O15247 (CLIC2_HUMAN) Reviewed, UniProtKB/Swiss-Prot

Names and origin

Protein names

Recommended name:
Chloride intracellular channel protein 2

Alternative name(s):
XAP121

Gene names

Name:

CLIC2

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	247 AA.
Sequence status	Complete.
Protein existence	Evidence at protein level

General annotation (Comments)

Function	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. Ref.7 Ref.8 Ref.11
Subunit structure	Monomer. Interacts with TRAPPC2 and RYR2. Ref.6 Ref.7 Ref.8 Ref.11
Subcellular location	Cytoplasm. Membrane; Single-pass membrane protein Probable. Note: Exists both as soluble cytoplasmic protein and as membrane protein with probably a single transmembrane domain. Ref.8
Tissue specificity	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. Ref.7 Ref.10
Domain	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.
Involvement in disease	Defects in CLIC2 are a cause of a mental retardation with cardiopathy and seizures. Cardiac features include atrial fibrillation, cardiomegaly, and congestive heart failure.
Sequence similarities	Belongs to the chloride channel CLIC family. Contains 1 GST C-terminal domain.
Sequence caution	The sequence CAA73228.1 differs from that shown. Reason: Frameshift at position 244.

Ontologies

Keywords
Biological process	Ion transport Transport
Cellular component	Cytoplasm Membrane
Disease	Disease mutation Mental retardation
Domain	Transmembrane Transmembrane helix
Ligand	Chloride
Molecular function	Chloride channel Ion channel Voltage-gated channel
PTM	Disulfide bond
Technical term	3D-structure Complete proteome Reference proteome
Gene Ontology (GO)
Biological_process	negative regulation of ryanodine-sensitive calcium-release channel activity Inferred from direct assay Ref.7Ref.8. Source: BHF-UCL positive regulation of binding Inferred from direct assay Ref.8. Source: BHF-UCL regulation of cardiac muscle contraction by regulation of the release of sequestered calcium ion Inferred by curator Ref.7. Source: BHF-UCL
Cellular_component	chloride channel complex Inferred from electronic annotation. Source: UniProtKB-KW cytoplasm Traceable author statement PubMed 16130169. Source: UniProtKB nucleus Traceable author statement PubMed 16130169. Source: UniProtKB
Molecular_function	chloride channel activity Traceable author statement Ref.1. Source: ProtInc glutathione peroxidase activity Inferred from direct assay Ref.7. Source: BHF-UCL voltage-gated chloride channel activity Inferred from electronic annotation. Source: InterPro
Complete GO annotation...

Sequence annotation (Features)

Feature key

Position(s)

Length

Description

Graphical view

Feature identifier

Molecule processing

Chain

1 – 247

247

Chloride intracellular channel protein 2

PRO_0000144205

Regions

Transmembrane

32 – 52

21

Helical; Note=After insertion into the membrane; Potential

Domain

99 – 239

141

GST C-terminal

Region

1 – 96

96

Required for insertion into the membrane By similarity

Region

1 – 94

94

N-terminal

Region

95 – 106

12

Joint loop

Region

107 – 247

141

C-terminal

Region

151 – 171

21

Foot loop

Amino acid modifications

Disulfide bond

30 ↔ 33

In soluble form Ref.11 Ref.12

Natural variations

Natural variant

101

1

H → Q Probable disease-associated mutation found in mental retardation with cardiopathy and seizures; results in stimulation of RYR channels activity with channels remaining open for longer times. Ref.10

VAR_068898

Experimental info

Sequence conflict

109

1

S → C in CAA03948. Ref.1

Sequence conflict

164

1

E → G in CAA73228. Ref.1

Secondary structure

1

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247

Helix Strand Turn

Details...

