Reviewed, UniProtKB/Swiss-Prot P51788 (CLCN2_HUMAN)

Names and origin

Protein names

Recommended name:
    Chloride channel protein 2
      Short name=ClC-2

Gene names

Name:

CLCN2

Organism

Homo sapiens (Human) [Complete proteome]

Taxonomic identifier

9606 [NCBI]

Taxonomic lineage

Eukaryota › Metazoa › Chordata › Craniata › Vertebrata › Euteleostomi › Mammalia › Eutheria › Euarchontoglires › Primates › Haplorrhini › Catarrhini › Hominidae › Homo

Protein attributes

Sequence length	898 AA.
Sequence status	Complete.
Sequence processing	The displayed sequence is not processed.
Protein existence	Evidence at protein level.

General annotation (Comments)

Function	Voltage-gated chloride channel. Chloride channels have several functions including the regulation of cell volume; membrane potential stabilization, signal transduction and transepithelial transport. Ref.5 Ref.9
Subcellular location	Membrane; Multi-pass membrane protein.
Tissue specificity	Ubiquitously expressed. Moderately expressed in aortic and coronary vascular smooth muscle cells and expressed at a low level in aortic endothelial cells. Ref.4
Involvement in disease	Defects in CLCN2 may be the cause of epilepsy with grand mal seizures on awakening (EGMA) [MIM:607628]. EGMA is a subtype of idiopathic generalized epilepsy (IGE) characterized by generalized tonic-clonic seizures (GTCS) occurring predominantly on awakening. The GTCS can be the only symptom or they can be combined with the other subsyndromes of IGE in childhood or adolescence. Defects in CLCN2 are the cause of childhood absence epilepsy type 3 (ECA3) [MIM:607682]. ECA3 is a subtype of idiopathic generalized epilepsy (IGE) characterized by onset at age 6-7 years, frequent absence seizures (several per day) and bilateral, synchronous, symmetric 3 Hz spike waves on EEG. During adolescence, tonic-clonic and myoclonic seizures develop. Ref.8 Defects in CLCN2 are a cause of juvenile absence epilepsy (JAE) [MIM:607631]. JAE is a subtype of idiopathic generalized epilepsy (IGE) characterized by onset occurring around puberty, absence seizures, generalized tonic-clonic seizures (GTCS), GTCS on awakening and myoclonic seizures. Ref.6
Miscellaneous	The CLC channel family contains both chloride channels and proton-coupled anion transporters that exchange chloride or another anion for protons. The absence of conserved gating glutamate residues is typical for family members that function as channels By similarity.
Sequence similarities	Belongs to the chloride channel (TC 2.A.49) family. [View classification] Contains 2 CBS domains.
Sequence caution	The sequence AAH21578.1 differs from that shown. Reason: Erroneous translation. Wrong choice of frame.

Ontologies

Keywords
Biological process	Ion transport Transport
Cellular component	Membrane
Coding sequence diversity	Alternative splicing Polymorphism
Disease	Disease mutation Epilepsy
Domain	CBS domain Repeat Transmembrane
Ligand	Chloride
Molecular function	Chloride channel Ionic channel Voltage-gated channel
Technical term	Complete proteome
Gene Ontology (GO)
Biological process	chloride transport Inferred from electronic annotation. Source: InterPro
Cellular component	chloride channel complex Inferred from electronic annotation. Source: UniProtKB-KW
Molecular function	chloride ion binding Inferred from electronic annotation. Source: UniProtKB-KW voltage-gated chloride channel activity Ref.1 Traceable author statement. Source: ProtInc
Complete GO annotation...

Alternative products

This entry describes 3 isoforms produced by alternative splicing. [Align] [Select]

Isoform 1 (identifier: P51788-1)

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: P51788-2)

The sequence of this isoform differs from the canonical sequence as follows:
     1-359: Missing.
     443-485: FWMSALATTI...SMAAWFPDGI → HLGVWWVKAW...WSGQLRWQER
     486-898: Missing.

Note: May be produced at very low levels due to a premature stop codon in the mRNA, leading to nonsense-mediated mRNA decay.

Isoform 3 (identifier: P51788-3)

The sequence of this isoform differs from the canonical sequence as follows:
     466-482: Missing.

