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P51788 (CLCN2_HUMAN) Reviewed, UniProtKB/Swiss-Prot

Last modified January 25, 2012. Version 112. Feed History...

Clusters with 100%, 90%, 50% identity | Documents (5) | Third-party data text xml rdf/xml gff fasta
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to top of pageNames·Attributes·General annotation·Ontologies·Alt products·Sequence annotation·Sequences·References·Web links·Cross-refs·Entry info·DocumentsCustomize order

Names and origin

Protein namesRecommended name:
Chloride channel protein 2
Short name=ClC-2
Gene names
Name:CLCN2
OrganismHomo sapiens (Human)
Taxonomic identifier9606 [NCBI]
Taxonomic lineageEukaryota › Metazoa › Chordata › Craniata › Vertebrata › Euteleostomi › Mammalia › Eutheria › Euarchontoglires › Primates › Haplorrhini › Catarrhini › Hominidae › Homo

Protein attributes

Sequence length898 AA.
Sequence statusComplete.
Protein existenceEvidence 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 are associated with susceptibility to idiopathic generalized epilepsy type 11 (IGE11) [MIM:607628]. A disorder characterized by recurring generalized seizures in the absence of detectable brain lesions and/or metabolic abnormalities. Generalized seizures arise diffusely and simultaneously from both hemispheres of the brain.

Defects in CLCN2 are associated with juvenile absence epilepsy type 2 (JAE2) [MIM:607628]. 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.

Defects in CLCN2 are associated with juvenile myoclonic epilepsy type 8 (EJM8) [MIM:607628]. A subtype of idiopathic generalized epilepsy. Patients have afebrile seizures only, with onset in adolescence (rather than in childhood) and myoclonic jerks which usually occur after awakening and are triggered by sleep deprivation and fatigue.

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. ClC-2/CLCN2 subfamily. [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 processIon transport
Transport
   Cellular componentMembrane
   Coding sequence diversityAlternative splicing
Polymorphism
   DiseaseDisease mutation
Epilepsy
   DomainCBS domain
Repeat
Transmembrane
Transmembrane helix
   LigandChloride
   Molecular functionChloride channel
Ionic channel
Voltage-gated channel
   Technical termComplete proteome
Reference proteome
Gene Ontology (GO)
   Cellular componentchloride channel complex

Inferred from electronic annotation. Source: UniProtKB-KW

   Molecular functionvoltage-gated chloride channel activity

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 keyPosition(s)LengthDescriptionGraphical viewFeature identifier

Molecule processing

Chain1 – 898898Chloride channel protein 2
PRO_0000094433

Regions

Topological domain1 – 8787Cytoplasmic By similarity
Transmembrane88 – 12134Helical; By similarity
Transmembrane130 – 15526Helical; By similarity
Intramembrane164 – 1718Helical; Potential
Transmembrane180 – 19819Helical; By similarity
Transmembrane205 – 22319Helical; By similarity
Intramembrane239 – 25113Helical; By similarity
Intramembrane255 – 2639Helical; By similarity
Transmembrane275 – 29521Helical; By similarity
Transmembrane321 – 34929Helical; By similarity
Transmembrane358 – 37720Helical; By similarity
Transmembrane429 – 44921Helical; By similarity
Transmembrane457 – 48024Helical; By similarity
Intramembrane497 – 51115Helical; By similarity
Intramembrane512 – 5132Note=Loop between two helices; By similarity
Intramembrane514 – 52512Helical; By similarity
Intramembrane526 – 5305Note=Loop between two helices; By similarity
Transmembrane531 – 54818Helical; By similarity
Topological domain549 – 898350Cytoplasmic By similarity
Domain584 – 64259CBS 1
Domain790 – 85061CBS 2
Motif161 – 1655Selectivity filter part_1 By similarity
Motif203 – 2075Selectivity filter part_2 By similarity
Motif457 – 4615Selectivity filter part_3 By similarity
Compositional bias2 – 65Poly-Ala

Sites

Binding site1621Chloride By similarity
Binding site4591Chloride; via amide nitrogen By similarity
Binding site5531Chloride By similarity

Natural variations

Alternative sequence1 – 359359Missing in isoform 2.
VSP_007831
Alternative sequence443 – 48543FWMSA…FPDGI → HLGVWWVKAWLPGSQMEFIR TAAPTGLCLGATLWSGQLRW QER in isoform 2.
VSP_007832
Alternative sequence466 – 48217Missing in isoform 3.
VSP_036456
Alternative sequence486 – 898413Missing in isoform 2.
VSP_036455
Natural variant481P → R Reduces channel activity. Ref.7
VAR_057886
Natural variant681R → H Reduces channel activity. Ref.7
VAR_057887
Natural variant1991G → A No effect. Ref.7
VAR_057888
Natural variant2351R → Q Confers susceptibility to juvenile myoclonic epilepsy type 8; the mutant channel has accelerated deactivation rates compared to wild-type, but normal activation and peak current. Ref.9
VAR_057889
Natural variant5771R → Q Confers susceptibility to idiopathic generalized epilepsy type 11; the mutant channel has accelerated deactivation rates compared to wild-type, but normal activation and peak current. Ref.9
VAR_057890
Natural variant6441R → C No effect. Ref.9
VAR_057891
Natural variant6461R → Q Reduces channel activity. Ref.7
VAR_057892
Natural variant6681T → S. Ref.1 Ref.7
Corresponds to variant rs9820367 [ dbSNP | Ensembl ].
VAR_054550
Natural variant7151G → E May confer susceptibility to juvenile absence epilepsy type 2. Ref.6
Corresponds to variant rs28938470 [ dbSNP | Ensembl ].
VAR_015989
Natural variant7181E → D.
Corresponds to variant rs2228292 [ dbSNP | Ensembl ].
VAR_054551
Natural variant7191S → L in a patient with childhood absence epilepsy. Ref.8
VAR_058426
Natural variant7251R → W Slightly faster channel activation. Ref.7
VAR_057893
Natural variant7471R → H Slightly faster channel activation. Ref.7
VAR_057894

