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1.A.1.20.1
K+ voltage-gated ether-a-go-go-related channel, H-ERG (KCNH2; Erg; HErg; Erg1) subunit Kv11.1 (long QT syndrome type 2) (Gong et al., 2006; Chartrand et al. 2010; McBride et al. 2013).  Forms a heteromeric K+ channel regulating cardiac repolarization, neuronal firing frequency and neoplastic cell growth (Szabó et al., 2011). Oligomerization is due to N-terminal interactions between two splice variants, hERG1a and hERG1b (Phartiyal et al., 2007). Structure function relationships of ERG channel activation and inhibition have been reviewed (Durdagi et al., 2010). Interactions between the N-terminal domain and the transmembrane core modulate hERG K channel gating (Fernández-Trillo et al., 2011). The marine algal toxin azaspiracid is an open state blocker (Twiner et al., 2012). Verapamil blocks channel activity by binding to Y652 and F656 in TMS S6 (Duan et al. 2007).  Hydrophobic interactions between the voltage sensor and the channel domain mediate inactivation (Perry et al. 2013), but voltage sensing by the S4 segment can be transduced to the channel gate in the absence of physical continuity between the two modules (Lörinczi et al. 2015).  Mutations give rise to long QT syndrome (Osterbur et al. 2015).  Polyphenols such as caffeic acid phenylethyl ester (CAPE) and curcumin inhibit by modification of gating, not by blocking the pore (Choi et al. 2013). Potassium ions can inhibit tumorigenesis through inducing apoptosis of hepatoma cells by upregulating potassium ion transport channel proteins HERG and VDAC1 (Xia et al. 2016).  Incorrectly folded hERG can be degraded by Bag1-stimulated Trc-8-dependent proteolysis (Hantouche et al. 2016). The S1 helix regulates channel activity. Thus, S1 region mutations reduce both the action potential repolarizing current passed by Kv11.1 channels in cardiac myocytes, as well as the current passed in response to premature depolarizations that normally helps protect against the formation of ectopic beats (Phan et al. 2017). Interactions of beta1 integrins with hERG1 channels in cancer cells stimulate distinct signaling pathways that depended on the conformational state of hERG1 (Becchetti et al. 2017). ERG1 is sensitive to the alkaloid, ginsenoside 20(S) Rg3 which alters the gating of hERG1 channels by interacting with and stabilizing the voltage sensor domain in an activated state (Gardner et al. 2017).

Accession Number:Q12809
Protein Name:H-ERG aka Erg1
Length:1159
Molecular Weight:126655.00
Species:Homo sapiens (Human) [9606]
Number of TMSs:7
Location1 / Topology2 / Orientation3: Membrane1 / Multi-pass membrane protein2
Substrate K+, potassium ions

Cross database links:

Genevestigator: Q12809
HEGENOM: HBG717083
RefSeq: NP_000229.1    NP_742053.1    NP_742054.1   
Entrez Gene ID: 3757   
Pfam: PF00027    PF00520    PF00989   
Drugbank: Drugbank Link   
OMIM: 152427  gene+phenotype
609620  phenotype
KEGG: hsa:3757   

Gene Ontology

GO:0008076 C:voltage-gated potassium channel complex
GO:0005251 F:delayed rectifier potassium channel activity
GO:0000155 F:two-component sensor activity
GO:0008015 P:blood circulation
GO:0006936 P:muscle contraction
GO:0006813 P:potassium ion transport
GO:0008016 P:regulation of heart contraction
GO:0006355 P:regulation of transcription, DNA-dependent
GO:0007165 P:signal transduction
GO:0055085 P:transmembrane transport
GO:0000160 P:two-component signal transduction system (p...

