are glycosylated both co-translationally and post-translationally, whereas the N5Q and T7I mutants lack the co-translational gylcosylation, which in turn severely lowers their proclivity to be glycosylated post-translationally and therefore their proper function. ^[13]

P127T mutants

It has been shown that KCNE1 P127T mutation led to decrease in IKs currents by impairing their stimulation by cAMP. Specifically, it prevented the phosphorylation of KCNQ1 at S27 following cAMP stimulation. ^[14]

Other

Mutations in KCNE1 may be a cause for hightened susceptibility to the Noise-Induced Hearing Loss. ^[15]

References

↑ 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
↑ 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
↑ 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
↑ 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
↑ 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
↑ 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
↑ Dvir M, Strulovich R, Sachyani D, Ben-Tal Cohen I, Haitin Y, Dessauer C, Pongs O, Kass R, Hirsch JA, Attali B. Long QT mutations at the interface between KCNQ1 helix C and KCNE1 disrupt I(KS) regulation by PKA and PIP(2). J Cell Sci. 2014 Sep 15;127(Pt 18):3943-55. doi: 10.1242/jcs.147033. Epub 2014, Jul 18. PMID:25037568 doi:http://dx.doi.org/10.1242/jcs.147033
↑ Van Laer L, Carlsson PI, Ottschytsch N, Bondeson ML, Konings A, Vandevelde A, Dieltjens N, Fransen E, Snyders D, Borg E, Raes A, Van Camp G. The contribution of genes involved in potassium-recycling in the inner ear to noise-induced hearing loss. Hum Mutat. 2006 Aug;27(8):786-95. PMID:16823764 doi:http://dx.doi.org/10.1002/humu.20360

Proteopedia Page Contributors and Editors (what is this?)

Milan Horňák

Retrieved from "http://52.214.119.220/wiki/index.php/User:Milan_Hor%C5%88%C3%A1k/Sandbox_1"

@@ Line 28: / Line 28: @@
 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. <ref> PMID:13435203 </ref> <ref>PMID:9354783</ref> <ref>PMID:9328483</ref> <ref>PMID:9445165</ref>
 === N5Q and T7I mutants ===
-These mutations inhibit the ability of KCNE1 to form fully functional IKs channels. Mutations that disrupt the proper glycosylation of KCNE1 (mutants N5Q and T7I) lead to the formation of channels that are unable of proper cell surface expression due to defect in anterograde trafficking.   WT subunits are glycosylated both co-translationally and post-translationally, whereas the N5Q and T7I mutants lack the co-translational gylcosylation, which in turn severely lowers their proclivity to be glycosylated post-translationally and therefore their proper function. <ref>PMID:21676880</ref>
+These mutations inhibit the ability of KCNE1 to form fully functional IKs channels. Mutations that disrupt the proper glycosylation of KCNE1 (i.e. N5Q and T7I) lead to the formation of channels that are unable of proper cell surface expression due to defect in anterograde trafficking.   WT subunits are glycosylated both co-translationally and post-translationally, whereas the N5Q and T7I mutants lack the co-translational gylcosylation, which in turn severely lowers their proclivity to be glycosylated post-translationally and therefore their proper function. <ref>PMID:21676880</ref>
 === P127T mutants ===
 It has been shown that KCNE1 P127T mutation led to decrease in IKs currents by impairing their stimulation by cAMP. Specifically, it prevented the phosphorylation of KCNQ1 at S27 following cAMP stimulation. <ref>PMID:25037568</ref>