P51790 (CLCN3_HUMAN) Reviewed, UniProtKB/Swiss-Prot

Names and origin

Protein names

Recommended name:
H(+)/Cl(-) exchange transporter 3

Alternative name(s):
Chloride channel protein 3
Short name=ClC-3
Chloride transporter ClC-3

Gene names

Name:

CLCN3

Organism

Homo sapiens (Human)

Taxonomic identifier

9606 [NCBI]

Taxonomic lineage

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

Protein attributes

Sequence length	818 AA.
Sequence status	Complete.
Protein existence	Evidence at protein level

General annotation (Comments)

Function	Mediates the exchange of chloride ions against protons. Functions as antiporter and contributes to the acidification of the endosome and synaptic vesicle lumen, and may thereby affect vesicle trafficking and exocytosis. May play an important role in neuronal cell function through regulation of membrane excitability by protein kinase C. It could help neuronal cells to establish short-term memory. Ref.4
Subunit structure	Homo- or heterodimer. Isoform 2 interacts with GOPC, PDZK1 and SLC9A3R1/EBP50. Ref.4 Ref.9
Subcellular location	Isoform 1: Membrane; Multi-pass membrane protein. Early endosome membrane; Multi-pass membrane protein. Late endosome membrane; Multi-pass membrane protein. Cytoplasmic vesicle › secretory vesicle membrane; Multi-pass membrane protein By similarity. Note: Isoform 1 is localized mainly in early and late endosomes. Ref.3 Ref.9 Isoform 2: Membrane; Multi-pass membrane protein. Early endosome membrane; Multi-pass membrane protein. Late endosome membrane; Multi-pass membrane protein. Golgi apparatus membrane; Multi-pass membrane protein. Note: Isoform 2 partially colocalized with isoform 1 but is mainly enriched in the Golgi. Ref.3 Ref.9
Tissue specificity	Expressed primarily in tissues derived from neuroectoderm. Within the brain, its expression is particularly evident in the hippocampus, olfactory cortex, and olfactory bulb. Highly expressed in aortic and coronary vascular smooth muscle cells, and aortic endothelial cells. Also expressed in tracheal and alveolar epithelial cells, and intima and media of the pulmonary vessels. Expressed in bronchus and colon (at protein level). Ref.4 Ref.8 Ref.9
Domain	Isoform 2 contains a C-terminal PDZ-binding motif mediating the interaction with GOPC. Ref.4
Post-translational modification	N-glycosylated. Ref.3 Ref.9
Miscellaneous	The CLC channel family contains both chloride channels and proton-coupled anion transporters that exchange chloride or another anion for protons. The presence of conserved gating glutamate residues is typical for family members that function as antiporters By similarity.
Sequence similarities	Belongs to the chloride channel (TC 2.A.49) family. ClC-3/CLCN3 subfamily. [View classification] Contains 2 CBS domains.
Sequence caution	The sequence BAC54560.1 differs from that shown. Reason: Erroneous initiation. Translation N-terminally extended. The sequence CAA55281.1 differs from that shown. Reason: Erroneous initiation. Translation N-terminally extended.

Ontologies

Keywords
Biological process	Antiport Ion transport Transport
Cellular component	Cytoplasmic vesicle Endosome Golgi apparatus Membrane
Coding sequence diversity	Alternative splicing
Domain	CBS domain Repeat Transmembrane Transmembrane helix
Ligand	ATP-binding Chloride Nucleotide-binding
PTM	Glycoprotein
Technical term	Complete proteome Reference proteome
Gene Ontology (GO)
Biological process	endosomal lumen acidification Traceable author statement Ref.9. Source: UniProtKB
Cellular component	Golgi membrane Inferred from electronic annotation. Source: UniProtKB-SubCell cell surface Non-traceable author statement Ref.9. Source: UniProtKB early endosome membrane Inferred from electronic annotation. Source: UniProtKB-SubCell integral to membrane Traceable author statement Ref.9. Source: UniProtKB late endosome membrane Inferred from electronic annotation. Source: UniProtKB-SubCell transport vesicle membrane Inferred from electronic annotation. Source: UniProtKB-SubCell
Molecular function	ATP binding Inferred from electronic annotation. Source: UniProtKB-KW PDZ domain binding Inferred from direct assay Ref.9. Source: UniProtKB antiporter activity Inferred from electronic annotation. Source: UniProtKB-KW protein heterodimerization activity Inferred from direct assay Ref.9. Source: UniProtKB protein homodimerization activity Non-traceable author statement Ref.9. Source: UniProtKB voltage-gated chloride channel activity Traceable author statement. Source: ProtInc
Complete GO annotation...