References (39)

[1] “A family of potassium channel genes related to eag in Drosophila and mammals.”  Warmke J.W.et.al.   8159766
[2] “Genomic organization and mutational analysis of HERG, a gene responsible for familial long QT syndrome.”  Itoh T.et.al.   9600240
[3] “Isolation of novel heart-specific genes using the BodyMap database.”  Soejima H.et.al.   11374908
[4] “Cell cycle-dependent expression of HERG1 and HERG1B isoforms in tumor cells.”  Crociani O.et.al.   12431979
[5] “Two isoforms of the mouse ether-a-go-go-related gene coassemble to form channels with properties similar to the rapidly activating component of the cardiac delayed rectifier K+ current.”  London B.et.al.   9351462
[6] “Electrophysiological characterization of an alternatively processed ERG K+ channel in mouse and human hearts.”  Lees-Miller J.P.et.al.   9351446
[7] “A K+ channel splice variant common in human heart lacks a C-terminal domain required for expression of rapidly activating delayed rectifier current.”  Kupershmidt S.et.al.   9765245
[8] “The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC).”  The MGC Project Teamet.al.   15489334
[9] “Role of glycosylation in cell surface expression and stability of HERG potassium channels.”  Gong Q.et.al.   12063277
[10] “Cyclic AMP regulates the HERG K(+) channel by dual pathways.”  Cui J.et.al.   10837251
[11] “A minK-HERG complex regulates the cardiac potassium current I(Kr).”  McDonald T.V.et.al.   9230439
[12] “MiRP1 forms IKr potassium channels with HERG and is associated with cardiac arrhythmia.”  Abbott G.W.et.al.   10219239
[13] “Quantitative phosphoproteomic analysis of T cell receptor signaling reveals system-wide modulation of protein-protein interactions.”  Mayya V.et.al.   19690332
[14] “Crystal structure and functional analysis of the HERG potassium channel N-terminus: a eukaryotic PAS domain.”  Morais Cabral J.H.et.al.   9845367
[15] “A molecular basis for cardiac arrhythmia: HERG mutations cause long QT syndrome.”  Curran M.E.et.al.   7889573
[16] “Novel missense mutation in the cyclic nucleotide-binding domain of HERG causes long QT syndrome.”  Satler C.A.et.al.   8914737
[17] “Missense mutation in the pore region of HERG causes familial long QT syndrome.”  Benson D.W.et.al.   8635257
[18] “A mutation in HERG associated with notched T waves in long QT syndrome.”  Dausse E.et.al.   8877771
[19] “Four novel KVLQT1 and four novel HERG mutations in familial long-QT syndrome.”  Tanaka T.et.al.   9024139
[20] “Genomic structure of three long QT syndrome genes: KVLQT1, HERG, and KCNE1.”  Splawski I.et.al.   9693036
[21] “Multiple different missense mutations in the pore region of HERG in patients with long QT syndrome.”  Satler C.A.et.al.   9544837
[22] “Novel missense mutation (G601S) of HERG in a Japanese long QT syndrome family.”  Akimoto K.et.al.   9452080
[23] “C-terminal HERG mutations: the role of hypokalemia and a KCNQ1-associated mutation in cardiac event occurrence.”  Berthet M.et.al.   10086971
[24] “Novel KCNQ1 and HERG missense mutations in Dutch long-QT families.”  Jongbloed R.J.E.et.al.   10220144
[25] “Long QT syndrome-associated mutations in the Per-Arnt-Sim (PAS) domain of HERG potassium channels accelerate channel deactivation.”  Chen J.et.al.   10187793
[26] “Characterization of a novel missense mutation in the pore of HERG in a patient with long QT syndrome.”  Yoshida H.et.al.   10517660
[27] “Long QT syndrome with a high mortality rate caused by a novel G572R missense mutation in KCNH2.”  Larsen L.A.et.al.   10735633
[28] “Spectrum of mutations in long-QT syndrome genes. KVLQT1, HERG, SCN5A, KCNE1, and KCNE2.”  Splawski I.et.al.   10973849
[29] “Analysis of the human KCNH2(HERG) gene: identification and characterization of a novel mutation Y667X associated with long QT syndrome and a non-pathological 9 bp insertion.”  Paulussen A.et.al.   10790218
[30] “Survey of the coding region of the HERG gene in long QT syndrome reveals six novel mutations and an amino acid polymorphism with possible phenotypic effects.”  Laitinen P.et.al.   10862094
[31] “Bradycardia-induced long QT syndrome caused by a de novo missense mutation in the S2-S3 inner loop of HERG.”  Yoshida H.et.al.   11170080
[32] “Characterization of a novel missense mutation E637K in the pore-S6 loop of HERG in a patient with long QT syndrome.”  Hayashi K.et.al.   12062363
[33] “Allelic variants in long-QT disease genes in patients with drug-associated torsades de pointes.”  Yang P.et.al.   11997281
[34] “A novel mutation (T65P) in the PAS domain of the human potassium channel HERG results in the long QT syndrome by trafficking deficiency.”  Paulussen A.et.al.   12354768
[35] “Clinical, genetic, and biophysical characterization of a homozygous HERG mutation causing severe neonatal long QT syndrome.”  Johnson W.H. Jr.et.al.   12621127
[36] “Sudden death associated with short-QT syndrome linked to mutations in HERG.”  Brugada R.et.al.   14676148
[37] “Compound mutations: a common cause of severe long-QT syndrome.”  Westenskow P.et.al.   15051636
[38] “Short QT syndrome and atrial fibrillation caused by mutation in KCNH2.”  Hong K.et.al.   15828882
[39] “Spectrum of pathogenic mutations and associated polymorphisms in a cohort of 44 unrelated patients with long QT syndrome.”  Millat G.et.al.   16922724
Structure:
1BYW   1UJL   2L0W   2L1M   2L4R   2LE7   4HP9   4HQA     