Sequence annotation (Features)

	Feature key	Position(s)	Length	Description	Graphical view	Feature identifier
Molecule processing
	Chain	1 – 898	898	Chloride channel protein 2		PRO_0000094433
Regions
	Topological domain	1 – 87	87	Cytoplasmic By similarity
	Transmembrane	88 – 121	34	By similarity
	Transmembrane	130 – 155	26	By similarity
	Transmembrane	180 – 198	19	By similarity
	Transmembrane	205 – 223	19	By similarity
	Transmembrane	275 – 295	21	By similarity
	Transmembrane	321 – 349	29	By similarity
	Transmembrane	358 – 377	20	By similarity
	Transmembrane	429 – 449	21	By similarity
	Transmembrane	457 – 480	24	By similarity
	Transmembrane	531 – 548	18	By similarity
	Topological domain	549 – 898	350	Cytoplasmic By similarity
	Domain	584 – 642	59	CBS 1
	Domain	790 – 850	61	CBS 2
	Region	164 – 171	8	In-membrane helix Potential
	Region	239 – 251	13	In-membrane helix By similarity
	Region	255 – 263	9	In-membrane helix By similarity
	Region	497 – 511	15	In-membrane helix By similarity
	Region	512 – 513	2	In-membrane loop between two helices By similarity
	Region	514 – 525	12	In-membrane helix By similarity
	Region	526 – 530	5	In-membrane loop between two helices By similarity
	Motif	161 – 165	5	Selectivity filter part_1 By similarity
	Motif	203 – 207	5	Selectivity filter part_2 By similarity
	Motif	457 – 461	5	Selectivity filter part_3 By similarity
	Compositional bias	2 – 6	5	Poly-Ala
Sites
	Binding site	162	1	Chloride By similarity
	Binding site	459	1	Chloride; via amide nitrogen By similarity
	Binding site	553	1	Chloride By similarity
Natural variations
	Alternative sequence	1 – 359	359	Missing in isoform 2.		VSP_007831
	Alternative sequence	443 – 485	43	FWMSA…FPDGI → HLGVWWVKAWLPGSQMEFIR TAAPTGLCLGATLWSGQLRW QER in isoform 2.		VSP_007832
	Alternative sequence	466 – 482	17	Missing in isoform 3.		VSP_036456
	Alternative sequence	486 – 898	413	Missing in isoform 2.		VSP_036455
	Natural variant	48	1	P → R Reduces channel activity. Ref.7		VAR_057886
	Natural variant	68	1	R → H Reduces channel activity. Ref.7		VAR_057887
	Natural variant	199	1	G → A No effect. Ref.7		VAR_057888
	Natural variant	235	1	R → Q No effect on channel activation, but alters channel deactivation. Ref.9		VAR_057889
	Natural variant	577	1	R → Q No effect on channel activation, but alters channel deactivation. Ref.9		VAR_057890
	Natural variant	644	1	R → C No effect. Ref.9		VAR_057891
	Natural variant	646	1	R → Q Reduces channel activity. Ref.7		VAR_057892
	Natural variant	668	1	S → T: dbSNP rs9820367. Ref.7 Ref.2 Ref.3		VAR_054550
	Natural variant	715	1	G → E in JAE. Ref.6		VAR_015989
	Natural variant	718	1	E → D: dbSNP rs2228292.		VAR_054551
	Natural variant	719	1	S → L in ECA3. Ref.8		VAR_058426
	Natural variant	725	1	R → W Slightly faster channel activation. Ref.7		VAR_057893
	Natural variant	747	1	R → H Slightly faster channel activation. Ref.7		VAR_057894
Experimental info
	Sequence conflict	17	1	H → Y in AAB88807. Ref.2
	Sequence conflict	17	1	H → Y in AAH72004. Ref.3
	Sequence conflict	537	1	A → V in AAH21578. Ref.3

