P56696 (KCNQ4_HUMAN) Reviewed, UniProtKB/Swiss-Prot

Names and origin

Protein names

Recommended name:
Potassium voltage-gated channel subfamily KQT member 4

Alternative name(s):
KQT-like 4
Potassium channel subunit alpha KvLQT4
Voltage-gated potassium channel subunit Kv7.4

Gene names

Name:

KCNQ4

Organism

Homo sapiens (Human) [Reference proteome]

Taxonomic identifier

9606 [NCBI]

Taxonomic lineage

cellular organisms › Eukaryota › Opisthokonta › Metazoa › Eumetazoa › Bilateria › Deuterostomia › Chordata › Craniata › Vertebrata › Gnathostomata › Teleostomi › Euteleostomi › Sarcopterygii › Tetrapoda › Amniota › Mammalia › Theria › Eutheria › Euarchontoglires › Primates › Haplorrhini › Simiiformes › Catarrhini › Hominoidea › Hominidae › Homininae › Homo

Protein attributes

Sequence length	695 AA.
Sequence status	Complete.
Protein existence	Evidence at protein level

General annotation (Comments)

Function	Probably important in the regulation of neuronal excitability. May underlie a potassium current involved in regulating the excitability of sensory cells of the cochlea. KCNQ4 channels are blocked by linopirdin, XE991 and bepridil, whereas clofilium is without significant effect. Muscarinic agonist oxotremorine-M strongly suppress KCNQ4 current in CHO cells in which cloned KCNQ4 channels were coexpressed with M1 muscarinic receptors. Ref.4
Subunit structure	Homotetramer. May form heteromultimers with KCNQ3. Ref.5
Subcellular location	Basal cell membrane; Multi-pass membrane protein. Note: Situated at the basal membrane of cochlear outer hair cells By similarity.
Tissue specificity	Expressed in the outer, but not the inner, sensory hair cells of the cochlea. Slightly expressed in heart, brain and skeletal muscle.
Domain	The segment S4 is probably the voltage-sensor and is characterized by a series of positively charged amino acids at every third position By similarity. Ref.5 The A-domain tail carries the major determinants of channel assembly specificity. Its coiled-coil region is Four-stranded. Ref.5
Involvement in disease	Deafness, autosomal dominant, 2A (DFNA2A) [MIM:600101]: A form of non-syndromic sensorineural hearing loss. Sensorineural deafness results from damage to the neural receptors of the inner ear, the nerve pathways to the brain, or the area of the brain that receives sound information. Note: The disease is caused by mutations affecting the gene represented in this entry. Ref.1 Ref.6 Ref.7 Ref.8 Ref.9
Miscellaneous	Mutagenesis experiments were carried out by expressing in Xenopus oocytes KCNQ4 mutants either individually (homomultimers) or in combination with wild-type KCNQ4 (mut/wt homomultimers) in a ratio of 1:1, to mimic the situation in a heterozygous DFNA2 patient.
Sequence similarities	Belongs to the potassium channel family. KQT (TC 1.A.1.15) subfamily. Kv7.4/KCNQ4 sub-subfamily. [View classification]

Ontologies

Keywords
Biological process	Hearing Ion transport Potassium transport Transport
Cellular component	Cell membrane Membrane
Coding sequence diversity	Alternative splicing
Disease	Deafness Disease mutation Non-syndromic deafness
Domain	Coiled coil Transmembrane Transmembrane helix
Ligand	Potassium
Molecular function	Ion channel Potassium channel Voltage-gated channel
Technical term	3D-structure Complete proteome Reference proteome
Gene Ontology (GO)
Biological_process	inner ear morphogenesis Inferred from electronic annotation. Source: Compara sensory perception of sound Traceable author statement Ref.1. Source: ProtInc synaptic transmission Traceable author statement. Source: Reactome
Cellular_component	basal plasma membrane Inferred from electronic annotation. Source: UniProtKB-SubCell plasma membrane Traceable author statement. Source: Reactome voltage-gated potassium channel complex Inferred from electronic annotation. Source: InterPro
Molecular_function	delayed rectifier potassium channel activity Inferred from Biological aspect of Ancestor. Source: RefGenome
Complete GO annotation...

Alternative products

This entry describes 2 isoforms produced by alternative splicing. [Align] [Select]

Note: Additional isoforms seem to exist.

Isoform 1 (identifier: P56696-1)

This isoform has been chosen as the 'canonical' sequence. All positional information in this entry refers to it. This is also the sequence that appears in the downloadable versions of the entry.

