P51793 (CLCN4_HUMAN) Reviewed, UniProtKB/Swiss-Prot

Names and origin

Protein names

Recommended name:
H(+)/Cl(-) exchange transporter 4

Alternative name(s):
Chloride channel protein 4
Short name=ClC-4
Chloride transporter ClC-4

Gene names

Name:

CLCN4

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

General annotation (Comments)

Function	Proton-coupled chloride transporter. Functions as antiport system and exchanges chloride ions against protons. Ref.7
Subcellular location	Early endosome membrane; Multi-pass membrane protein By similarity. Late endosome membrane; Multi-pass membrane protein By similarity.
Tissue specificity	Abundant in skeletal muscle and also detectable in brain and heart.
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.
Sequence similarities	Belongs to the chloride channel (TC 2.A.49) family. ClC-4/CLCN4 subfamily. [View classification] Contains 2 CBS domains.

Ontologies

Keywords
Biological process	Antiport Ion transport Transport
Cellular component	Endosome Membrane
Domain	CBS domain Repeat Transmembrane Transmembrane helix
Ligand	ATP-binding Chloride Nucleotide-binding
Technical term	Complete proteome Reference proteome
Gene Ontology (GO)
Cellular_component	early endosome membrane Inferred from electronic annotation. Source: UniProtKB-SubCell endosome membrane Traceable author statement. Source: Reactome integral to membrane Inferred from electronic annotation. Source: UniProtKB-KW late endosome membrane Inferred from electronic annotation. Source: UniProtKB-SubCell
Molecular_function	ATP binding Inferred from electronic annotation. Source: UniProtKB-KW antiporter activity Inferred from electronic annotation. Source: UniProtKB-KW voltage-gated chloride channel activity Traceable author statement Ref.1. Source: ProtInc
Complete GO annotation...

Sequence annotation (Features)

	Feature key	Position(s)	Length	Description	Graphical view	Feature identifier
Molecule processing
	Chain	1 – 760	760	H(+)/Cl(-) exchange transporter 4		PRO_0000094443
Regions
	Topological domain	1 – 67	67	Cytoplasmic By similarity
	Transmembrane	68 – 105	38	Helical; By similarity
	Transmembrane	151 – 174	24	Helical; By similarity
	Intramembrane	183 – 190	8	Helical; By similarity
	Transmembrane	200 – 218	19	Helical; By similarity
	Transmembrane	224 – 243	20	Helical; By similarity
	Intramembrane	255 – 267	13	Helical; By similarity
	Intramembrane	271 – 279	9	Helical; By similarity
	Transmembrane	291 – 309	19	Helical; By similarity
	Transmembrane	333 – 358	26	Helical; By similarity
	Transmembrane	365 – 385	21	Helical; By similarity
	Transmembrane	442 – 462	21	Helical; By similarity
	Transmembrane	467 – 486	20	Helical; By similarity
	Intramembrane	514 – 528	15	Helical; By similarity
	Intramembrane	532 – 543	12	Helical; By similarity
	Intramembrane	544 – 547	4	Note=Loop between two helices; By similarity
	Transmembrane	548 – 566	19	Helical; By similarity
	Topological domain	567 – 760	194	Cytoplasmic By similarity
	Domain	600 – 666	67	CBS 1
	Domain	697 – 755	59	CBS 2
	Nucleotide binding	631 – 633	3	ATP By similarity
	Nucleotide binding	738 – 741	4	ATP By similarity
	Motif	180 – 184	5	Selectivity filter part_1 By similarity
	Motif	222 – 226	5	Selectivity filter part_2 By similarity
	Motif	467 – 471	5	Selectivity filter part_3 By similarity
Sites
	Binding site	181	1	Chloride By similarity
	Binding site	469	1	Chloride; via amide nitrogen By similarity
	Binding site	572	1	Chloride By similarity
	Binding site	610	1	ATP; via amide nitrogen and carbonyl oxygen By similarity
	Site	224	1	Mediates proton transfer from the outer aqueous phase to the interior of the protein; involved in linking H(+) and Cl(-) transport
	Site	281	1	Mediates proton transfer from the protein to the inner aqueous phase
Experimental info
	Mutagenesis	224	1	E → A: Restores chloride translocation, but not proton transport; when associated with A-281. Ref.7
	Mutagenesis	281	1	E → A: Abolishes translocation of protons and chloride ions. Ref.7
	Sequence conflict	178	1	A → R in CAA54417. Ref.1
	Sequence conflict	498 – 499	2	II → YY in CAA54417. Ref.1
	Sequence conflict	659	1	K → N in CAA54417. Ref.1