Alternative products

This entry describes 2 isoforms produced by alternative splicing. [Align] [Select]

Isoform 1 (identifier: P51790-1)

Also known as: ClC-3A;

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: P51790-2)

Also known as: ClC-3B;

The sequence of this isoform differs from the canonical sequence as follows:
     790-818: RLLGIITKKDILRHMAQTANQDPASIMFN → IVLGIITKKN...EVYLLNSTTL

Sequence annotation (Features)

	Feature key	Position(s)	Length	Description	Graphical view	Feature identifier
Molecule processing
	Chain	1 – 818	818	H(+)/Cl(-) exchange transporter 3		PRO_0000094438
Regions
	Topological domain	1 – 125	125	Cytoplasmic By similarity
	Transmembrane	126 – 163	38	Helical; By similarity
	Transmembrane	209 – 232	24	Helical; By similarity
	Intramembrane	241 – 248	8	Helical; By similarity
	Transmembrane	258 – 276	19	Helical; By similarity
	Transmembrane	282 – 301	20	Helical; By similarity
	Intramembrane	313 – 325	13	Helical; By similarity
	Intramembrane	329 – 337	9	Helical; By similarity
	Transmembrane	349 – 367	19	Helical; By similarity
	Transmembrane	391 – 416	26	Helical; By similarity
	Transmembrane	423 – 443	21	Helical; By similarity
	Transmembrane	500 – 520	21	Helical; By similarity
	Transmembrane	525 – 544	20	Helical; By similarity
	Intramembrane	572 – 586	15	Helical; By similarity
	Intramembrane	590 – 601	12	Helical; By similarity
	Intramembrane	602 – 605	4	Note=Loop between two helices; By similarity
	Transmembrane	606 – 624	19	Helical; By similarity
	Topological domain	625 – 818	194	Cytoplasmic By similarity
	Domain	658 – 722	65	CBS 1
	Domain	755 – 812	58	CBS 2
	Nucleotide binding	689 – 691	3	ATP By similarity
	Nucleotide binding	796 – 799	4	ATP By similarity
	Motif	238 – 242	5	Selectivity filter part_1 By similarity
	Motif	280 – 284	5	Selectivity filter part_2 By similarity
	Motif	525 – 529	5	Selectivity filter part_3 By similarity
Sites
	Binding site	239	1	Chloride By similarity
	Binding site	527	1	Chloride; via amide nitrogen By similarity
	Binding site	630	1	Chloride By similarity
	Site	282	1	Mediates proton transfer from the outer aqueous phase to the interior of the protein; involved in linking H(+) and Cl(-) transport By similarity
	Site	339	1	Mediates proton transfer from the protein to the inner aqueous phase By similarity
Amino acid modifications
	Glycosylation	177	1	N-linked (GlcNAc...) Potential
	Glycosylation	451	1	N-linked (GlcNAc...) Potential
	Glycosylation	479	1	N-linked (GlcNAc...) Potential
Natural variations
	Alternative sequence	790 – 818	29	RLLGI…SIMFN → IVLGIITKKNILEHLEQLKQ HVEPLAPPWHYNKKRYPPAY GPDGKPRPRFNNVQLNLTDE EREETEEEVYLLNSTTL in isoform 2.		VSP_016073
Experimental info
	Mutagenesis	280	1	G → E: Changes channel selectivity from I(-)>Cl(-) to Cl(-)>I(-). Ref.3
	Sequence conflict	209	1	M → T in BX647119. Ref.5
	Sequence conflict	551	1	Y → C in BX647119. Ref.5
	Sequence conflict	570	1	T → A in BX647119. Ref.5
	Sequence conflict	646	1	E → EEF in CAA55280. Ref.1
	Sequence conflict	646	1	E → EEF in CAA55281. Ref.1
	Sequence conflict	646	1	E → EEF in BAC54560. Ref.4
	Sequence conflict	723	1	Q → R in BX647119. Ref.5