Isoform 2 (identifier: P56696-2)

The sequence of this isoform differs from the canonical sequence as follows:
     377-430: Missing.

Sequence annotation (Features)

Feature key

Position(s)

Length

Description

Graphical view

Feature identifier

Molecule processing

Chain

1 – 695

695

Potassium voltage-gated channel subfamily KQT member 4

PRO_0000054037

Regions

Topological domain

1 – 97

97

Cytoplasmic

Transmembrane

98 – 118

21

Helical; Name=Segment S1; Potential

Topological domain

119 – 131

13

Extracellular

Transmembrane

132 – 152

21

Helical; Name=Segment S2; Potential

Topological domain

153 – 172

20

Cytoplasmic

Transmembrane

173 – 193

21

Helical; Name=Segment S3; Potential

Topological domain

194 – 201

8

Extracellular

Transmembrane

202 – 224

23

Helical; Voltage-sensor; Name=Segment S4; Potential

Topological domain

225 – 237

13

Cytoplasmic

Transmembrane

238 – 258

21

Helical; Name=Segment S5; Potential

Topological domain

259 – 270

12

Extracellular

Intramembrane

271 – 292

22

Pore-forming; Name=Segment H5; Potential

Topological domain

293 – 296

4

Extracellular

Transmembrane

297 – 317

21

Helical; Name=Segment S6; Potential

Topological domain

318 – 695

378

Cytoplasmic

Region

546 – 650

105

A-domain (Tetramerization)

Coiled coil

610 – 645

36

Ref.5

Motif

283 – 288

6

Selectivity filter By similarity

Natural variations

Alternative sequence

377 – 430

54

Missing in isoform 2.

VSP_001013

Natural variant

274

1

L → H in DFNA2A. Ref.8

VAR_010936

Natural variant

276

1

W → S in DFNA2A. Ref.6

VAR_008726

Natural variant

281

1

L → S in DFNA2A. Ref.7

VAR_010937

Natural variant

285

1

G → C in DFNA2A; loss of potassium selectivity of the pore. Ref.6

VAR_008727

Natural variant

285

1

G → S in DFNA2A; dominant negative effect; abolishes potassium current. Ref.1
Corresponds to variant rs28937588 [ dbSNP | Ensembl ].

VAR_001547

Natural variant

287

1

G → R in DFNA2A. Ref.9

VAR_065779

Natural variant

321

1

G → S in DFNA2A. Ref.6
Corresponds to variant rs28939710 [ dbSNP | Ensembl ].

VAR_008728

Natural variant

455

1

H → Q. Ref.1
Corresponds to variant rs34287852 [ dbSNP | Ensembl ].

VAR_058971

Secondary structure

1

.

.

.

.

.

695

Helix Strand Turn

Details...

