KCNE1

KCNE1
Dostupne strukture
PDB	Pretraga Human UniProta: PDBe RCSB
Spisak PDB ID kodova
	2K21
Identifikatori
Aliasi	KCNE1
Vanjski ID-jevi	OMIM: 176261 GeneCards: KCNE1
Lokacija gena (čovjek)
Hrom.	Hromosom 21 (čovjek)
Kraj	34,512,214 bp
Obrazac RNK ekspresije
	Više referentnih podataka o ekspresiji
Ontologija gena
Molekularna funkcija	• potassium channel activity; • delayed rectifier potassium channel activity; • voltage-gated potassium channel activity involved in cardiac muscle cell action potential repolarization; • voltage-gated ion channel activity; • telethonin binding; • potassium channel regulator activity; • GO:0001948, GO:0016582 vezivanje za proteine; • voltage-gated potassium channel activity involved in ventricular cardiac muscle cell action potential repolarization; • voltage-gated potassium channel activity; • transmembrane transporter binding;
Ćelijska komponenta	• membrana; • integral component of membrane; • voltage-gated potassium channel complex; • ćelijska membrana; • cell surface; • Z discdkac; • apical plasma membrane; • Lipidni splav; • Lizozom;
Biološki proces	• regulation of ion transmembrane transport; • protein O-linked glycosylation; • ventricular cardiac muscle cell action potential; • cardiac muscle cell action potential involved in contraction; • ion transport; • sluh; • potassium ion transport; • membrane repolarization; • negative regulation of protein targeting to membrane; • membrane repolarization during action potential; • regulation of delayed rectifier potassium channel activity; • cardiac conduction; • potassium ion transmembrane transport; • positive regulation of potassium ion transmembrane transport; • protein N-linked glycosylation; • membrane repolarization during cardiac muscle cell action potential; • regulation of heart rate by cardiac conduction; • regulation of potassium ion transmembrane transport; • negative regulation of delayed rectifier potassium channel activity; • cellular response to cAMP; • regulation of ventricular cardiac muscle cell membrane repolarization; • membrane repolarization during ventricular cardiac muscle cell action potential; • GO:0015915 transport; • potassium ion export across plasma membrane;
	Izvori:Amigo / QuickGO
Ortolozi
	3753
	n/a
	ENSG00000180509
	n/a
	P15382; Q6FHJ6
	n/a
NM_000219; NM_001127668; NM_001127669; NM_001127670; NM_001270402;
	NM_001270403; NM_001270404; NM_001270405
	n/a
NP_000210; NP_001121140; NP_001121141; NP_001121142; NP_001257331;
	NP_001257332; NP_001257333; NP_001257334; NP_000210.2
	n/a
	Wikipodaci
Pogledaj/uredi – čovjek

Član 1 naponski otvorenog kalijskog kanala potporodice E jest protein koji je kod ljudi kodiran genom KCNE1 sa hromosoma 21.^[3]^[4]

Naponski vođeni kalijski kanali (Kv) predstavljaju najkompleksniju klasu naponsko vođenih ionskih kanala, i sa funkcionalnog i sa strukturnog stanovišta. Njihove različite funkcije uključuju regulaciju oslobađanja neurotransmitera, otkucaja srca, lučenja insulina, neuronske ekscitabilnosti, epitelnog transporta elektrolita, kontrakcije glatkih mišića i ćelijskog volumena.

Gen KCNE1 je jedan od pet članova porodice KCNE pomoćnih ili β-podjedinica Kv kanala. Takođe je poznat kao minK (minimalna podjedinica kalijevog kanala).