Sequences

	Sequence		Length	Mass (Da)
	Isoform 1 (ClC-3A) [UniParc]. Last modified April 14, 2009. Version 2. Checksum: 30FF0A6A2D6EF3B8	FASTA	818	90,966
	10 20 30 40 50 60 MESEQLFHRG YYRNSYNSIT SASSDEELLD GAGVIMDFQT SEDDNLLDGD TAVGTHYTMT 70 80 90 100 110 120 NGGSINSSTH LLDLLDEPIP GVGTYDDFHT IDWVREKCKD RERHRRINSK KKESAWEMTK 130 140 150 160 170 180 SLYDAWSGWL VVTLTGLASG ALAGLIDIAA DWMTDLKEGI CLSALWYNHE QCCWGSNETT 190 200 210 220 230 240 FEERDKCPQW KTWAELIIGQ AEGPGSYIMN YIMYIFWALS FAFLAVSLVK VFAPYACGSG 250 260 270 280 290 300 IPEIKTILSG FIIRGYLGKW TLMIKTITLV LAVASGLSLG KEGPLVHVAC CCGNIFSYLF 310 320 330 340 350 360 PKYSTNEAKK REVLSAASAA GVSVAFGAPI GGVLFSLEEV SYYFPLKTLW RSFFAALVAA 370 380 390 400 410 420 FVLRSINPFG NSRLVLFYVE YHTPWYLFEL FPFILLGVFG GLWGAFFIRA NIAWCRRRKS 430 440 450 460 470 480 TKFGKYPVLE VIIVAAITAV IAFPNPYTRL NTSELIKELF TDCGPLESSS LCDYRNDMNA 490 500 510 520 530 540 SKIVDDIPDR PAGIGVYSAI WQLCLALIFK IIMTVFTFGI KVPSGLFIPS MAIGAIAGRI 550 560 570 580 590 600 VGIAVEQLAY YHHDWFIFKE WCEVGADCIT PGLYAMVGAA ACLGGVTRMT VSLVVIVFEL 610 620 630 640 650 660 TGGLEYIVPL MAAVMTSKWV GDAFGREGIY EAHIRLNGYP FLDAKEEFTH TTLAADVMRP 670 680 690 700 710 720 RRNDPPLAVL TQDNMTVDDI ENMINETSYN GFPVIMSKES QRLVGFALRR DLTIAIESAR 730 740 750 760 770 780 KKQEGIVGSS RVCFAQHTPS LPAESPRPLK LRSILDMSPF TVTDHTPMEI VVDIFRKLGL 790 800 810 RQCLVTHNGR LLGIITKKDI LRHMAQTANQ DPASIMFN
	Isoform 2 (ClC-3B) [UniParc]. Checksum: 1B2C8D0CC47CF592	FASTA	866	96,733
	10 20 30 40 50 60 MESEQLFHRG YYRNSYNSIT SASSDEELLD GAGVIMDFQT SEDDNLLDGD TAVGTHYTMT 70 80 90 100 110 120 NGGSINSSTH LLDLLDEPIP GVGTYDDFHT IDWVREKCKD RERHRRINSK KKESAWEMTK 130 140 150 160 170 180 SLYDAWSGWL VVTLTGLASG ALAGLIDIAA DWMTDLKEGI CLSALWYNHE QCCWGSNETT 190 200 210 220 230 240 FEERDKCPQW KTWAELIIGQ AEGPGSYIMN YIMYIFWALS FAFLAVSLVK VFAPYACGSG 250 260 270 280 290 300 IPEIKTILSG FIIRGYLGKW TLMIKTITLV LAVASGLSLG KEGPLVHVAC CCGNIFSYLF 310 320 330 340 350 360 PKYSTNEAKK REVLSAASAA GVSVAFGAPI GGVLFSLEEV SYYFPLKTLW RSFFAALVAA 370 380 390 400 410 420 FVLRSINPFG NSRLVLFYVE YHTPWYLFEL FPFILLGVFG GLWGAFFIRA NIAWCRRRKS 430 440 450 460 470 480 TKFGKYPVLE VIIVAAITAV IAFPNPYTRL NTSELIKELF TDCGPLESSS LCDYRNDMNA 490 500 510 520 530 540 SKIVDDIPDR PAGIGVYSAI WQLCLALIFK IIMTVFTFGI KVPSGLFIPS MAIGAIAGRI 550 560 570 580 590 600 VGIAVEQLAY YHHDWFIFKE WCEVGADCIT PGLYAMVGAA ACLGGVTRMT VSLVVIVFEL 610 620 630 640 650 660 TGGLEYIVPL MAAVMTSKWV GDAFGREGIY EAHIRLNGYP FLDAKEEFTH TTLAADVMRP 670 680 690 700 710 720 RRNDPPLAVL TQDNMTVDDI ENMINETSYN GFPVIMSKES QRLVGFALRR DLTIAIESAR 730 740 750 760 770 780 KKQEGIVGSS RVCFAQHTPS LPAESPRPLK LRSILDMSPF TVTDHTPMEI VVDIFRKLGL 790 800 810 820 830 840 RQCLVTHNGI VLGIITKKNI LEHLEQLKQH VEPLAPPWHY NKKRYPPAYG PDGKPRPRFN 850 860 NVQLNLTDEE REETEEEVYL LNSTTL