Sequences

	Sequence		Length	Mass (Da)
	Isoform 1 [UniParc]. Last modified October 1, 1996. Version 1. Checksum: 194386B4014E9FB5	FASTA	898	98,495
	10 20 30 40 50 60 MAAAAAEEGM EPRALQHEQT LMYGRYTQDL GAFAKEEAAR IRLGGPEPWK GPPSSRAAPE 70 80 90 100 110 120 LLEYGRSRCA RCRVCSVRCH KFLVSRVGED WIFLVLLGLL MALVSWVMDY AIAACLQAQQ 130 140 150 160 170 180 WMSRGLNTSI LLQYLAWVTY PVVLITFSAG FTQILAPQAV GSGIPEMKTI LRGVVLKEYL 190 200 210 220 230 240 TLKTFIAKVI GLTCALGSGM PLGKEGPFVH IASMCAALLS KFLSLFGGIY ENESRNTEML 250 260 270 280 290 300 AAACAVGVGC CFAAPIGGVL FSIEVTSTFF AVRNYWRGFF AATFSAFIFR VLAVWNRDEE 310 320 330 340 350 360 TITALFKTRF RLDFPFDLQE LPAFAVIGIA SGFGGALFVY LNRKIVQVMR KQKTINRFLM 370 380 390 400 410 420 RKRLLFPALV TLLISTLTFP PGFGQFMAGQ LSQKETLVTL FDNRTWVRQG LVEELEPPST 430 440 450 460 470 480 SQAWNPPRAN VFLTLVIFIL MKFWMSALAT TIPVPCGAFM PVFVIGAAFG RLVGESMAAW 490 500 510 520 530 540 FPDGIHTDSS TYRIVPGGYA VVGAAALAGA VTHTVSTAVI VFELTGQIAH ILPVMIAVIL 550 560 570 580 590 600 ANAVAQSLQP SLYDSIIRIK KLPYLPELGW GRHQQYRVRV EDIMVRDVPH VALSCTFRDL 610 620 630 640 650 660 RLALHRTKGR MLALVESPES MILLGSIERS QVVALLGAQL SPARRRQHMQ ERRATQTSPL 670 680 690 700 710 720 SDQEGPPSPE ASVCFQVNTE DSAFPAARGE THKPLKPALK RGPSVTRNLG ESPTGSAESA 730 740 750 760 770 780 GIALRSLFCG SPPPEAASEK LESCEKRKLK RVRISLASDA DLEGEMSPEE ILEWEEQQLD 790 800 810 820 830 840 EPVNFSDCKI DPAPFQLVER TSLHKTHTIF SLLGVDHAYV TSIGRLIGIV TLKELRKAIE 850 860 870 880 890 GSVTAQGVKV RPPLASFRDS ATSSSDTETT EVHALWGPHS RHGLPREGSP SDSDDKCQ
	Isoform 2. Checksum: 69843C961A8FC3DF	FASTA	126	14,383
	10 20 30 40 50 60 MRKRLLFPAL VTLLISTLTF PPGFGQFMAG QLSQKETLVT LFDNRTWVRQ GLVEELEPPS 70 80 90 100 110 120 TSQAWNPPRA NVFLTLVIFI LMKHLGVWWV KAWLPGSQME FIRTAAPTGL CLGATLWSGQ LRWQER
	Isoform 3. Checksum: A35EC93E19436684	FASTA	881	96,746
	10 20 30 40 50 60 MAAAAAEEGM EPRALQHEQT LMYGRYTQDL GAFAKEEAAR IRLGGPEPWK GPPSSRAAPE 70 80 90 100 110 120 LLEYGRSRCA RCRVCSVRCH KFLVSRVGED WIFLVLLGLL MALVSWVMDY AIAACLQAQQ 130 140 150 160 170 180 WMSRGLNTSI LLQYLAWVTY PVVLITFSAG FTQILAPQAV GSGIPEMKTI LRGVVLKEYL 190 200 210 220 230 240 TLKTFIAKVI GLTCALGSGM PLGKEGPFVH IASMCAALLS KFLSLFGGIY ENESRNTEML 250 260 270 280 290 300 AAACAVGVGC CFAAPIGGVL FSIEVTSTFF AVRNYWRGFF AATFSAFIFR VLAVWNRDEE 310 320 330 340 350 360 TITALFKTRF RLDFPFDLQE LPAFAVIGIA SGFGGALFVY LNRKIVQVMR KQKTINRFLM 370 380 390 400 410 420 RKRLLFPALV TLLISTLTFP PGFGQFMAGQ LSQKETLVTL FDNRTWVRQG LVEELEPPST 430 440 450 460 470 480 SQAWNPPRAN VFLTLVIFIL MKFWMSALAT TIPVPCGAFM PVFVIDGIHT DSSTYRIVPG 490 500 510 520 530 540 GYAVVGAAAL AGAVTHTVST AVIVFELTGQ IAHILPVMIA VILANAVAQS LQPSLYDSII 550 560 570 580 590 600 RIKKLPYLPE LGWGRHQQYR VRVEDIMVRD VPHVALSCTF RDLRLALHRT KGRMLALVES 610 620 630 640 650 660 PESMILLGSI ERSQVVALLG AQLSPARRRQ HMQERRATQT SPLSDQEGPP SPEASVCFQV 670 680 690 700 710 720 NTEDSAFPAA RGETHKPLKP ALKRGPSVTR NLGESPTGSA ESAGIALRSL FCGSPPPEAA 730 740 750 760 770 780 SEKLESCEKR KLKRVRISLA SDADLEGEMS PEEILEWEEQ QLDEPVNFSD CKIDPAPFQL 790 800 810 820 830 840 VERTSLHKTH TIFSLLGVDH AYVTSIGRLI GIVTLKELRK AIEGSVTAQG VKVRPPLASF 850 860 870 880 RDSATSSSDT ETTEVHALWG PHSRHGLPRE GSPSDSDDKC Q