Aminokiselinska sekvenca

Dužina polipeptidnog lanca je 129 aminokiselina, a molekulska težina 14.645 Da.^[4]

C: Cistein

D: Asparaginska kiselina

E: Glutaminska kiselina

F: Fenilalanin

G: Glicin

H: Histidin

I: Izoleucin

K: Lizin

L: Leucin

M: Metionin

N: Asparagin

P: Prolin

Q: Glutamin

R: Arginin

S: Serin

T: Treonin

V: Valin

W: Triptofan

Y: Tirozin

10	20	30	40	50
MILSNTTAVT	PFLTKLWQET	VQQGGNMSGL	ARRSPRSGDG	KLEALYVLMV
LGFFGFFTLG	IMLSYIRSKK	LEHSNDPFNV	YIESDAWQEK	DKAYVQARVL
ESYRSCYVVE	NHLAIEQPNT	HLPETKPSP

Struktura

Velika većina studija o strukturnoj osnovi za KCNE1 modulaciju Kv kanala fokusira se na njegovu interakciju sa KCNQ1 (prethodno zvanim KvLQT1). Ostaci u transmembranskom domenu KCNE1 nalaze blizu filtera selektivnosti KCNQ1 unutar heteromernih kompleksa kanala KCNQ1-KCNE1.^[5]^[6]

C-terminalni domen KCNE1, posebno od aminokiselina 73 do 79, neophodan je za stimulaciju spore odložene kalijeve ispravljačke struje SGK1.^[7] Interakcija KCNE1 sa alfa-heliksom u domenu S6 KvLQT1 doprinosi većem afinitetu koji ovaj kanal ima za benzodiazepin L7 i hromanol 293B repozicioniranjem aminokiselinskih ostataka kako bi se to omogućilo. KCNE1 destabilizira vezu S4-S5 alfa-heliksa u proteinu kanala KCNQ1, uz destabilizaciju S6 alfa-heliksa, što dovodi do sporije aktivacije ovog kanala kada je povezan s KCNE1.^[8] Raspravljalo se o varijabilnim stehiometrijskim pokazateljima, ali vjerovatno postoje dvije podjedinice KCNE1 i četiri podjedinice KCNQ1 u IKs kompleksu plazmamembrana.^[9]

Transmembranski segment KCNE1 je α-heliksni kada je u membranskom okruženju.^[10]^[11] Predloženo je da transmembranski segment KCNE1 interraguje sa domenom pora KCNQ1 (S5/S6) i sa domenom S4 kanala KCNQ1 (KvLQT1).^[5] KCNE1 može se vezati za vanjski dio pore domena KCNQ1 i kliziti iz ove pozicije u “aktivacijski rascjep”, što dovodi do većih amplituda struje^[7]

KCNE1 usporava aktivaciju KCNQ1 nekoliko puta, a u toku su rasprave o preciznim mehanizmima koji su u osnovi toga. U studiji u kojoj je kretanje senzora napona KCNQ1 praćeno fluorimetrijom usmjerenom na mjesto, kao i mjerenjem pomaka naelektrisanja povezanog s kretanjem naelektrisanja unutar segmenta S4 naponskog senzora (strujnog napona), otkriveno je da KCNE1 toliko usporava kretanje S4. da struja zatvaranja više nije mjerljiva. Fluorometrijska mjerenja su pokazala da je kretanje kanala S4 KCNQ1-KCNE1 bilo 30 puta sporije od dobro proučenog Kv kanala "Drosophila" "Shaker".^[12] Nakajo i Kubo otkrili su da KCNE1 ili usporava kretanje KCNQ1 S4 nakon depolarizacije membrane ili mijenja ravnotežu S4 na datom membranskom potencijalu.^[13] U Laboratoriji Kass je zaključili su da dok homomerni KCNQ1 kanali mogu da se otvore nakon pomeranja jednog S4 segmenta, KCNQ1-KCNE1 kanali otvaraju se samo nakon što su sva četiri S4 segmenta aktivirana..^[14] Smatra se da se unutarćelijski C-terminalni domen KCNE1 nalazi na KCNQ1 S4-S5 linkeru, segmentu KCNQ1 ključnom za prenošenje statusa S4 u pore i na taj način kontrolira aktivaciju.^[15]

Funkcija

KCNE1 je prvenstveno poznat po modulaciji alfa podjedinice srčanog i epitelnog Kv kanala, KCNQ1. KCNQ1 i KCNE1 formiraju kompleks u ljudskim srčanokomorsim kardiomiocitima koji stvaraju sporo aktivirajuću K+ struju, IKs. Zajedno sa brzo aktivirajućom K+ strujom (IKr), IKs je važan za repolarizaciju ljudskih komora.^[16]^[17] KCNQ1 je također neophodan za normalnu funkciju mnogih različitih epitelnih tkiva, ali smatra se da je u ovim neekscitabilnim ćelijama pretežno reguliran preko KCNE2 ili KCNE3.^[18]