Helix

526 – 548

23

Helix

612 – 637

26

Sequences

	Sequence		Length	Mass (Da)
	Isoform 1 [UniParc]. Last modified September 22, 2009. Version 2. Checksum: 51390F5E00E8C157	FASTA	695	77,101
	10 20 30 40 50 60 MAEAPPRRLG LGPPPGDAPR AELVALTAVQ SEQGEAGGGG SPRRLGLLGS PLPPGAPLPG 70 80 90 100 110 120 PGSGSGSACG QRSSAAHKRY RRLQNWVYNV LERPRGWAFV YHVFIFLLVF SCLVLSVLST 130 140 150 160 170 180 IQEHQELANE CLLILEFVMI VVFGLEYIVR VWSAGCCCRY RGWQGRFRFA RKPFCVIDFI 190 200 210 220 230 240 VFVASVAVIA AGTQGNIFAT SALRSMRFLQ ILRMVRMDRR GGTWKLLGSV VYAHSKELIT 250 260 270 280 290 300 AWYIGFLVLI FASFLVYLAE KDANSDFSSY ADSLWWGTIT LTTIGYGDKT PHTWLGRVLA 310 320 330 340 350 360 AGFALLGISF FALPAGILGS GFALKVQEQH RQKHFEKRRM PAANLIQAAW RLYSTDMSRA 370 380 390 400 410 420 YLTATWYYYD SILPSFRELA LLFEHVQRAR NGGLRPLEVR RAPVPDGAPS RYPPVATCHR 430 440 450 460 470 480 PGSTSFCPGE SSRMGIKDRI RMGSSQRRTG PSKQHLAPPT MPTSPSSEQV GEATSPTKVQ 490 500 510 520 530 540 KSWSFNDRTR FRASLRLKPR TSAEDAPSEE VAEEKSYQCE LTVDDIMPAV KTVIRSIRIL 550 560 570 580 590 600 KFLVAKRKFK ETLRPYDVKD VIEQYSAGHL DMLGRIKSLQ TRVDQIVGRG PGDRKAREKG 610 620 630 640 650 660 DKGPSDAEVV DEISMMGRVV KVEKQVQSIE HKLDLLLGFY SRCLRSGTSA SLGAVQVPLF 670 680 690 DPDITSDYHS PVDHEDISVS AQTLSISRSV STNMD
	Isoform 2 [UniParc]. Checksum: 769D085366D51552	FASTA	641	71,196
	10 20 30 40 50 60 MAEAPPRRLG LGPPPGDAPR AELVALTAVQ SEQGEAGGGG SPRRLGLLGS PLPPGAPLPG 70 80 90 100 110 120 PGSGSGSACG QRSSAAHKRY RRLQNWVYNV LERPRGWAFV YHVFIFLLVF SCLVLSVLST 130 140 150 160 170 180 IQEHQELANE CLLILEFVMI VVFGLEYIVR VWSAGCCCRY RGWQGRFRFA RKPFCVIDFI 190 200 210 220 230 240 VFVASVAVIA AGTQGNIFAT SALRSMRFLQ ILRMVRMDRR GGTWKLLGSV VYAHSKELIT 250 260 270 280 290 300 AWYIGFLVLI FASFLVYLAE KDANSDFSSY ADSLWWGTIT LTTIGYGDKT PHTWLGRVLA 310 320 330 340 350 360 AGFALLGISF FALPAGILGS GFALKVQEQH RQKHFEKRRM PAANLIQAAW RLYSTDMSRA 370 380 390 400 410 420 YLTATWYYYD SILPSFSSRM GIKDRIRMGS SQRRTGPSKQ HLAPPTMPTS PSSEQVGEAT 430 440 450 460 470 480 SPTKVQKSWS FNDRTRFRAS LRLKPRTSAE DAPSEEVAEE KSYQCELTVD DIMPAVKTVI 490 500 510 520 530 540 RSIRILKFLV AKRKFKETLR PYDVKDVIEQ YSAGHLDMLG RIKSLQTRVD QIVGRGPGDR 550 560 570 580 590 600 KAREKGDKGP SDAEVVDEIS MMGRVVKVEK QVQSIEHKLD LLLGFYSRCL RSGTSASLGA 610 620 630 640 VQVPLFDPDI TSDYHSPVDH EDISVSAQTL SISRSVSTNM D