Beta strand

14 – 20

7

Beta strand

24 – 27

4

Helix

31 – 43

13

Beta strand

48 – 52

5

Helix

57 – 60

4

Beta strand

68 – 70

3

Beta strand

72 – 75

4

Beta strand

78 – 80

3

Helix

83 – 93

11

Turn

96 – 98

3

Helix

108 – 111

4

Turn

112 – 115

4

Helix

116 – 125

10

Helix

129 – 131

3

Helix

132 – 151

20

Turn

160 – 162

3

Beta strand

163 – 165

3

Beta strand

172 – 178

7

Helix

181 – 201

21

Helix

210 – 220

11

Helix

223 – 226

4

Helix

232 – 239

8

Turn

240 – 242

3

Sequences

	Sequence		Length	Mass (Da)
	O15247 [UniParc]. Last modified September 13, 2005. Version 3. Checksum: 9DB896034DD103E8	FASTA	247	28,356
	10 20 30 40 50 60 MSGLRPGTQV DPEIELFVKA GSDGESIGNC PFCQRLFMIL WLKGVKFNVT TVDMTRKPEE 70 80 90 100 110 120 LKDLAPGTNP PFLVYNKELK TDFIKIEEFL EQTLAPPRYP HLSPKYKESF DVGCNLFAKF 130 140 150 160 170 180 SAYIKNTQKE ANKNFEKSLL KEFKRLDDYL NTPLLDEIDP DSAEEPPVSR RLFLDGDQLT 190 200 210 220 230 240 LADCSLLPKL NIIKVAAKKY RDFDIPAEFS GVWRYLHNAY AREEFTHTCP EDKEIENTYA NVAKQKS

