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Protein

Chloride intracellular channel protein 2

Gene

CLIC2

Organism
Homo sapiens (Human)
Status
Reviewed-Annotation score: Annotation score: 5 out of 5-Experimental evidence at protein leveli

Functioni

Can insert into membranes and form chloride ion channels. Channel activity depends on the pH. Membrane insertion seems to be redox-regulated and may occur only under oxydizing conditions. Modulates the activity of RYR2 and inhibits calcium influx.3 Publications

GO - Molecular functioni

  • chloride channel activity Source: ProtInc
  • glutathione peroxidase activity Source: BHF-UCL
  • voltage-gated ion channel activity Source: UniProtKB-KW

GO - Biological processi

  • negative regulation of ryanodine-sensitive calcium-release channel activity Source: BHF-UCL
  • positive regulation of binding Source: BHF-UCL
  • regulation of cardiac muscle contraction by regulation of the release of sequestered calcium ion Source: BHF-UCL
  • regulation of release of sequestered calcium ion into cytosol by sarcoplasmic reticulum Source: BHF-UCL
  • signal transduction Source: UniProtKB
  • transport Source: ProtInc
Complete GO annotation...

Keywords - Molecular functioni

Chloride channel, Ion channel, Voltage-gated channel

Keywords - Biological processi

Ion transport, Transport

Keywords - Ligandi

Chloride

Enzyme and pathway databases

BioCyciZFISH:ENSG00000155962-MONOMER.
ReactomeiR-HSA-2672351. Stimuli-sensing channels.
R-HSA-5578775. Ion homeostasis.

Protein family/group databases

TCDBi1.A.12.1.5. the intracellular chloride channel (clic) family.

Names & Taxonomyi

Protein namesi
Recommended name:
Chloride intracellular channel protein 2
Alternative name(s):
XAP121
Gene namesi
Name:CLIC2
OrganismiHomo sapiens (Human)
Taxonomic identifieri9606 [NCBI]
Taxonomic lineageiEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresPrimatesHaplorrhiniCatarrhiniHominidaeHomo
Proteomesi
  • UP000005640 Componenti: Chromosome X

Organism-specific databases

HGNCiHGNC:2063. CLIC2.

Subcellular locationi

  • Cytoplasm 1 Publication
  • Membrane 1 Publication; Single-pass membrane protein 1 Publication

  • Note: Exists both as soluble cytoplasmic protein and as membrane protein with probably a single transmembrane domain.

Topology

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Transmembranei32 – 52Helical; Note=After insertion into the membraneSequence analysisAdd BLAST21

GO - Cellular componenti

  • chloride channel complex Source: UniProtKB-KW
  • cytoplasm Source: UniProtKB
  • intracellular Source: LIFEdb
  • nucleus Source: UniProtKB
Complete GO annotation...

Keywords - Cellular componenti

Cytoplasm, Membrane

Pathology & Biotechi

Involvement in diseasei

Mental retardation, X-linked, syndromic, 32 (MRXS32)1 Publication
The disease is caused by mutations affecting the gene represented in this entry.
Disease descriptionA mental retardation syndrome characterized by profound intellectual deficit, delayed psychomotor development beginning in infancy and little or no speech development. Additional features include seizures, large joint contractures, and abnormal positioning of the thumbs. Mental retardation is defined by significantly below average general intellectual functioning associated with impairments in adaptive behavior and manifested during the developmental period.
See also OMIM:300886
Feature keyPosition(s)DescriptionActionsGraphical viewLength
Natural variantiVAR_068898101H → Q in MRXS32; results in stimulation of RYR channels activity with channels remaining open for longer times; the mutation may impair insertion of the protein into the membrane to form a functioning ion channel. 1 PublicationCorresponds to variant rs398122917dbSNPEnsembl.1

Keywords - Diseasei

Disease mutation, Mental retardation

Organism-specific databases

DisGeNETi1193.
MalaCardsiCLIC2.
MIMi300886. phenotype.
OpenTargetsiENSG00000155962.
Orphaneti324410. X-linked intellectual disability - cardiomegaly - congestive heart failure.
PharmGKBiPA26589.

PTM / Processingi

Molecule processing

Feature keyPosition(s)DescriptionActionsGraphical viewLength
ChainiPRO_00001442051 – 247Chloride intracellular channel protein 2Add BLAST247

Amino acid modifications

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Disulfide bondi30 ↔ 33In soluble form2 Publications

Keywords - PTMi

Disulfide bond

Proteomic databases

EPDiO15247.
MaxQBiO15247.
PaxDbiO15247.
PeptideAtlasiO15247.
PRIDEiO15247.

