Q9Y696 (CLIC4_HUMAN) Reviewed, UniProtKB/Swiss-Prot

Names and origin

Protein names

Recommended name:
Chloride intracellular channel protein 4

Alternative name(s):
Intracellular chloride ion channel protein p64H1

Gene names

Name:

CLIC4

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	253 AA.
Sequence status	Complete.
Sequence processing	The displayed sequence is further processed into a mature form.
Protein existence	Evidence at protein level

General annotation (Comments)

Function	Can insert into membranes and form poorly selective ion channels that may also transport chloride ions. Channel activity depends on the pH. Membrane insertion seems to be redox-regulated and may occur only under oxydizing conditions. Promotes cell-surface expression of HRH3. Has alternate cellular functions like a potential role in angiogenesis or in maintaining apical-basolateral membrane polarity during mitosis and cytokinesis. Could also promote endothelial cell proliferation and regulate endothelial morphogenesis (tubulogenesis). Ref.7 Ref.9 Ref.10 Ref.13 Ref.14 Ref.18
Subunit structure	Component of a multimeric complex consisting of several cytoskeletal proteins, including actin, ezrin, alpha-actinin, gelsolin, IQGAP1 and CLIC5A. Binds directly to brain dynamin I in a complex containing actin, tubulin and 14-3-3 isoforms. Monomer. Interacts with HRH3. Interacts with AKAP9. Ref.6 Ref.8 Ref.13 Ref.18
Subcellular location	Cytoplasm › cytoskeleton › centrosome. Cytoplasmic vesicle membrane; Single-pass membrane protein Probable. Nucleus matrix. Cell membrane; Single-pass membrane protein Probable. Mitochondrion. Cell junction. Note: Colocalized with AKAP9 at the centrosome and midbody. Exists both as soluble cytoplasmic protein and as membrane protein with probably a single transmembrane domain. Present in an intracellular vesicular compartment that likely represent trans-Golgi network vesicles. Ref.9 Ref.11 Ref.12 Ref.13 Ref.18
Tissue specificity	Detected in epithelial cells from colon, esophagus and kidney (at protein level). Expression is prominent in heart, kidney, placenta and skeletal muscle. Ref.6 Ref.11 Ref.12
Induction	Up-regulated by calcium ions in differentiating keratinocytes. Up-regulated in myofibroblasts. Ref.7 Ref.12
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. Ref.19
Sequence similarities	Belongs to the chloride channel CLIC family. Contains 1 GST C-terminal domain.

Ontologies

Keywords
Biological process	Ion transport Transport
Cellular component	Cell junction Cell membrane Cytoplasm Cytoplasmic vesicle Cytoskeleton Membrane Mitochondrion Nucleus
Domain	Transmembrane Transmembrane helix
Ligand	Chloride
Molecular function	Chloride channel Ion channel Voltage-gated channel
PTM	Acetylation Phosphoprotein
Technical term	3D-structure Complete proteome Direct protein sequencing Reference proteome
Gene Ontology (GO)
Biological_process	angiogenesis Inferred from electronic annotation. Source: Compara branching morphogenesis of an epithelial tube Inferred from electronic annotation. Source: Compara cellular response to calcium ion Inferred from mutant phenotype Ref.12. Source: UniProtKB endothelial cell morphogenesis Inferred from electronic annotation. Source: Compara establishment or maintenance of apical/basal cell polarity Non-traceable author statement Ref.9. Source: UniProtKB fertilization Inferred from electronic annotation. Source: Compara keratinocyte differentiation Inferred from mutant phenotype Ref.12. Source: UniProtKB multicellular organism growth Inferred from electronic annotation. Source: Compara negative regulation of cell migration Inferred from direct assay Ref.7. Source: UniProtKB regulation of cytoskeleton organization Non-traceable author statement Ref.9. Source: UniProtKB retina vasculature morphogenesis in camera-type eye Inferred from electronic annotation. Source: Compara vacuolar acidification Inferred from electronic annotation. Source: Compara
Cellular_component	actin cytoskeleton Traceable author statement Ref.7. Source: UniProtKB apical part of cell Inferred from direct assay Ref.9. Source: UniProtKB cell surface Inferred from direct assay Ref.9. Source: UniProtKB cell-cell junction Inferred from direct assay Ref.9. Source: UniProtKB centrosome Inferred from direct assay Ref.9. Source: UniProtKB chloride channel complex Inferred from electronic annotation. Source: UniProtKB-KW cytoplasmic vesicle membrane Inferred from electronic annotation. Source: UniProtKB-SubCell cytosol Inferred from direct assay PubMed 10026142PubMed 19776349. Source: UniProtKB microvillus Inferred from direct assay Ref.9. Source: UniProtKB midbody Inferred from direct assay Ref.9. Source: UniProtKB mitochondrion Inferred from direct assay Ref.9. Source: UniProtKB nuclear matrix Inferred from direct assay Ref.9. Source: UniProtKB perinuclear region of cytoplasm Inferred from direct assay Ref.9. Source: UniProtKB plasma membrane Inferred from direct assay PubMed 19776349. Source: UniProtKB vacuole Inferred from electronic annotation. Source: Compara
Molecular_function	chloride channel activity Traceable author statement PubMed 9295337. Source: ProtInc 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