References

	« Hide 'large scale' referencesShow 'large scale' references »
[1]	"Genomic structure of a novel chloride channel gene, CLIC2, in Xq28." Heiss N.S., Poustka A. Genomics 45:224-228(1997) [PubMed] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [GENOMIC DNA / MRNA].
[2]	"Complete sequencing and characterization of 21,243 full-length human cDNAs." Ota T., Suzuki Y., Nishikawa T., Otsuki T., Sugiyama T., Irie R., Wakamatsu A., Hayashi K., Sato H., Nagai K., Kimura K., Makita H., Sekine M., Obayashi M., Nishi T., Shibahara T., Tanaka T., Ishii S. , Yamamoto J., Saito K., Kawai Y., Isono Y., Nakamura Y., Nagahari K., Murakami K., Yasuda T., Iwayanagi T., Wagatsuma M., Shiratori A., Sudo H., Hosoiri T., Kaku Y., Kodaira H., Kondo H., Sugawara M., Takahashi M., Kanda K., Yokoi T., Furuya T., Kikkawa E., Omura Y., Abe K., Kamihara K., Katsuta N., Sato K., Tanikawa M., Yamazaki M., Ninomiya K., Ishibashi T., Yamashita H., Murakawa K., Fujimori K., Tanai H., Kimata M., Watanabe M., Hiraoka S., Chiba Y., Ishida S., Ono Y., Takiguchi S., Watanabe S., Yosida M., Hotuta T., Kusano J., Kanehori K., Takahashi-Fujii A., Hara H., Tanase T.-O., Nomura Y., Togiya S., Komai F., Hara R., Takeuchi K., Arita M., Imose N., Musashino K., Yuuki H., Oshima A., Sasaki N., Aotsuka S., Yoshikawa Y., Matsunawa H., Ichihara T., Shiohata N., Sano S., Moriya S., Momiyama H., Satoh N., Takami S., Terashima Y., Suzuki O., Nakagawa S., Senoh A., Mizoguchi H., Goto Y., Shimizu F., Wakebe H., Hishigaki H., Watanabe T., Sugiyama A., Takemoto M., Kawakami B., Yamazaki M., Watanabe K., Kumagai A., Itakura S., Fukuzumi Y., Fujimori Y., Komiyama M., Tashiro H., Tanigami A., Fujiwara T., Ono T., Yamada K., Fujii Y., Ozaki K., Hirao M., Ohmori Y., Kawabata A., Hikiji T., Kobatake N., Inagaki H., Ikema Y., Okamoto S., Okitani R., Kawakami T., Noguchi S., Itoh T., Shigeta K., Senba T., Matsumura K., Nakajima Y., Mizuno T., Morinaga M., Sasaki M., Togashi T., Oyama M., Hata H., Watanabe M., Komatsu T., Mizushima-Sugano J., Satoh T., Shirai Y., Takahashi Y., Nakagawa K., Okumura K., Nagase T., Nomura N., Kikuchi H., Masuho Y., Yamashita R., Nakai K., Yada T., Nakamura Y., Ohara O., Isogai T., Sugano S. Nat. Genet. 36:40-45(2004) [PubMed] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA]. Tissue: Trachea.
[3]	"The DNA sequence of the human X chromosome." Ross M.T., Grafham D.V., Coffey A.J., Scherer S., McLay K., Muzny D., Platzer M., Howell G.R., Burrows C., Bird C.P., Frankish A., Lovell F.L., Howe K.L., Ashurst J.L., Fulton R.S., Sudbrak R., Wen G., Jones M.C. , Hurles M.E., Andrews T.D., Scott C.E., Searle S., Ramser J., Whittaker A., Deadman R., Carter N.P., Hunt S.E., Chen R., Cree A., Gunaratne P., Havlak P., Hodgson A., Metzker M.L., Richards S., Scott G., Steffen D., Sodergren E., Wheeler D.A., Worley K.C., Ainscough R., Ambrose K.D., Ansari-Lari M.A., Aradhya S., Ashwell R.I., Babbage A.K., Bagguley C.L., Ballabio A., Banerjee R., Barker G.E., Barlow K.F., Barrett I.P., Bates K.N., Beare D.M., Beasley H., Beasley O., Beck A., Bethel G., Blechschmidt K., Brady N., Bray-Allen S., Bridgeman A.M., Brown A.J., Brown M.J., Bonnin D., Bruford E.A., Buhay C., Burch P., Burford D., Burgess J., Burrill W., Burton J., Bye J.M., Carder C., Carrel L., Chako J., Chapman J.C., Chavez D., Chen E., Chen G., Chen Y., Chen Z., Chinault C., Ciccodicola A., Clark S.Y., Clarke G., Clee C.M., Clegg S., Clerc-Blankenburg K., Clifford K., Cobley V., Cole C.G., Conquer J.S., Corby N., Connor R.E., David R., Davies J., Davis C., Davis J., Delgado O., Deshazo D., Dhami P., Ding Y., Dinh H., Dodsworth S., Draper H., Dugan-Rocha S., Dunham A., Dunn M., Durbin K.J., Dutta I., Eades T., Ellwood M., Emery-Cohen A., Errington H., Evans K.L., Faulkner L., Francis F., Frankland J., Fraser A.E., Galgoczy P., Gilbert J., Gill R., Gloeckner G., Gregory S.G., Gribble S., Griffiths C., Grocock R., Gu Y., Gwilliam R., Hamilton C., Hart E.A., Hawes A., Heath P.D., Heitmann K., Hennig S., Hernandez J., Hinzmann B., Ho S., Hoffs M., Howden P.J., Huckle E.J., Hume J., Hunt P.J., Hunt A.R., Isherwood J., Jacob L., Johnson D., Jones S., de Jong P.J., Joseph S.S., Keenan S., Kelly S., Kershaw J.K., Khan Z., Kioschis P., Klages S., Knights A.J., Kosiura A., Kovar-Smith C., Laird G.K., Langford C., Lawlor S., Leversha M., Lewis L., Liu W., Lloyd C., Lloyd D.M., Loulseged H., Loveland J.E., Lovell J.D., Lozado R., Lu J., Lyne R., Ma J., Maheshwari M., Matthews L.H., McDowall