PTM databases

iPTMnetiO15247.
PhosphoSitePlusiO15247.

Expressioni

Tissue specificityi

Expressed in adult and fetal brain, heart, skeletal muscle, liver, lung, and spleen. Detected in adult stomach and testis. Expressed in fetal thymus and kidney.2 Publications

Gene expression databases

BgeeiENSG00000155962.
CleanExiHS_CLIC2.
ExpressionAtlasiO15247. baseline and differential.
GenevisibleiO15247. HS.

Organism-specific databases

HPAiHPA060101.

Interactioni

Subunit structurei

Monomer. Interacts with TRAPPC2 and RYR2.4 Publications

Protein-protein interaction databases

BioGridi107605. 6 interactors.
IntActiO15247. 1 interactor.
MINTiMINT-4713986.
STRINGi9606.ENSP00000358460.

Structurei

Secondary structure

1247
Legend: HelixTurnBeta strandPDB Structure known for this area
Show more details
Feature keyPosition(s)DescriptionActionsGraphical viewLength
Beta strandi14 – 20Combined sources7
Beta strandi24 – 27Combined sources4
Helixi31 – 43Combined sources13
Beta strandi48 – 52Combined sources5
Helixi57 – 60Combined sources4
Beta strandi68 – 70Combined sources3
Beta strandi72 – 75Combined sources4
Beta strandi78 – 80Combined sources3
Helixi83 – 93Combined sources11
Turni96 – 98Combined sources3
Helixi108 – 111Combined sources4
Turni112 – 115Combined sources4
Helixi116 – 125Combined sources10
Helixi129 – 131Combined sources3
Helixi132 – 151Combined sources20
Turni160 – 162Combined sources3
Beta strandi163 – 165Combined sources3
Beta strandi172 – 178Combined sources7
Helixi181 – 201Combined sources21
Helixi210 – 220Combined sources11
Helixi223 – 226Combined sources4
Helixi232 – 239Combined sources8
Turni240 – 242Combined sources3

3D structure databases

Select the link destinations:
PDBei
RCSB PDBi
PDBji
Links Updated
PDB entryMethodResolution (Å)ChainPositionsPDBsum
2PERX-ray2.00A1-247[»]
2R4VX-ray1.85A1-247[»]
2R5GX-ray1.86A1-247[»]
ProteinModelPortaliO15247.
SMRiO15247.
ModBaseiSearch...
MobiDBiSearch...

Miscellaneous databases

EvolutionaryTraceiO15247.

Family & Domainsi

Domains and Repeats

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Domaini99 – 239GST C-terminalAdd BLAST141

Region

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Regioni1 – 96Required for insertion into the membraneBy similarityAdd BLAST96
Regioni1 – 94N-terminalAdd BLAST94
Regioni95 – 106Joint loopAdd BLAST12
Regioni107 – 247C-terminalAdd BLAST141
Regioni151 – 171Foot loopAdd BLAST21

Domaini

Members of this family may change from a globular, soluble state to a state where the N-terminal domain is inserted into the membrane and functions as chloride channel. A conformation change of the N-terminal domain is thought to expose hydrophobic surfaces that trigger membrane insertion.

Sequence similaritiesi

Belongs to the chloride channel CLIC family.Curated
Contains 1 GST C-terminal domain.Curated

Keywords - Domaini

Transmembrane, Transmembrane helix

Phylogenomic databases

eggNOGiKOG1422. Eukaryota.
ENOG410ZRK6. LUCA.
GeneTreeiENSGT00550000074477.
HOGENOMiHOG000231548.
HOVERGENiHBG050994.
InParanoidiO15247.
KOiK05022.
OMAiSYMKSIF.
OrthoDBiEOG091G0IHT.
PhylomeDBiO15247.
TreeFamiTF315438.

Family and domain databases

Gene3Di1.20.1050.10. 1 hit.
3.40.30.10. 1 hit.
InterProiIPR002946. CLIC.
IPR030253. CLIC-2.
IPR010987. Glutathione-S-Trfase_C-like.
IPR004045. Glutathione_S-Trfase_N.
IPR012336. Thioredoxin-like_fold.
[Graphical view]
PANTHERiPTHR11260:SF133. PTHR11260:SF133. 2 hits.
PfamiPF13409. GST_N_2. 1 hit.
[Graphical view]
PRINTSiPR01263. INTCLCHANNEL.
SUPFAMiSSF47616. SSF47616. 1 hit.
SSF52833. SSF52833. 1 hit.
TIGRFAMsiTIGR00862. O-ClC. 1 hit.
PROSITEiPS50405. GST_CTER. 1 hit.
[Graphical view]

Sequencei

Sequence statusi: Complete.