KCNE1 usporava aktivaciju KCNQ1 5-10 puta, povećavajući njegovu jedinstvenu provodljivost za četiri puta, eliminišući njegovu inaktivaciju i mijenjajući način na koji KCNQ1 reguliraju ostali proteini, lipidi i male molekule. Povezanost KCNE1 i KCNQ1 otkrivena je osam godina nakon što su Takumi et al. izvijestili o izolaciji frakcije RNK iz pacovskog bubrega koji je, kada se ubrizgava u oocite vrsta roda Xenopus, proizveo neobično sporo aktivirajuću, naponski ovisnu, kalij-selektivnu struju. Otkrili su gen KCNE1^[19] i tačno je predviđeno da kodira protein sa jednim transmembranskom domenom sa vanćelijskim N-terminalnim i citosolnim C-terminalnim domenom. Sposobnost KCNE1 da generira ovu struju bila je zbunjujuća zbog svoje jednostavne primarne strukture i topologije, u suprotnosti sa topologijom 6-transmembranskog domena drugih poznatih Kv α podjedinica kao ��to je Shaker iz Drosophila, klonirana dvije godine ranije. Misterija je riješena kada je KCNQ1 kloniran i otkriveno da se kokonstituira sa KCNE1, a pokazalo se da oociti Xenopus laevis endogeno eksprimiraju KCNQ1, koji je pojačan egzogenom ekspresijom KCNE1 kako bi se stvorila karakteristična sporo aktivirajuća struja.^[16]^[17] KCNQ1 je također neophodan za normalnu funkciju mnogih različitih epitelnih tkiva, ali se smatra da je u ovim ne-ekscitabilnim ćelijama pretežno reguliran putem KCNE2 ili KCNE3.^[18]

Također se navodi da KCNE1 reguliše i dvije druge α podjedinice porodice KCNQ, KCNQ4 i KCNQ5. KCNE1 je povećao obje njihove vršne struje u studijama ekspresije oocita i usporio aktivaciju potonjih.^[20]^[21]

KCNE1 takođe regulira hERG, što je Kv α podjedinica koja generira srčanokomorski IKr. KCNE1 je udvostručio hERG struju kada su ova dva eksprimirana u ćelijama sisara, iako mehanizam za to ostaje nepoznat.^[22]

Iako KCNE1 nije imao efekta kada se koeksprimirao sa podjedinicom Kv1.1 α u ćelijama jajnika kineskog hrčka (CHO), KCNE1 hvata N-tip (brzo inaktivirajuću) podjedinicu Kv1.4 α u ER/Golgijevom transportu kada se koeksprimira sa tim. KCNE1 (i KCNE2) također ima ovaj efekt na dvije druge kanonske podjedinice N-tipa Kv α, Kv3.3 i Kv3.4. Čini se da je ovo mehanizam koji osigurava da homomerni kanali N-tipa ne stignu do površine ćelije, jer se ovaj način supresija prfeko KCNE1 ili KCNE2 ublažava koekspresijom odloženih ispravljača iste potporodice (sporo inaktivirajućih) α podjedinica. Tako je Kv1.1 spasio Kv1.4, Kv3.1 je spasio Kv3.4; u svakom od ovih slučajeva rezultirajući kanali na membrani bili su heteromeri (npr. Kv3.1-Kv3.4) i pokazivali su posrednu kinetiku inaktivacije u odnosu na onu bilo koje α podjedinice same.^[23]^[24]

K CNE1 također regulira kinetiku ulaza Kv2.1, Kv3.1 i Kv3.2, u svakom slučaju usporavajući njihovo aktiviranje i deaktiviranje i ubrzavajući deaktivaciju posljednja dva.^[25]^[26] No effects were observed upon oocyte co-expression of KCNE1 and Kv4.2,^[27] but KCNE1 was found to slow the gating and increase macroscopic current of Kv4.3 in HEK cells.^[28] Nasuprot tome, ionski kanali formirani od Kv4.3 i citosolne pomoćne podjedinice KChIP2 pokazali su bržu aktivaciju i izmijenjenu inaktivaciju kada su koeksprimirani s KCNE1 u ćelijama kineskog hrčka (CHO).^[29] Finally, KCNE1 inhibited Kv12.2 in Xenopus oocytes.^[30]