Initiator methionine

1

1

Removed Ref.5

Chain

2 – 253

252

Chloride intracellular channel protein 4

PRO_0000144210

Regions

Transmembrane

37 – 57

21

Helical; Note=After insertion into the membrane; Potential

Domain

104 – 244

141

GST C-terminal

Region

2 – 101

100

Required for insertion into the membrane Probable

Amino acid modifications

Modified residue

2

1

N-acetylalanine Ref.5 Ref.17

Modified residue

4

1

Phosphoserine Ref.17

Modified residue

130

1

N6-acetyllysine Ref.15

Experimental info

Sequence conflict

14

1

D → Y in AAD26136. Ref.2

Sequence conflict

133 – 134

2

RP → SA in AAD38446. Ref.1

Sequence conflict

133 – 134

2

RP → SA in AAD26136. Ref.2

Sequence conflict

225

1

Y → S in AAD26136. Ref.2

Sequence conflict

233

1

T → A in AAD26136. Ref.2

Secondary structure

1

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253

Helix Strand Turn

Details...

Beta strand

19 – 25

7

Beta strand

29 – 32

4

Helix

36 – 48

13

Beta strand

53 – 57

5

Helix

64 – 69

6

Beta strand

77 – 80

4

Beta strand

83 – 85

3

Helix

88 – 98

11

Turn

101 – 103

3

Helix

112 – 115

4

Turn

116 – 120

5

Helix

121 – 130

10

Helix

134 – 136

3

Helix

137 – 156

20

Beta strand

181 – 183

3

Helix

186 – 206

21

Helix

215 – 225

11

Helix

228 – 231

4

Helix

237 – 243

7

Turn

244 – 247

4

Sequences

	Sequence		Length	Mass (Da)
	Q9Y696 [UniParc]. Last modified January 23, 2007. Version 4. Checksum: 3DD21A33C66626A5	FASTA	253	28,772
	10 20 30 40 50 60 MALSMPLNGL KEEDKEPLIE LFVKAGSDGE SIGNCPFSQR LFMILWLKGV VFSVTTVDLK 70 80 90 100 110 120 RKPADLQNLA PGTHPPFITF NSEVKTDVNK IEEFLEEVLC PPKYLKLSPK HPESNTAGMD 130 140 150 160 170 180 IFAKFSAYIK NSRPEANEAL ERGLLKTLQK LDEYLNSPLP DEIDENSMED IKFSTRKFLD 190 200 210 220 230 240 GNEMTLADCN LLPKLHIVKV VAKKYRNFDI PKEMTGIWRY LTNAYSRDEF TNTCPSDKEV 250 EIAYSDVAKR LTK