References

	« Hide 'large scale' referencesShow 'large scale' references »
[1]	"Characterization of a human and murine gene (CLCN3) sharing similarities to voltage-gated chloride channels and to a yeast integral membrane protein." Borsani G., Rugarli E.I., Taglialatela M., Wong C., Ballabio A. Genomics 27:131-141(1995) [PubMed: 7665160] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1). Tissue: Retina.
[2]	"Ion transporters and receptors in cDNA libraries from lens and cornea epithelia." Shepard A.R., Rae J.L. Curr. Eye Res. 17:708-719(1998) [PubMed: 9678416] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1). Tissue: Lens epithelium.
[3]	"Regulation of human CLC-3 channels by multifunctional Ca2+/calmodulin-dependent protein kinase." Huang P., Liu J., Di A., Robinson N.C., Musch M.W., Kaetzel M.A., Nelson D.J. J. Biol. Chem. 276:20093-20100(2001) [PubMed: 11274166] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1), GLYCOSYLATION, SUBCELLULAR LOCATION, MUTAGENESIS OF GLY-280. Tissue: Colon tumor.
[4]	"ClC-3B, a novel ClC-3 splicing variant that interacts with EBP50 and facilitates expression of CFTR-regulated ORCC." Ogura T., Furukawa T., Toyozaki T., Yamada K., Zheng Y.-J., Katayama Y., Nakaya H., Inagaki N. FASEB J. 16:863-865(2002) [PubMed: 11967229] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 2), TISSUE SPECIFICITY, INTERACTION WITH SLC9A3R1, DOMAIN, FUNCTION.
[5]	"The full-ORF clone resource of the German cDNA consortium." Bechtel S., Rosenfelder H., Duda A., Schmidt C.P., Ernst U., Wellenreuther R., Mehrle A., Schuster C., Bahr A., Bloecker H., Heubner D., Hoerlein A., Michel G., Wedler H., Koehrer K., Ottenwaelder B., Poustka A., Wiemann S., Schupp I. BMC Genomics 8:399-399(2007) [PubMed: 17974005] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA]. Tissue: Colon endothelium.
[6]	"Generation and annotation of the DNA sequences of human chromosomes 2 and 4." Hillier L.W., Graves T.A., Fulton R.S., Fulton L.A., Pepin K.H., Minx P., Wagner-McPherson C., Layman D., Wylie K., Sekhon M., Becker M.C., Fewell G.A., Delehaunty K.D., Miner T.L., Nash W.E., Kremitzki C., Oddy L., Du H. , Sun H., Bradshaw-Cordum H., Ali J., Carter J., Cordes M., Harris A., Isak A., van Brunt A., Nguyen C., Du F., Courtney L., Kalicki J., Ozersky P., Abbott S., Armstrong J., Belter E.A., Caruso L., Cedroni M., Cotton M., Davidson T., Desai A., Elliott G., Erb T., Fronick C., Gaige T., Haakenson W., Haglund K., Holmes A., Harkins R., Kim K., Kruchowski S.S., Strong C.M., Grewal N., Goyea E., Hou S., Levy A., Martinka S., Mead K., McLellan M.D., Meyer R., Randall-Maher J., Tomlinson C., Dauphin-Kohlberg S., Kozlowicz-Reilly A., Shah N., Swearengen-Shahid S., Snider J., Strong J.T., Thompson J., Yoakum M., Leonard S., Pearman C., Trani L., Radionenko M., Waligorski J.E., Wang C., Rock S.M., Tin-Wollam A.-M., Maupin R., Latreille P., Wendl M.C., Yang S.-P., Pohl C., Wallis J.W., Spieth J., Bieri T.A., Berkowicz N., Nelson J.O., Osborne J., Ding L., Meyer R., Sabo A., Shotland Y., Sinha P., Wohldmann P.E., Cook L.L., Hickenbotham M.T., Eldred J., Williams D., Jones T.A., She X., Ciccarelli F.D., Izaurralde E., Taylor J., Schmutz J., Myers R.M., Cox D.R., Huang X., McPherson J.D., Mardis E.R., Clifton S.W., Warren W.C., Chinwalla A.T., Eddy S.R., Marra M.A., Ovcharenko I., Furey T.S., Miller W., Eichler E.E., Bork P., Suyama M., Torrents D., Waterston R.H., Wilson R.K. Nature 434:724-731(2005) [PubMed: 15815621] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
[7]	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].
[8]	"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, Fetal lung and Vascular smooth muscle.
[9]	"The PDZ-binding chloride channel ClC-3B localizes to the Golgi and associates with cystic fibrosis transmembrane conductance regulator-interacting PDZ proteins." Gentzsch M., Cui L., Mengos A., Chang X.-B., Chen J.-H., Riordan J.R. J. Biol. Chem. 278:6440-6449(2003) [PubMed: 12471024] [Abstract] Cited for: INTERACTION WITH GOPC; PDZK1 AND SLC9A3R1, GLYCOSYLATION, TISSUE SPECIFICITY, SUBCELLULAR LOCATION.
+	Additional computationally mapped references.