References

	« Hide 'large scale' referencesShow 'large scale' references »
[1]	"KCNQ4, a novel potassium channel expressed in sensory outer hair cells, is mutated in dominant deafness." Kubisch C., Schroeder B.C., Friedrich T., Luetjohann B., El-Amraoui A., Marlin S., Petit C., Jentsch T.J. Cell 96:437-446(1999) [PubMed] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [GENOMIC DNA / MRNA] (ISOFORMS 1 AND 2), VARIANT DFNA2A SER-285, VARIANT GLN-455, CHARACTERIZATION OF VARIANT DFNA2A SER-285. Tissue: Retina.
[2]	"The DNA sequence and biological annotation of human chromosome 1." Gregory S.G., Barlow K.F., McLay K.E., Kaul R., Swarbreck D., Dunham A., Scott C.E., Howe K.L., Woodfine K., Spencer C.C.A., Jones M.C., Gillson C., Searle S., Zhou Y., Kokocinski F., McDonald L., Evans R., Phillips K. , Atkinson A., Cooper R., Jones C., Hall R.E., Andrews T.D., Lloyd C., Ainscough R., Almeida J.P., Ambrose K.D., Anderson F., Andrew R.W., Ashwell R.I.S., Aubin K., Babbage A.K., Bagguley C.L., Bailey J., Beasley H., Bethel G., Bird C.P., Bray-Allen S., Brown J.Y., Brown A.J., Buckley D., Burton J., Bye J., Carder C., Chapman J.C., Clark S.Y., Clarke G., Clee C., Cobley V., Collier R.E., Corby N., Coville G.J., Davies J., Deadman R., Dunn M., Earthrowl M., Ellington A.G., Errington H., Frankish A., Frankland J., French L., Garner P., Garnett J., Gay L., Ghori M.R.J., Gibson R., Gilby L.M., Gillett W., Glithero R.J., Grafham D.V., Griffiths C., Griffiths-Jones S., Grocock R., Hammond S., Harrison E.S.I., Hart E., Haugen E., Heath P.D., Holmes S., Holt K., Howden P.J., Hunt A.R., Hunt S.E., Hunter G., Isherwood J., James R., Johnson C., Johnson D., Joy A., Kay M., Kershaw J.K., Kibukawa M., Kimberley A.M., King A., Knights A.J., Lad H., Laird G., Lawlor S., Leongamornlert D.A., Lloyd D.M., Loveland J., Lovell J., Lush M.J., Lyne R., Martin S., Mashreghi-Mohammadi M., Matthews L., Matthews N.S.W., McLaren S., Milne S., Mistry S., Moore M.J.F., Nickerson T., O'Dell C.N., Oliver K., Palmeiri A., Palmer S.A., Parker A., Patel D., Pearce A.V., Peck A.I., Pelan S., Phelps K., Phillimore B.J., Plumb R., Rajan J., Raymond C., Rouse G., Saenphimmachak C., Sehra H.K., Sheridan E., Shownkeen R., Sims S., Skuce C.D., Smith M., Steward C., Subramanian S., Sycamore N., Tracey A., Tromans A., Van Helmond Z., Wall M., Wallis J.M., White S., Whitehead S.L., Wilkinson J.E., Willey D.L., Williams H., Wilming L., Wray P.W., Wu Z., Coulson A., Vaudin M., Sulston J.E., Durbin R.M., Hubbard T., Wooster R., Dunham I., Carter N.P., McVean G., Ross M.T., Harrow J., Olson M.V., Beck S., Rogers J., Bentley D.R. Nature 441:315-321(2006) [PubMed] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
[3]	"Inhibition of KCNQ1-4 potassium channels expressed in mammalian cells via M1 muscarinic acetylcholine receptors." Selyanko A.A., Hadley J.K., Wood I.C., Abogadie F.C., Jentsch T.J., Brown D.A. J. Physiol. (Lond.) 522:349-355(2000) [PubMed] [Europe PMC] [Abstract] Cited for: INHIBITION BY M1 MUSCARINIC RECEPTORS.
[4]	"KCNQ4 channels expressed in mammalian cells: functional characteristics and pharmacology." Soegaard R., Ljungstroem T., Pedersen K.A., Oelesen S.-P., Jensen B.S. Am. J. Physiol. 280:C859-C866(2001) [PubMed] [Europe PMC] [Abstract] Cited for: PHARMACOLOGICAL CHARACTERIZATION, POSSIBLE FUNCTION.
[5]	"Structural insight into KCNQ (Kv7) channel assembly and channelopathy." Howard R.J., Clark K.A., Holton J.M., Minor D.L. Jr. Neuron 53:663-675(2007) [PubMed] [Europe PMC] [Abstract] Cited for: X-RAY CRYSTALLOGRAPHY (2.07 ANGSTROMS) OF 610-640, SUBUNIT, DOMAIN COILED-COIL DOMAIN.
[6]	"Mutations in the KCNQ4 gene are responsible for autosomal dominant deafness in four DFNA2 families." Coucke P.J., Van Hauwe P., Kelley P.M., Kunst H., Schatteman I., Van Velzen D., Meyers J., Ensink R.J., Verstreken M., Declau F., Marres H., Kastury K., Bhasin S., McGuirt W.T., Smith R.J.H., Cremers C.W.R.J., Van de Heyning P., Willems P.J., Smith S.D., Van Camp G. Hum. Mol. Genet. 8:1321-1328(1999) [PubMed] [Europe PMC] [Abstract] Cited for: VARIANTS DFNA2A SER-276; CYS-285 AND SER-321.
[7]	"Novel mutation in the KCNQ4 gene in a large kindred with dominant progressive hearing loss." Talebizadeh Z., Kelley P.M., Askew J.W., Beisel K.W., Smith S.D. Hum. Mutat. 14:493-501(1999) [PubMed] [Europe PMC] [Abstract] Cited for: VARIANT DFNA2A SER-281.
[8]	"Mutations in the KCNQ4 K+ channel gene, responsible for autosomal dominant hearing loss, cluster in the channel pore region." Van Hauwe P., Coucke P.J., Ensink R.J., Huygen P., Cremers C.W.R.J., Van Camp G. Am. J. Med. Genet. 93:184-187(2000) [PubMed] [Europe PMC] [Abstract] Cited for: VARIANT DFNA2A HIS-274.
[9]	"Autosomal dominant progressive sensorineural hearing loss due to a novel mutation in the KCNQ4 gene." Arnett J., Emery S.B., Kim T.B., Boerst A.K., Lee K., Leal S.M., Lesperance M.M. Arch. Otolaryngol. Head Neck Surg. 137:54-59(2011) [PubMed] [Europe PMC] [Abstract] Cited for: VARIANT DFNA2A ARG-287.
+	Additional computationally mapped references.