J., McLaren S., McMurray A., Meidl P., Meitinger T., Milne S., Miner G., Mistry S.L., Morgan M., Morris S., Mueller I., Mullikin J.C., Nguyen N., Nordsiek G., Nyakatura G., O'dell C.N., Okwuonu G., Palmer S., Pandian R., Parker D., Parrish J., Pasternak S., Patel D., Pearce A.V., Pearson D.M., Pelan S.E., Perez L., Porter K.M., Ramsey Y., Reichwald K., Rhodes S., Ridler K.A., Schlessinger D., Schueler M.G., Sehra H.K., Shaw-Smith C., Shen H., Sheridan E.M., Shownkeen R., Skuce C.D., Smith M.L., Sotheran E.C., Steingruber H.E., Steward C.A., Storey R., Swann R.M., Swarbreck D., Tabor P.E., Taudien S., Taylor T., Teague B., Thomas K., Thorpe A., Timms K., Tracey A., Trevanion S., Tromans A.C., d'Urso M., Verduzco D., Villasana D., Waldron L., Wall M., Wang Q., Warren J., Warry G.L., Wei X., West A., Whitehead S.L., Whiteley M.N., Wilkinson J.E., Willey D.L., Williams G., Williams L., Williamson A., Williamson H., Wilming L., Woodmansey R.L., Wray P.W., Yen J., Zhang J., Zhou J., Zoghbi H., Zorilla S., Buck D., Reinhardt R., Poustka A., Rosenthal A., Lehrach H., Meindl A., Minx P.J., Hillier L.W., Willard H.F., Wilson R.K., Waterston R.H., Rice C.M., Vaudin M., Coulson A., Nelson D.L., Weinstock G., Sulston J.E., Durbin R.M., Hubbard T., Gibbs R.A., Beck S., Rogers J., Bentley D.R. Nature 434:325-337(2005) [PubMed] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
[4]	Mural R.J., Istrail S., Sutton G.G., Florea L., Halpern A.L., Mobarry C.M., Lippert R., Walenz B., Shatkay H., Dew I., Miller J.R., Flanigan M.J., Edwards N.J., Bolanos R., Fasulo D., Halldorsson B.V., Hannenhalli S., Turner R. , Yooseph S., Lu F., Nusskern D.R., Shue B.C., Zheng X.H., Zhong F., Delcher A.L., Huson D.H., Kravitz S.A., Mouchard L., Reinert K., Remington K.A., Clark A.G., Waterman M.S., Eichler E.E., Adams M.D., Hunkapiller M.W., Myers E.W., Venter J.C. Submitted (SEP-2005) to the EMBL/GenBank/DDBJ databases Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
[5]	"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] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA]. Tissue: Lung.
[6]	"Interaction of sedlin with chloride intracellular channel proteins." Fan L., Yu W., Zhu X. FEBS Lett. 540:77-80(2003) [PubMed] [Europe PMC] [Abstract] Cited for: INTERACTION WITH TRAPPC2.
[7]	"CLIC-2 modulates cardiac ryanodine receptor Ca2+ release channels." Board P.G., Coggan M., Watson S., Gage P.W., Dulhunty A.F. Int. J. Biochem. Cell Biol. 36:1599-1612(2004) [PubMed] [Europe PMC] [Abstract] Cited for: FUNCTION, SUBUNIT, 3D-STRUCTURE MODELING, TISSUE SPECIFICITY, INTERACTION WITH RYR2.
[8]	"A recently identified member of the glutathione transferase structural family modifies cardiac RyR2 substate activity, coupled gating and activation by Ca2+ and ATP." Dulhunty A.F., Pouliquin P., Coggan M., Gage P.W., Board P.G. Biochem. J. 390:333-343(2005) [PubMed] [Europe PMC] [Abstract] Cited for: FUNCTION, SUBCELLULAR LOCATION, INTERACTION WITH RYR2.
[9]	"Initial characterization of the human central proteome." Burkard T.R., Planyavsky M., Kaupe I., Breitwieser F.P., Buerckstuemmer T., Bennett K.L., Superti-Furga G., Colinge J. BMC Syst. Biol. 5:17-17(2011) [PubMed] [Europe PMC] [Abstract] Cited for: IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
[10]	"An X-linked channelopathy with cardiomegaly due to a CLIC2 mutation enhancing ryanodine receptor channel activity." Takano K., Liu D., Tarpey P., Gallant E., Lam A., Witham S., Alexov E., Chaubey A., Stevenson R.E., Schwartz C.E., Board P.G., Dulhunty A.F. Hum. Mol. Genet. 21:4497-4507(2012) [PubMed] [Europe PMC] [Abstract] Cited for: TISSUE SPECIFICITY, INVOLVEMENT IN MENTAL RETARDATION, VARIANT GLN-101, CHARACTERIZATION OF VARIANT GLN-101.
[11]	"Structure of the Janus protein human CLIC2." Cromer B.A., Gorman M.A., Hansen G., Adams J.J., Coggan M., Littler D.R., Brown L.J., Mazzanti M., Breit S.N., Curmi P.M.G., Dulhunty A.F., Board P.G., Parker M.W. J. Mol. Biol. 374:719-731(2007) [PubMed] [Europe PMC] [Abstract] Cited for: X-RAY CRYSTALLOGRAPHY (1.85 ANGSTROMS) IN COMPLEX WITH GLUTATHIONE, SUBUNIT, FUNCTION, PH DEPENDENCE, DISULFIDE BOND.
[12]	"The crystal structure of human chloride intracellular channel protein 2: a disulfide bond with functional implications." Mi W., Liang Y.-H., Li L., Su X.-D. Proteins 71:509-513(2008) [PubMed] [Europe PMC] [Abstract] Cited for: X-RAY CRYSTALLOGRAPHY (2.0 ANGSTROMS), DISULFIDE BOND.
+	Additional computationally mapped references.