Sequences

	Sequence		Length	Mass (Da)
	P51793 [UniParc]. Last modified February 11, 2002. Version 2. Checksum: 3A5A25D1FEF3F217	FASTA	760	84,917
	10 20 30 40 50 60 MVNAGAMSGS GNLMDFLDEP FPDVGTYEDF HTIDWLREKS RDTDRHRKIT SKSKESIWEF 70 80 90 100 110 120 IKSLLDAWSG WVVMLLIGLL AGTLAGVIDL AVDWMTDLKE GVCLSAFWYS HEQCCWTSNE 130 140 150 160 170 180 TTFEDRDKCP LWQKWSELLV NQSEGASAYI LNYLMYILWA LLFAFLAVSL VRVFAPYACG 190 200 210 220 230 240 SGIPEIKTIL SGFIIRGYLG KWTLLIKTVT LVLVVSSGLS LGKEGPLVHV ACCCGNFFSS 250 260 270 280 290 300 LFSKYSKNEG KRREVLSAAA AAGVSVAFGA PIGGVLFSLE EVSYYFPLKT LWRSFFAALV 310 320 330 340 350 360 AAFTLRSINP FGNSRLVLFY VEYHTPWYMA ELFPFILLGV FGGLWGTLFI RCNIAWCRRR 370 380 390 400 410 420 KTTRLGKYPV LEVIVVTAIT AIIAYPNPYT RQSTSELISE LFNDCGALES SQLCDYINDP 430 440 450 460 470 480 NMTRPVDDIP DRPAGVGVYT AMWQLALALI FKIVVTIFTF GMKIPSGLFI PSMAVGAIAG 490 500 510 520 530 540 RMVGIGVEQL AYHHHDWIIF RNWCRPGADC VTPGLYAMVG AAACLGGVTR MTVSLVVIMF 550 560 570 580 590 600 ELTGGLEYIV PLMAAAVTSK WVADAFGKEG IYEAHIHLNG YPFLDVKDEF THRTLATDVM 610 620 630 640 650 660 RPRRGEPPLS VLTQDSMTVE DVETLIKETD YNGFPVVVSR DSERLIGFAQ RRELILAIKN 670 680 690 700 710 720 ARQRQEGIVS NSIMYFTEEP PELPANSPHP LKLRRILNLS PFTVTDHTPM ETVVDIFRKL 730 740 750 760 GLRQCLVTRS GRLLGIITKK DVLRHMAQMA NQDPESIMFN

References

	« Hide 'large scale' referencesShow 'large scale' references »
[1]	"A gene from the Xp22.3 region shares homology with voltage-gated chloride channels." van Slegtenhorst M.A., Bassi M.T., Borsani G., Wapenaar M.C., Ferrero G.B., de Conciliis L., Rugarli E.I., Grillo A., Franco B., Zoghbi H.Y., Ballabio A. Hum. Mol. Genet. 3:547-552(1994) [PubMed] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA]. Tissue: Retina.
[2]	"Identification of an acid-activated Cl- channel from human skeletal muscles." Kawasaki M., Fukuma T., Yamauchi K., Sakamoto H., Marumo F., Sasaki S. Am. J. Physiol. 277:C948-C954(1999) [PubMed] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA]. Tissue: Skeletal muscle.
[3]	"A chloride channel (ClC-4) in human lens epithelium." Rae J.L. Submitted (JUL-1999) to the EMBL/GenBank/DDBJ databases Cited for: NUCLEOTIDE SEQUENCE [MRNA]. Tissue: Lens epithelium.
[4]	"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: Cerebellum.
[5]	Mural R.J., Istrail S., Sutton 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 (JUL-2005) to the EMBL/GenBank/DDBJ databases Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
[6]	"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: Brain.
[7]	"Determinants of anion-proton coupling in mammalian endosomal CLC proteins." Zdebik A.A., Zifarelli G., Bergsdorf E.-Y., Soliani P., Scheel O., Jentsch T.J., Pusch M. J. Biol. Chem. 283:4219-4227(2008) [PubMed] [Europe PMC] [Abstract] Cited for: FUNCTION, MUTAGENESIS OF GLU-224 AND GLU-281.
+	Additional computationally mapped references.