External Searches:

  • Search: DB with
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  • 2° Structure (Network Protein Sequence Analysis)

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Predict TMSs (Predict number of transmembrane segments)
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FASTA formatted sequence
1:	MPVRRGHVAP QNTFLDTIIR KFEGQSRKFI IANARVENCA VIYCNDGFCE LCGYSRAEVM 
61:	QRPCTCDFLH GPRTQRRAAA QIAQALLGAE ERKVEIAFYR KDGSCFLCLV DVVPVKNEDG 
121:	AVIMFILNFE VVMEKDMVGS PAHDTNHRGP PTSWLAPGRA KTFRLKLPAL LALTARESSV 
181:	RSGGAGGAGA PGAVVVDVDL TPAAPSSESL ALDEVTAMDN HVAGLGPAEE RRALVGPGSP 
241:	PRSAPGQLPS PRAHSLNPDA SGSSCSLART RSRESCASVR RASSADDIEA MRAGVLPPPP 
301:	RHASTGAMHP LRSGLLNSTS DSDLVRYRTI SKIPQITLNF VDLKGDPFLA SPTSDREIIA 
361:	PKIKERTHNV TEKVTQVLSL GADVLPEYKL QAPRIHRWTI LHYSPFKAVW DWLILLLVIY 
421:	TAVFTPYSAA FLLKETEEGP PATECGYACQ PLAVVDLIVD IMFIVDILIN FRTTYVNANE 
481:	EVVSHPGRIA VHYFKGWFLI DMVAAIPFDL LIFGSGSEEL IGLLKTARLL RLVRVARKLD 
541:	RYSEYGAAVL FLLMCTFALI AHWLACIWYA IGNMEQPHMD SRIGWLHNLG DQIGKPYNSS 
601:	GLGGPSIKDK YVTALYFTFS SLTSVGFGNV SPNTNSEKIF SICVMLIGSL MYASIFGNVS 
661:	AIIQRLYSGT ARYHTQMLRV REFIRFHQIP NPLRQRLEEY FQHAWSYTNG IDMNAVLKGF 
721:	PECLQADICL HLNRSLLQHC KPFRGATKGC LRALAMKFKT THAPPGDTLV HAGDLLTALY 
781:	FISRGSIEIL RGDVVVAILG KNDIFGEPLN LYARPGKSNG DVRALTYCDL HKIHRDDLLE 
841:	VLDMYPEFSD HFWSSLEITF NLRDTNMIPG SPGSTELEGG FSRQRKRKLS FRRRTDKDTE 
901:	QPGEVSALGP GRAGAGPSSR GRPGGPWGES PSSGPSSPES SEDEGPGRSS SPLRLVPFSS 
961:	PRPPGEPPGG EPLMEDCEKS SDTCNPLSGA FSGVSNIFSF WGDSRGRQYQ ELPRCPAPTP 
1021:	SLLNIPLSSP GRRPRGDVES RLDALQRQLN RLETRLSADM ATVLQLLQRQ MTLVPPAYSA 
1081:	VTTPGPGPTS TSPLLPVSPL PTLTLDSLSQ VSQFMACEEL PPGAPELPQE GPTRRLSLPG 
1141:	QLGALTSQPL HRHGSDPGS