O15247-1 [UniParc]FASTAAdd to basket

« Hide

        10         20         30         40         50
MSGLRPGTQV DPEIELFVKA GSDGESIGNC PFCQRLFMIL WLKGVKFNVT
60 70 80 90 100
TVDMTRKPEE LKDLAPGTNP PFLVYNKELK TDFIKIEEFL EQTLAPPRYP
110 120 130 140 150
HLSPKYKESF DVGCNLFAKF SAYIKNTQKE ANKNFEKSLL KEFKRLDDYL
160 170 180 190 200
NTPLLDEIDP DSAEEPPVSR RLFLDGDQLT LADCSLLPKL NIIKVAAKKY
210 220 230 240
RDFDIPAEFS GVWRYLHNAY AREEFTHTCP EDKEIENTYA NVAKQKS
Length:247
Mass (Da):28,356
Last modified:September 13, 2005 - v3
Checksum:i9DB896034DD103E8
GO

Sequence cautioni

The sequence CAA73228 differs from that shown. Reason: Frameshift at position 244.Curated

Experimental Info

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Sequence conflicti109S → C in CAA03948 (PubMed:9339381).Curated1
Sequence conflicti164E → G in CAA73228 (PubMed:9339381).Curated1

Natural variant

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Natural variantiVAR_068898101H → Q in MRXS32; results in stimulation of RYR channels activity with channels remaining open for longer times; the mutation may impair insertion of the protein into the membrane to form a functioning ion channel. 1 PublicationCorresponds to variant rs398122917dbSNPEnsembl.1

Sequence databases

Select the link destinations:
EMBLi
GenBanki
DDBJi
Links Updated
Y12696 mRNA. Translation: CAA73228.1. Frameshift.
AJ000217, AJ000218, AJ000219 Genomic DNA. Translation: CAA03948.1.
AK292785 mRNA. Translation: BAF85474.1.
AL356738 Genomic DNA. Translation: CAI41464.1.
CH471172 Genomic DNA. Translation: EAW72624.1.
BC022305 mRNA. Translation: AAH22305.1.
CCDSiCCDS14767.1.
RefSeqiNP_001280.3. NM_001289.5.
UniGeneiHs.655445.

Genome annotation databases

EnsembliENST00000369449; ENSP00000358460; ENSG00000155962.
GeneIDi1193.
KEGGihsa:1193.
UCSCiuc004fnf.5. human.

Cross-referencesi

Sequence databases

Select the link destinations:
EMBLi
GenBanki
DDBJi
Links Updated
Y12696 mRNA. Translation: CAA73228.1. Frameshift.
AJ000217, AJ000218, AJ000219 Genomic DNA. Translation: CAA03948.1.
AK292785 mRNA. Translation: BAF85474.1.
AL356738 Genomic DNA. Translation: CAI41464.1.
CH471172 Genomic DNA. Translation: EAW72624.1.
BC022305 mRNA. Translation: AAH22305.1.
CCDSiCCDS14767.1.
RefSeqiNP_001280.3. NM_001289.5.
UniGeneiHs.655445.

3D structure databases

Select the link destinations:
PDBei
RCSB PDBi
PDBji
Links Updated
PDB entryMethodResolution (Å)ChainPositionsPDBsum
2PERX-ray2.00A1-247[»]
2R4VX-ray1.85A1-247[»]
2R5GX-ray1.86A1-247[»]
ProteinModelPortaliO15247.
SMRiO15247.
ModBaseiSearch...
MobiDBiSearch...

Protein-protein interaction databases

BioGridi107605. 6 interactors.
IntActiO15247. 1 interactor.
MINTiMINT-4713986.
STRINGi9606.ENSP00000358460.

Protein family/group databases

TCDBi1.A.12.1.5. the intracellular chloride channel (clic) family.

PTM databases

iPTMnetiO15247.
PhosphoSitePlusiO15247.

Proteomic databases

EPDiO15247.
MaxQBiO15247.
PaxDbiO15247.
PeptideAtlasiO15247.
PRIDEiO15247.