Tkivna distribucija

KCNE1 je eksprimiran u ljudskom srcu (pretkomori i komomori), dok je kod odraslih miševa njegova ekspresija ograničena na pretkomoru i/ili provodni sistem.^[31] KCNE1 je takođe eksprimiran i u unutrašnjem uhu i bubrezima ljudi i miševa^[32]^[33] KCNE1 je otkriven i u mišjem mozgu^[34] ali ovaj nalaz je predmet tekuće debate.

Klinički značaj

Naslijeđene ili sporadične mutacije gena KCNE mogu uzrokovati Romano-Wardov sindrom (heterozigoti) i Jervell Lange-Nielsenov sindrom (homozigoti). Oba ova sindroma karakterizira sindrom dugog QT intervala, kašnjenje u repolarizaciji komofra. Pored toga, Jervellov i Lange-Nielsenov sindrom također uključuje bilateralnu senzornrvu gluhoću. Mutacija D76N u proteinu KCNE1 može dovesti do sindroma dugog QT, zbog strukturnih promjena u kompleksu KvLQT1/KCNE1, a osobama s ovim mutacijama se savjetuje da izbjegavaju okidače srčane aritmije i produženih QT intervala, kao što su stres ili naporna vježba.

Dok mutacije gubitka funkcije u KCNE1 uzrokuju sindrom dugog QT intervala, mutacije pojačanja funkcije KCNE1 povezane su s ranom pretkomorskom fibrilacijom.^[35] Uobičajeni polimorfizam KCNE1, S38G, povezan je s promijenjenom predispozicijom za sporadičnu pretkomorsku fibrilaciju ^[36] i postoperativnu fibrilaciju pretkomora.^[37] Pretkomorska ekspresija KCNE1 smanjena je na svinjskom modelu postoperativne pretkomorske fibrilacije, nakon lobektomije pluća.^[38]

Nedavno analiza 32 varijante KCNE1 pokazala je da navodne/potvrđene varijante KCNE1 gubitka funkcije predisponiraju produžetak QT intervala, ali uočena niska penetrabilnost EKG-a sugerira da se ne manifestiraju klinički kod većine osoba, u skladu s blagim fenotipom uočenim za pacijente sa JLNS2.^[39]

Također pogledajte

Reference

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^ Olesen MS, Bentzen BH, Nielsen JB, Steffensen AB, David JP, Jabbari J, Jensen HK, Haunsø S, Svendsen JH, Schmitt N (3. 4. 2012). "Mutations in the potassium channel subunit KCNE1 are associated with early-onset familial atrial fibrillation". BMC Medical Genetics. 13: 24. doi:10.1186/1471-2350-13-24. PMC 3359244. PMID 22471742.
^ Han HG, Wang HS, Yin Z, Jiang H, Fang M, Han J (20. 10. 2014). "KCNE1 112G>a polymorphism and atrial fibrillation risk: a meta-analysis". Genetics and Molecular Research. 13 (4): 8367–77. doi:10.4238/2014.October.20.12. PMID 25366730.
^ Voudris KV, Apostolakis S, Karyofillis P, Doukas K, Zaravinos A, Androutsopoulos VP, Michalis A, Voudris V, Spandidos DA (Feb 2014). "Genetic diversity of the KCNE1 gene and susceptibility to postoperative atrial fibrillation". American Heart Journal. 167 (2): 274–280.e1. doi:10.1016/j.ahj.2013.09.020. PMID 24439990.
^ Heerdt PM, Kant R, Hu Z, Kanda VA, Christini DJ, Malhotra JK, Abbott GW (Sep 2012). "Transcriptomic analysis reveals atrial KCNE1 down-regulation following lung lobectomy". Journal of Molecular and Cellular Cardiology. 53 (3): 350–3. doi:10.1016/j.yjmcc.2012.05.010. PMC 3418454. PMID 22641150.
^ Roberts JD, Asaki SY, Mazzanti A, Bos JM, Tuleta I, Muir AR, Crotti L, Krahn AD, Kutyifa V, Shoemaker MB, Johnsrude CL, Aiba T, Marcondes L, Baban A, Udupa S, Dechert B, Fischbach P, Knight LM, Vittinghoff E, Kukavica D, Stallmeyer B, Giudicessi JR, Spazzolini C, Shimamoto K, Tadros R, Cadrin-Tourigny J, Duff HJ, Simpson CS, Roston TM, Wijeyeratne YD, El Hajjaji I, Yousif MD, Gula LJ, Leong-Sit P, Chavali N, Landstrom AP, Marcus GM, Dittmann S, Wilde AA, Behr ER, Tfelt-Hansen J, Scheinman MM, Perez MV, Kaski JP, Gow RM, Drago F, Aziz PF, Abrams DJ, Gollob MH, Skinner JR, Shimizu W, Kaufman ES, Roden DM, Zareba W, Schwartz PJ, Schulze-Bahr E, Etheridge SP, Priori SG, Ackerman MJ (16. 1. 2020). "An International Multi-Center Evaluation of Type 5 Long QT Syndrome: A Low Penetrant Primary Arrhythmic Condition". Circulation. 141 (6): 429–439. doi:10.1161/CIRCULATIONAHA.119.043114. PMC 7035205. PMID 31941373.