Cross-references

Sequence databases
EMBL GenBank DDBJ	X77197 mRNA. Translation: CAA54417.1. AB019432 mRNA. Translation: BAA77327.1. AF170492 mRNA. Translation: AAD50981.1. AK289564 mRNA. Translation: BAF82253.1. CH471074 Genomic DNA. Translation: EAW98778.1. BC130278 mRNA. Translation: AAI30279.1.
IPI	IPI00294055.
PIR	I37242.
RefSeq	NP_001821.2. NM_001830.3.
UniGene	Hs.495674.
3D structure databases
ProteinModelPortal	P51793.
ModBase	Search...
Protein-protein interaction databases
MINT	MINT-3019161.
STRING	9606.ENSP00000370213.
Protein family/group databases
TCDB	2.A.49.2.8. chloride carrier/channel (ClC) family.
PTM databases
PhosphoSite	P51793.
Polymorphism databases
DMDM	20141247.
Proteomic databases
PaxDb	P51793.
PRIDE	P51793.
Protocols and materials databases
DNASU	1183.
StructuralBiologyKnowledgebase	Search...
Genome annotation databases
Ensembl	ENST00000380833; ENSP00000370213; ENSG00000073464.
GeneID	1183.
KEGG	hsa:1183.
UCSC	uc004csy.4. human.
Organism-specific databases
CTD	1183.
GeneCards	GC0XP010085.
H-InvDB	HIX0056096.
HGNC	HGNC:2022. CLCN4.
HPA	HPA031313.
MIM	302910. gene.
neXtProt	NX_P51793.
PharmGKB	PA26549.
GenAtlas	Search...
Phylogenomic databases
eggNOG	COG0038.
HOGENOM	HOG000164493.
HOVERGEN	HBG050984.
InParanoid	P51793.
KO	K05012.
OMA	VITESGM.
OrthoDB	EOG4XD3QH.
PhylomeDB	P51793.
Gene expression databases
ArrayExpress	P51793.
Bgee	P51793.
CleanEx	HS_CLCN4.
Genevestigator	P51793.
GermOnline	ENSG00000073464. Homo sapiens.
Family and domain databases
Gene3D	1.10.3080.10. 3 hits.
InterPro	IPR014743. Cl-channel_core. IPR001807. Cl-channel_volt-gated. IPR002246. Cl_channel-4. IPR000644. Cysta_beta_synth_core. [Graphical view]
Pfam	PF00571. CBS. 2 hits. PF00654. Voltage_CLC. 1 hit. [Graphical view]
PRINTS	PR00762. CLCHANNEL. PR01115. CLCHANNEL4.
SMART	SM00116. CBS. 2 hits. [Graphical view]
SUPFAM	SSF81340. Cl-channel_core. 1 hit.
PROSITE	PS51371. CBS. 2 hits. [Graphical view]
ProtoNet	Search...
Other
ChiTaRS	CLCN4. human.
GenomeRNAi	1183.
NextBio	4890.
SOURCE	Search...

Entry information

Entry name

CLCN4_HUMAN

Accession

Primary (citable) accession number: P51793
Secondary accession number(s): A1L3U1, Q9UBU1

Entry history

Integrated into UniProtKB/Swiss-Prot:	October 1, 1996
Last sequence update:	February 11, 2002
Last modified:	May 29, 2013
This is version 118 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.