Cross-references

Sequence databases

EMBL
GenBank
DDBJ

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.

IPI

IPI00221328.

RefSeq

NP_001280.3. NM_001289.4.

UniGene

Hs.655445.

3D structure databases

PDBe
RCSB PDB
PDBj

Entry	Method	Resolution (Å)	Chain	Positions	PDBsum
2PER	X-ray	2.00	A	1-247	[»]
2R4V	X-ray	1.85	A	1-247	[»]
2R5G	X-ray	1.86	A	1-247	[»]

ProteinModelPortal

O15247.

ModBase

Search...

Protein-protein interaction databases

IntAct

O15247. 1 interaction.

STRING

9606.ENSP00000358460.

Protein family/group databases

TCDB

1.A.12.1.5. intracellular chloride channel (CLIC) family.

PTM databases

PhosphoSite

O15247.

Proteomic databases

PaxDb

O15247.

PRIDE

O15247.

Protocols and materials databases

DNASU

1193.

StructuralBiologyKnowledgebase

Search...

Genome annotation databases

Ensembl

ENST00000369449; ENSP00000358460; ENSG00000155962.
ENST00000596972; ENSP00000469202; ENSG00000268943.

GeneID

1193.

KEGG

hsa:1193.

UCSC

uc004fnf.3. human.

Organism-specific databases

CTD

1193.

GeneCards

GC0XM154505.

HGNC

HGNC:2063. CLIC2.

MIM

300138. gene.

neXtProt

NX_O15247.

PharmGKB

PA26589.

GenAtlas

Search...

Phylogenomic databases

eggNOG

NOG282171.

HOGENOM

HOG000231548.

HOVERGEN

HBG050994.

InParanoid

O15247.

KO

K05022.

OMA

QADPEIE.

OrthoDB

EOG4GQQ5Q.

PhylomeDB

O15247.

Gene expression databases

ArrayExpress

O15247.

Bgee

O15247.

CleanEx

HS_CLIC2.

Genevestigator

O15247.

GermOnline

ENSG00000155962. Homo sapiens.

Family and domain databases

Gene3D

1.20.1050.10. 1 hit.
3.40.30.10. 1 hit.

InterPro

IPR010987. Glutathione-S-Trfase_C-like.
IPR017933. Glutathione_S_Trfase/Cl_chnl_C.
IPR002946. Int_Cl_channel.
IPR012336. Thioredoxin-like_fold.
[Graphical view]

PRINTS

PR01263. INTCLCHANNEL.

SUPFAM

SSF47616. GST_C_like. 1 hit.
SSF52833. Thiordxn-like_fd. 1 hit.

TIGRFAMs

TIGR00862. O-ClC. 1 hit.

PROSITE

PS50405. GST_CTER. 1 hit.
[Graphical view]

ProtoNet

Search...

Other

EvolutionaryTrace

O15247.

GenomeRNAi

1193.

NextBio

4932.

SOURCE

Search...

Entry information

Entry name

CLIC2_HUMAN

Accession

Primary (citable) accession number: O15247
Secondary accession number(s): A8K9S0 , O15174, Q5JT80, Q8TCE3

Entry history

Integrated into UniProtKB/Swiss-Prot:	July 15, 1998
Last sequence update:	September 13, 2005
Last modified:	May 1, 2013
This is version 118 of the entry and version 3 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.