References

	« Hide 'large scale' referencesShow 'large scale' references »
[1]	"A novel p64-related Cl- channel: subcellular distribution and nephron segment-specific expression." Edwards J.C. Am. J. Physiol. 276:F398-F408(1999) [PubMed] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA].
[2]	"A 29 kDa intracellular chloride channel p64H1 is associated with large dense-core vesicles in rat hippocampal neurons." Chuang J.Z., Milner T.A., Zhu M., Sung C.H. J. Neurosci. 19:2919-2928(1999) [PubMed] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA].
[3]	"Towards a catalog of human genes and proteins: sequencing and analysis of 500 novel complete protein coding human cDNAs." Wiemann S., Weil B., Wellenreuther R., Gassenhuber J., Glassl S., Ansorge W., Boecher M., Bloecker H., Bauersachs S., Blum H., Lauber J., Duesterhoeft A., Beyer A., Koehrer K., Strack N., Mewes H.-W., Ottenwaelder B., Obermaier B. , Tampe J., Heubner D., Wambutt R., Korn B., Klein M., Poustka A. Genome Res. 11:422-435(2001) [PubMed] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA]. Tissue: Kidney.
[4]	"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: Ovary.
[5]	Bienvenut W.V., Claeys D. Submitted (FEB-2006) to UniProtKB Cited for: PROTEIN SEQUENCE OF 2-24; 41-60; 62-85 AND 125-130, CLEAVAGE OF INITIATOR METHIONINE, ACETYLATION AT ALA-2, MASS SPECTROMETRY. Tissue: Platelet.
[6]	"Identification of a novel member of the chloride intracellular channel gene family (CLIC5) that associates with the actin cytoskeleton of placental microvilli." Berryman M., Bretscher A. Mol. Biol. Cell 11:1509-1521(2000) [PubMed] [Europe PMC] [Abstract] Cited for: SUBUNIT, TISSUE SPECIFICITY.
[7]	"Differential expression of a chloride intracellular channel gene, CLIC4, in transforming growth factor-beta1-mediated conversion of fibroblasts to myofibroblasts." Ronnov-Jessen L., Villadsen R., Edwards J.C., Petersen O.W. Am. J. Pathol. 161:471-480(2002) [PubMed] [Europe PMC] [Abstract] Cited for: INDUCTION, FUNCTION.
[8]	"AKAP350 at the Golgi apparatus. II. Association of AKAP350 with a novel chloride intracellular channel (CLIC) family member." Shanks R.A., Larocca M.C., Berryman M., Edwards J.C., Urushidani T., Navarre J., Goldenring J.R. J. Biol. Chem. 277:40973-40980(2002) [PubMed] [Europe PMC] [Abstract] Cited for: INTERACTION WITH AKAP9.
[9]	"CLIC4 is enriched at cell-cell junctions and colocalizes with AKAP350 at the centrosome and midbody of cultured mammalian cells." Berryman M.A., Goldenring J.R. Cell Motil. Cytoskeleton 56:159-172(2003) [PubMed] [Europe PMC] [Abstract] Cited for: FUNCTION, SUBCELLULAR LOCATION.
[10]	"Proteomic analysis of vascular endothelial growth factor-induced endothelial cell differentiation reveals a role for chloride intracellular channel 4 (CLIC4) in tubular morphogenesis." Bohman S., Matsumoto T., Suh K., Dimberg A., Jakobsson L., Yuspa S., Claesson-Welsh L. J. Biol. Chem. 280:42397-42404(2005) [PubMed] [Europe PMC] [Abstract] Cited for: FUNCTION.
[11]	"Reciprocal modifications of CLIC4 in tumor epithelium and stroma mark malignant progression of multiple human cancers." Suh K.S., Crutchley J.M., Koochek A., Ryscavage A., Bhat K., Tanaka T., Oshima A., Fitzgerald P., Yuspa S.H. Clin. Cancer Res. 13:121-131(2007) [PubMed] [Europe PMC] [Abstract] Cited for: SUBCELLULAR LOCATION, TISSUE SPECIFICITY.
[12]	"CLIC4 mediates and is required for Ca2+-induced keratinocyte differentiation." Suh K.S., Mutoh M., Mutoh T., Li L., Ryscavage A., Crutchley J.M., Dumont R.A., Cheng C., Yuspa S.H. J. Cell Sci. 120:2631-2640(2007) [PubMed] [Europe PMC] [Abstract] Cited for: TISSUE SPECIFICITY, INDUCTION, SUBCELLULAR LOCATION.
[13]	"CLIC4 interacts with histamine H3 receptor and enhances the receptor cell surface expression." Maeda K., Haraguchi M., Kuramasu A., Sato T., Ariake K., Sakagami H., Kondo H., Yanai K., Fukunaga K., Yanagisawa T., Sukegawa J. Biochem. Biophys. Res. Commun. 369:603-608(2008) [PubMed] [Europe PMC] [Abstract] Cited for: INTERACTION WITH HRH3, FUNCTION, SUBCELLULAR LOCATION.
[14]	"Chloride intracellular channel 4 is involved in endothelial proliferation and morphogenesis in vitro." Tung J.J., Hobert O., Berryman M., Kitajewski J. Angiogenesis 12:209-220(2009) [PubMed] [Europe PMC] [Abstract] Cited for: FUNCTION.
[15]	"Lysine acetylation targets protein complexes and co-regulates major cellular functions." Choudhary C., Kumar C., Gnad F., Nielsen M.L., Rehman M., Walther T.C., Olsen J.V., Mann M. Science 325:834-840(2009) [PubMed] [Europe PMC] [Abstract] Cited for: ACETYLATION [LARGE SCALE ANALYSIS] AT LYS-130, MASS SPECTROMETRY.
[16]	"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].
[17]	"System-wide temporal characterization of the proteome and phosphoproteome of human embryonic stem cell differentiation." Rigbolt K.T., Prokhorova T.A., Akimov V., Henningsen J., Johansen P.T., Kratchmarova I., Kassem M., Mann M., Olsen J.V., Blagoev B. Sci. Signal. 4:RS3-RS3(2011) [PubMed] [Europe PMC] [Abstract] Cited for: ACETYLATION [LARGE SCALE ANALYSIS] AT ALA-2, PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-4, MASS SPECTROMETRY.
[18]	"Crystal structure of the soluble form of the redox-regulated chloride ion channel protein CLIC4." Littler D.R., Assaad N.N., Harrop S.J., Brown L.J., Pankhurst G.J., Luciani P., Aguilar M.-I., Mazzanti M., Berryman M.A., Breit S.N., Curmi P.M.G. FEBS J. 272:4996-5007(2005) [PubMed] [Europe PMC] [Abstract] Cited for: X-RAY CRYSTALLOGRAPHY (1.8 ANGSTROMS), SUBUNIT, FUNCTION, SUBCELLULAR LOCATION.
[19]	"Trimeric structure of the wild soluble chloride intracellular ion channel CLIC4 observed in crystals." Li Y., Li D., Zeng Z., Wang D. Biochem. Biophys. Res. Commun. 343:1272-1278(2006) [PubMed] [Europe PMC] [Abstract] Cited for: X-RAY CRYSTALLOGRAPHY (2.2 ANGSTROMS), DOMAIN.
+	Additional computationally mapped references.