Protocols and materials databases

DNASUi1193.
Structural Biology KnowledgebaseSearch...

Genome annotation databases

EnsembliENST00000369449; ENSP00000358460; ENSG00000155962.
GeneIDi1193.
KEGGihsa:1193.
UCSCiuc004fnf.5. human.

Organism-specific databases

CTDi1193.
DisGeNETi1193.
GeneCardsiCLIC2.
HGNCiHGNC:2063. CLIC2.
HPAiHPA060101.
MalaCardsiCLIC2.
MIMi300138. gene.
300886. phenotype.
neXtProtiNX_O15247.
OpenTargetsiENSG00000155962.
Orphaneti324410. X-linked intellectual disability - cardiomegaly - congestive heart failure.
PharmGKBiPA26589.
GenAtlasiSearch...

Phylogenomic databases

eggNOGiKOG1422. Eukaryota.
ENOG410ZRK6. LUCA.
GeneTreeiENSGT00550000074477.
HOGENOMiHOG000231548.
HOVERGENiHBG050994.
InParanoidiO15247.
KOiK05022.
OMAiSYMKSIF.
OrthoDBiEOG091G0IHT.
PhylomeDBiO15247.
TreeFamiTF315438.

Enzyme and pathway databases

BioCyciZFISH:ENSG00000155962-MONOMER.
ReactomeiR-HSA-2672351. Stimuli-sensing channels.
R-HSA-5578775. Ion homeostasis.

Miscellaneous databases

EvolutionaryTraceiO15247.
GeneWikiiCLIC2.
GenomeRNAii1193.
PROiO15247.
SOURCEiSearch...

Gene expression databases

BgeeiENSG00000155962.
CleanExiHS_CLIC2.
ExpressionAtlasiO15247. baseline and differential.
GenevisibleiO15247. HS.

Family and domain databases

Gene3Di1.20.1050.10. 1 hit.
3.40.30.10. 1 hit.
InterProiIPR002946. CLIC.
IPR030253. CLIC-2.
IPR010987. Glutathione-S-Trfase_C-like.
IPR004045. Glutathione_S-Trfase_N.
IPR012336. Thioredoxin-like_fold.
[Graphical view]
PANTHERiPTHR11260:SF133. PTHR11260:SF133. 2 hits.
PfamiPF13409. GST_N_2. 1 hit.
[Graphical view]
PRINTSiPR01263. INTCLCHANNEL.
SUPFAMiSSF47616. SSF47616. 1 hit.
SSF52833. SSF52833. 1 hit.
TIGRFAMsiTIGR00862. O-ClC. 1 hit.
PROSITEiPS50405. GST_CTER. 1 hit.
[Graphical view]
ProtoNetiSearch...

Entry informationi

Entry nameiCLIC2_HUMAN
AccessioniPrimary (citable) accession number: O15247
Secondary accession number(s): A8K9S0
, O15174, Q5JT80, Q8TCE3
Entry historyi
Integrated into UniProtKB/Swiss-Prot: July 15, 1998
Last sequence update: September 13, 2005
Last modified: November 2, 2016
This is version 151 of the entry and version 3 of the sequence. [Complete history]
Entry statusiReviewed (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.

Miscellaneousi

Keywords - Technical termi

3D-structure, Complete proteome, Reference proteome

Documents

  1. Human chromosome X
    Human chromosome X: entries, gene names and cross-references to MIM
  2. Human entries with polymorphisms or disease mutations
    List of human entries with polymorphisms or disease mutations
  3. Human polymorphisms and disease mutations
    Index of human polymorphisms and disease mutations
  4. MIM cross-references
    Online Mendelian Inheritance in Man (MIM) cross-references in UniProtKB/Swiss-Prot
  5. PDB cross-references
    Index of Protein Data Bank (PDB) cross-references
  6. SIMILARITY comments
    Index of protein domains and families

Similar proteinsi

Links to similar proteins from the UniProt Reference Clusters (UniRef) at 100%, 90% and 50% sequence identity:
100%UniRef100 combines identical sequences and sub-fragments with 11 or more residues from any organism into one UniRef entry.
90%UniRef90 is built by clustering UniRef100 sequences that have at least 90% sequence identity to, and 80% overlap with, the longest sequence (a.k.a seed sequence).
50%UniRef50 is built by clustering UniRef90 seed sequences that have at least 50% sequence identity to, and 80% overlap with, the longest sequence in the cluster.