References

	« Hide 'large scale' referencesShow 'large scale' references »
[1]	"Cloning of a putative human voltage-gated chloride channel (ClC-2) cDNA widely expressed in human tissues." Cid L.P., Montrose-Rafizadeh C., Smith D.I., Guggino W.B., Cutting G.R. Hum. Mol. Genet. 4:407-413(1995) [PubMed: 7795595] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1). Tissue: Placenta.
[2]	Rae J.L., Shepard A.R. Submitted (SEP-1997) to the EMBL/GenBank/DDBJ databases Cited for: NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1), VARIANT THR-668. Tissue: Lens epithelium.
[3]	"The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC)." The MGC Project Team Genome Res. 14:2121-2127(2004) [PubMed: 15489334] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORMS 2 AND 3), VARIANT THR-668. Tissue: Lung and Uterus.
[4]	"Expression of CLCN voltage-gated chloride channel genes in human blood vessels." Lamb F.S., Clayton G.H., Liu B.-X., Smith R.L., Barna T.J., Schutte B.C. J. Mol. Cell. Cardiol. 31:657-666(1999) [PubMed: 10198195] [Abstract] Cited for: TISSUE SPECIFICITY. Tissue: Aortic endothelium and Vascular smooth muscle.
[5]	"Voltage-dependent and -independent titration of specific residues accounts for complex gating of a ClC chloride channel by extracellular protons." Niemeyer M.I., Cid L.P., Yusef Y.R., Briones R., Sepulveda F.V. J. Physiol. (Lond.) 587:1387-1400(2009) [PubMed: 19153159] [Abstract] Cited for: FUNCTION.
[6]	"Mutations in CLCN2 encoding a voltage-gated chloride channel are associated with idiopathic generalized epilepsies." Haug K., Warnstedt M., Alekov A.K., Sander T., Ramirez A., Poser B., Maljevic S., Hebeisen S., Kubisch C., Rebstock J., Horvath S., Hallmann K., Dullinger J.S., Rau B., Haverkamp F., Beyenburg S., Schulz H., Janz D. , Giese B., Mueller-Newen G., Propping P., Elger C.E., Fahlke C., Lerche H., Heils A. Nat. Genet. 33:527-532(2003) [PubMed: 12612585] [Abstract] Cited for: VARIANT JAE GLU-715.
[7]	"Alterations in the cytoplasmic domain of CLCN2 result in altered gating kinetics." Paul J., Jeyaraj S., Huber S.M., Seebohm G., Boehmer C., Lang F., Kremsner P.G., Kun J.F.J. Cell. Physiol. Biochem. 20:441-454(2007) [PubMed: 17762171] [Abstract] Cited for: VARIANTS ARG-48; HIS-68; ALA-199; GLN-646; THR-668; TRP-725 AND HIS-747, CHARACTERIZATION OF VARIANTS ARG-48; HIS-68; ALA-199; GLN-646; TRP-725 AND HIS-747.
[8]	"Clinical and genetic familial study of a large cohort of Italian children with idiopathic epilepsy." Combi R., Grioni D., Contri M., Redaelli S., Redaelli F., Bassi M.T., Barisani D., Lavitrano M.L., Tredici G., Tenchini M.L., Bertolini M., Dalpra L. Brain Res. Bull. 79:89-96(2009) [PubMed: 19200853] [Abstract] Cited for: VARIANT ECA3 LEU-719.
[9]	"Two novel CLCN2 mutations accelerating chloride channel deactivation are associated with idiopathic generalized epilepsy." Saint-Martin C., Gauvain G., Teodorescu G., Gourfinkel-An I., Fedirko E., Weber Y.G., Maljevic S., Ernst J.-P., Garcia-Olivares J., Fahlke C., Nabbout R., LeGuern E., Lerche H., Christophe Poncer J., Depienne C. Hum. Mutat. 30:397-405(2009) [PubMed: 19191339] [Abstract] Cited for: VARIANTS GLN-235; GLN-577 AND CYS-644, CHARACTERIZATION OF VARIANTS GLN-235; GLN-577 AND CYS-644, FUNCTION.
+	Additional computationally mapped references.