Web resources

Hereditary hearing loss homepage

Gene page

GeneReviews

Cross-references

Sequence databases

EMBL
GenBank
DDBJ

AF105202 mRNA. Translation: AAD14680.1.
AF105216 , AF105203, AF105204, AF105205, AF105206, AF105207, AF105208, AF105209, AF105210, AF105211, AF105212, AF105213, AF105214, AF105215 Genomic DNA. Translation: AAD14681.1.
AC119677 Genomic DNA. No translation available.

IPI

IPI00293679.
IPI00293680.

RefSeq

NP_004691.2. NM_004700.3.
NP_751895.1. NM_172163.2.

UniGene

Hs.473058.

3D structure databases

PDBe
RCSB PDB
PDBj

Entry	Method	Resolution (Å)	Chain	Positions	PDBsum
2OVC	X-ray	2.07	A	610-640	[»]
4GOW	X-ray	2.60	A	522-593	[»]

ProteinModelPortal

P56696.

ModBase

Search...

Protein-protein interaction databases

STRING

9606.ENSP00000262916.

Protein family/group databases

TCDB

1.A.1.15.4. voltage-gated ion channel (VIC) superfamily.

PTM databases

PhosphoSite

P56696.

Polymorphism databases

DMDM

259016259.

Proteomic databases

PaxDb

P56696.

PRIDE

P56696.

Protocols and materials databases

StructuralBiologyKnowledgebase

Search...

Genome annotation databases

Ensembl

ENST00000347132; ENSP00000262916; ENSG00000117013.
ENST00000509682; ENSP00000423756; ENSG00000117013.

GeneID

9132.

KEGG

hsa:9132.

UCSC

uc001cgh.2. human.
uc001cgi.2. human.

Organism-specific databases

CTD

9132.

GeneCards

GC01P041249.

H-InvDB

HIX0200020.

HGNC

HGNC:6298. KCNQ4.

HPA

HPA018305.

MIM

600101. phenotype.
603537. gene.

neXtProt

NX_P56696.

Orphanet

90635. Autosomal dominant nonsyndromic sensorineural deafness type DFNA.

PharmGKB

PA30076.

GenAtlas

Search...

Phylogenomic databases

eggNOG

COG1226.

HOGENOM

HOG000220839.

HOVERGEN

HBG059014.

InParanoid

P56696.

KO

K04929.

OMA

WAFVYHV.

OrthoDB

EOG4HQDHW.

PhylomeDB

P56696.

Enzyme and pathway databases

Reactome

REACT_13685. Neuronal System.

Gene expression databases

Bgee

P56696.

CleanEx

HS_KCNQ4.

Genevestigator

P56696.

GermOnline

ENSG00000117013. Homo sapiens.

Family and domain databases

InterPro

IPR005821. Ion_trans_dom.
IPR003091. K_chnl.
IPR003937. K_chnl_volt-dep_KCNQ.
IPR013821. K_chnl_volt-dep_KCNQ_C.
IPR015573. K_chnl_volt-dep_KCQN4.
[Graphical view]

PANTHER

PTHR11537. PTHR11537. 1 hit.
PTHR11537:SF4. PTHR11537:SF4. 1 hit.

Pfam

PF00520. Ion_trans. 1 hit.
PF03520. KCNQ_channel. 1 hit.
[Graphical view]

PRINTS

PR00169. KCHANNEL.
PR01459. KCNQCHANNEL.

ProtoNet

Search...

Other

ChEMBL

CHEMBL3576.

EvolutionaryTrace

P56696.

GenomeRNAi

9132.

NextBio

34237.

SOURCE

Search...

Entry information

Entry name

KCNQ4_HUMAN

Accession

Primary (citable) accession number: P56696
Secondary accession number(s): O96025

Entry history

Integrated into UniProtKB/Swiss-Prot:	July 15, 1999
Last sequence update:	September 22, 2009
Last modified:	May 1, 2013
This is version 126 of the entry and version 2 of the sequence. [Complete history]

Entry status

Reviewed (UniProtKB/Swiss-Prot)

Annotation program

Chordata Protein Annotation Program

Disclaimer

Any medical or genetic information present in this entry is provided for research, educational and informational purposes only. It is not in any way intended to be used as a substitute for professional medical advice, diagnosis, treatment or care.