Cross-references

Sequence databases

EMBL
GenBank
DDBJ

AF097330 mRNA. Translation: AAD38446.1.
AF109196 mRNA. Translation: AAD26136.1.
AL117424 mRNA. Translation: CAB55916.1.
BC012444 mRNA. Translation: AAH12444.1.

IPI

IPI00001960.

PIR

T17226.

RefSeq

NP_039234.1. NM_013943.2.

UniGene

Hs.440544.
Hs.595507.

3D structure databases

PDBe
RCSB PDB
PDBj

Entry	Method	Resolution (Å)	Chain	Positions	PDBsum
2AHE	X-ray	1.80	A	1-251	[»]
2D2Z	X-ray	2.20	A/B/C	1-252	[»]
3OQS	X-ray	2.00	B	198-207	[»]

ProteinModelPortal

Q9Y696.

ModBase

Search...

Protein-protein interaction databases

IntAct

Q9Y696. 2 interactions.

STRING

9606.ENSP00000363500.

Protein family/group databases

TCDB

1.A.12.1.6. intracellular chloride channel (CLIC) family.

PTM databases

PhosphoSite

Q9Y696.

Polymorphism databases

DMDM

20141285.

2D gel databases

OGP

Q9Y696.

REPRODUCTION-2DPAGE

IPI00001960.

Proteomic databases

PaxDb

Q9Y696.

PeptideAtlas

Q9Y696.

PRIDE

Q9Y696.

Protocols and materials databases

DNASU

25932.

StructuralBiologyKnowledgebase

Search...

Genome annotation databases

Ensembl

ENST00000374379; ENSP00000363500; ENSG00000169504.
ENST00000488683; ENSP00000436538; ENSG00000169504.

GeneID

25932.

KEGG

hsa:25932.

UCSC

uc001bjo.2. human.

Organism-specific databases

CTD

25932.

GeneCards

GC01P025071.

HGNC

HGNC:13518. CLIC4.

HPA

HPA008019.

MIM

606536. gene.

neXtProt

NX_Q9Y696.

PharmGKB

PA26591.

GenAtlas

Search...

Phylogenomic databases

eggNOG

NOG282171.

HOGENOM

HOG000231548.

HOVERGEN

HBG050994.

InParanoid

Q9Y696.

KO

K05024.

OMA

IPKGMTG.

OrthoDB

EOG40S0FN.

PhylomeDB

Q9Y696.

Gene expression databases

ArrayExpress

Q9Y696.

Bgee

Q9Y696.

CleanEx

HS_CLIC4.

Genevestigator

Q9Y696.

GermOnline

ENSG00000169504. 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

ChiTaRS

CLIC4. human.

EvolutionaryTrace

Q9Y696.

GenomeRNAi

25932.

NextBio

47480.

SOURCE

Search...

Entry information

Entry name

CLIC4_HUMAN

Accession

Primary (citable) accession number: Q9Y696
Secondary accession number(s): Q9UFW9, Q9UQJ6

Entry history

Integrated into UniProtKB/Swiss-Prot:	May 30, 2000
Last sequence update:	January 23, 2007
Last modified:	May 1, 2013
This is version 123 of the entry and version 4 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.