Web resources

GeneReviews

Cross-references

Sequence databases
EMBLGenBankDDBJ	S77770 Unassigned DNA. Translation: AAB34722.2. AF026004 mRNA. Translation: AAB88807.1. BC021578 mRNA. Translation: AAH21578.1. Sequence problems. BC072004 mRNA. Translation: AAH72004.1.
IPI	IPI00020504. IPI00290972. IPI00922766.
RefSeq	NP_004357.3.
UniGene	Hs.436847
3D structure databases
ModBase	Search...
Protein-protein interaction databases
STRING	P51788.
Proteomic databases
PRIDE	P51788.
Genome annotation databases
Ensembl	ENST00000265593; ENSP00000265593; ENSG00000114859; Homo sapiens. [Genome view] ENST00000344937; ENSP00000345056; ENSG00000114859; Homo sapiens. [Genome view] ENST00000423355; ENSP00000412226; ENSG00000114859; Homo sapiens. [Genome view] ENST00000430397; ENSP00000396231; ENSG00000114859; Homo sapiens. [Genome view] ENST00000434054; ENSP00000400425; ENSG00000114859; Homo sapiens. [Genome view] ENST00000457512; ENSP00000391928; ENSG00000114859; Homo sapiens. [Genome view]
GeneID	1181.
KEGG	hsa:1181.
UCSC	uc003foh.2. human. uc003foi.2. human. uc010hya.1. human.
Organism-specific databases
CTD	1181.
GeneCards	GC03M185546.
H-InvDB	HIX0003908.
HGNC	HGNC:2020. CLCN2.
HPA	CAB009397. HPA014545. HPA024108.
MIM	600570. gene. 607628. phenotype. 607631. phenotype. 607682. phenotype.
Orphanet	64280. Epilepsy, childhood absence. 1941. Juvenile absence epilepsy. 307. Juvenile myoclonic epilepsy.
PharmGKB	PA26547.
GenAtlas	Search...
Phylogenomic databases
HOGENOM	P51788.
HOVERGEN	P51788.
Gene expression databases
ArrayExpress	P51788.
Bgee	P51788.
CleanEx	HS_CLCN2.
Genevestigator	P51788.
GermOnline	ENSG00000114859. Homo sapiens.
Family and domain databases
InterPro	IPR002244. Cl-channel2. IPR014743. Cl-channel_core. IPR001807. Cl-channel_volt. IPR000644. Cysta_beta_synth_core. [Graphical view]
Gene3D	G3DSA:1.10.3080.10. Cl-channel_core. 1 hit.
PANTHER	PTHR11689. Cl-channel_volt. 1 hit.
Pfam	PF00571. CBS. 1 hit. PF00654. Voltage_CLC. 1 hit. [Graphical view]
PRINTS	PR00762. CLCHANNEL. PR01113. CLCHANNEL2.
SMART	SM00116. CBS. 1 hit. [Graphical view]
PROSITE	PS51371. CBS. 2 hits. [Graphical view]
ProtoNet	Search...
Other Resources
DrugBank	DB01046. Lubiprostone.
NextBio	4880.
SOURCE	Search...

Entry information

Entry name

CLCN2_HUMAN

Accession

Primary (citable) accession number: P51788
Secondary accession number(s): O14864, Q6IPA9, Q8WU13

Entry history

Integrated into UniProtKB/Swiss-Prot:	October 1, 1996
Last sequence update:	October 1, 1996
Last modified:	October 13, 2009
This is version 91 of the entry and version 1 of the sequence. [Complete history]

Entry status

Reviewed (UniProtKB/Swiss-Prot)

Annotation project

HPI (Human Proteome Initiative)

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.