Cross-references

Sequence databases
EMBL GenBank DDBJ	X78520 mRNA. Translation: CAA55280.1. X78520 mRNA. Translation: CAA55281.1. Different initiation. AF029346 mRNA. Translation: AAB95161.1. AF172729 mRNA. Translation: AAD51034.1. AB019542 mRNA. Translation: BAC54560.1. Different initiation. BX647119 mRNA. No translation available. AC084724 Genomic DNA. No translation available. AC106878 Genomic DNA. No translation available. CH471056 Genomic DNA. Translation: EAX04782.1. CH471056 Genomic DNA. Translation: EAX04786.1.
IPI	IPI00398349. IPI00413568.
PIR	I37240.
RefSeq	NP_001820.2. NM_001829.3. NP_776297.2. NM_173872.3.
UniGene	Hs.481186.
3D structure databases
ProteinModelPortal	P51790.
SMR	P51790. Positions 127-811.
ModBase	Search...
Protein-protein interaction databases
IntAct	P51790. 5 interactions.
MINT	MINT-1783418.
STRING	P51790.
PTM databases
PhosphoSite	P51790.
Polymorphism databases
DMDM	226693513.
Proteomic databases
PRIDE	P51790.
Protocols and materials databases
StructuralBiologyKnowledgebase	Search...
Genome annotation databases
Ensembl	ENST00000360642; ENSP00000353857; ENSG00000109572.
GeneID	1182.
KEGG	hsa:1182.
UCSC	uc003ish.1. human. uc003isi.1. human. uc003isj.1. human.
Organism-specific databases
CTD	1182.
GeneCards	GC04P170541.
HGNC	HGNC:2021. CLCN3.
HPA	HPA044723.
MIM	600580. gene.
neXtProt	NX_P51790.
PharmGKB	PA26548.
GenAtlas	Search...
Phylogenomic databases
eggNOG	prNOG14051.
OMA	LAVCLVK.
PhylomeDB	P51790.
Gene expression databases
ArrayExpress	P51790.
Bgee	P51790.
CleanEx	HS_CLCN3.
Genevestigator	P51790.
GermOnline	ENSG00000109572. Homo sapiens.
Family and domain databases
InterPro	IPR014743. Cl-channel_core. IPR001807. Cl-channel_volt-gated. IPR002245. Cl_channel-3. IPR000644. Cysta_beta_synth_core. [Graphical view]
Gene3D	G3DSA:1.10.3080.10. Cl-channel_core. 3 hits.
KO	K05012.
PANTHER	PTHR11689. Cl-channel_volt. 1 hit.
Pfam	PF00571. CBS. 2 hits. PF00654. Voltage_CLC. 1 hit. [Graphical view]
PRINTS	PR00762. CLCHANNEL. PR01114. CLCHANNEL3.
SMART	SM00116. CBS. 2 hits. [Graphical view]
SUPFAM	SSF81340. Cl-channel_core. 1 hit.
PROSITE	PS51371. CBS. 2 hits. [Graphical view]
ProtoNet	Search...
Other
NextBio	4884.
SOURCE	Search...

Entry information

Entry name

CLCN3_HUMAN

Accession

Primary (citable) accession number: P51790
Secondary accession number(s): D3DP34, O14918, Q86Z21

Entry history

Integrated into UniProtKB/Swiss-Prot:	October 1, 1996
Last sequence update:	April 14, 2009
Last modified:	January 25, 2012
This is version 108 of the entry and version 2 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.