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Vanjski linkovi

GeneReviews/NIH/NCBI/UW entry on Romano-Ward Syndrome
KCNE1 protein, human na US National Library of Medicine Medical Subject Headings (MeSH)

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[36] Han HG, Wang HS, Yin Z, Jiang H, Fang M, Han J (20. 10. 2014). "KCNE1 112G>a polymorphism and atrial fibrillation risk: a meta-analysis". Genetics and Molecular Research. 13 (4): 8367–77. doi:10.4238/2014.October.20.12. PMID 25366730.

[37] Voudris KV, Apostolakis S, Karyofillis P, Doukas K, Zaravinos A, Androutsopoulos VP, Michalis A, Voudris V, Spandidos DA (Feb 2014). "Genetic diversity of the KCNE1 gene and susceptibility to postoperative atrial fibrillation". American Heart Journal. 167 (2): 274–280.e1. doi:10.1016/j.ahj.2013.09.020. PMID 24439990.

[38] Heerdt PM, Kant R, Hu Z, Kanda VA, Christini DJ, Malhotra JK, Abbott GW (Sep 2012). "Transcriptomic analysis reveals atrial KCNE1 down-regulation following lung lobectomy". Journal of Molecular and Cellular Cardiology. 53 (3): 350–3. doi:10.1016/j.yjmcc.2012.05.010. PMC 3418454. PMID 22641150.

[39] Roberts JD, Asaki SY, Mazzanti A, Bos JM, Tuleta I, Muir AR, Crotti L, Krahn AD, Kutyifa V, Shoemaker MB, Johnsrude CL, Aiba T, Marcondes L, Baban A, Udupa S, Dechert B, Fischbach P, Knight LM, Vittinghoff E, Kukavica D, Stallmeyer B, Giudicessi JR, Spazzolini C, Shimamoto K, Tadros R, Cadrin-Tourigny J, Duff HJ, Simpson CS, Roston TM, Wijeyeratne YD, El Hajjaji I, Yousif MD, Gula LJ, Leong-Sit P, Chavali N, Landstrom AP, Marcus GM, Dittmann S, Wilde AA, Behr ER, Tfelt-Hansen J, Scheinman MM, Perez MV, Kaski JP, Gow RM, Drago F, Aziz PF, Abrams DJ, Gollob MH, Skinner JR, Shimizu W, Kaufman ES, Roden DM, Zareba W, Schwartz PJ, Schulze-Bahr E, Etheridge SP, Priori SG, Ackerman MJ (16. 1. 2020). "An International Multi-Center Evaluation of Type 5 Long QT Syndrome: A Low Penetrant Primary Arrhythmic Condition". Circulation. 141 (6): 429–439. doi:10.1161/CIRCULATIONAHA.119.043114. PMC 7035205. PMID 31941373.

[1]