Experimental info

Sequence conflict171Y → H in AAB34722. Ref.1
Sequence conflict5371A → V in AAH21578. Ref.3

Sequences

Sequence LengthMass (Da)Tools
Isoform 1 [UniParc].

Last modified February 9, 2010. Version 2.
Checksum: 5F20FA8713C0C74E

FASTA89898,535
        10         20         30         40         50         60 
MAAAAAEEGM EPRALQYEQT 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 
SDQEGPPTPE 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

« Hide

Isoform 2 [UniParc].

Checksum: 69843C961A8FC3DF
Show »

FASTA12614,383
Isoform 3 [UniParc].

Checksum: F44E1264FC92758F
Show »

FASTA88196,786

References

« Hide '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), VARIANT SER-668.
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).
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).
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. expand/collapse author list , 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 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; SER-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 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

EMBL
GenBank
DDBJ		S77770 mRNA. Translation: AAB34722.2.
AF026004 mRNA. Translation: AAB88807.1.
BC021578 mRNA. Translation: AAH21578.1. Sequence problems.
BC072004 mRNA. Translation: AAH72004.1.
IPIIPI00020504.
IPI00290972.
IPI00922766.
RefSeqNP_001164558.1. NM_001171087.1.
NP_001164559.1. NM_001171088.1.
NP_001164560.1. NM_001171089.1.
NP_004357.3. NM_004366.4.
UniGeneHs.436847.

3D structure databases

ProteinModelPortalP51788.
SMRP51788. Positions 90-560, 570-841.
ModBaseSearch...

Protein-protein interaction databases

STRINGP51788.

PTM databases

PhosphoSiteP51788.

Polymorphism databases

DMDM288558807.

Proteomic databases

PRIDEP51788.

Protocols and materials databases

StructuralBiologyKnowledgebaseSearch...

Genome annotation databases

EnsemblENST00000265593; ENSP00000265593; ENSG00000114859.
GeneID1181.
KEGGhsa:1181.
UCSCuc003foh.2. human.
uc003foi.2. human.

Organism-specific databases

CTD1181.
GeneCardsGC03M184063.
HGNCHGNC:2020. CLCN2.
HPACAB009397.
HPA014545.
HPA024108.
MIM600570. gene.
607628. phenotype.
neXtProtNX_P51788.
Orphanet307. Juvenile myoclonic epilepsy.
GenAtlasSearch...

Phylogenomic databases

eggNOGprNOG10115.
GeneTreeENSGT00550000074179.
HOGENOMHBG755253.
HOVERGENHBG005332.
InParanoidP51788.
OMARRRQHMQ.
OrthoDBEOG4G7BXQ.
PhylomeDBP51788.

Gene expression databases

ArrayExpressP51788.
BgeeP51788.
CleanExHS_CLCN2.
GenevestigatorP51788.
GermOnlineENSG00000114859. Homo sapiens.

Family and domain databases

InterProIPR002244. Cl-channel-2.
IPR014743. Cl-channel_core.
IPR001807. Cl-channel_volt-gated.
IPR000644. Cysta_beta_synth_core.
[Graphical view]
Gene3DG3DSA:1.10.3080.10. Cl-channel_core. 1 hit.
KOK05011.
PANTHERPTHR11689. Cl-channel_volt. 1 hit.
PfamPF00571. CBS. 1 hit.
PF00654. Voltage_CLC. 1 hit.
[Graphical view]
PRINTSPR00762. CLCHANNEL.
PR01113. CLCHANNEL2.
SMARTSM00116. CBS. 1 hit.
[Graphical view]
SUPFAMSSF81340. Cl-channel_core. 1 hit.
PROSITEPS51371. CBS. 2 hits.
[Graphical view]
ProtoNetSearch...

Other

DrugBankDB01046. Lubiprostone.
NextBio4880.
SOURCESearch...

Entry information

Entry nameCLCN2_HUMAN
AccessionPrimary (citable) accession number: P51788
Secondary accession number(s): O14864, Q6IPA9, Q8WU13
Entry history
Integrated into UniProtKB/Swiss-Prot: October 1, 1996
Last sequence update: February 9, 2010
Last modified: January 25, 2012
This is version 112 of the entry and version 2 of the sequence. [Complete history]
Entry statusReviewed (UniProtKB/Swiss-Prot)
Annotation programChordata Protein Annotation Program
DisclaimerAny 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.

Relevant documents

Human chromosome 3

Human chromosome 3: entries, gene names and cross-references to MIM

Human entries with polymorphisms or disease mutations

List of human entries with polymorphisms or disease mutations

Human polymorphisms and disease mutations

Index of human polymorphisms and disease mutations

MIM cross-references

Online Mendelian Inheritance in Man (MIM) cross-references in UniProtKB/Swiss-Prot

SIMILARITY comments

Index of protein domains and families

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