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Protein

H(+)/Cl(-) exchange transporter 4

Gene

CLCN4

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

Functioni

Proton-coupled chloride transporter. Functions as antiport system and exchanges chloride ions against protons.2 Publications

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.

Sites

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Binding sitei181ChlorideBy similarity1
Sitei224Mediates proton transfer from the outer aqueous phase to the interior of the protein; involved in linking H(+) and Cl(-) transport1
Sitei281Mediates proton transfer from the protein to the inner aqueous phase1
Binding sitei469Chloride; via amide nitrogenBy similarity1
Binding sitei572ChlorideBy similarity1
Binding sitei610ATP; via amide nitrogen and carbonyl oxygenBy similarity1

Regions

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Nucleotide bindingi631 – 633ATPBy similarity3
Nucleotide bindingi738 – 741ATPBy similarity4

GO - Molecular functioni

  • antiporter activity Source: UniProtKB
  • ATP binding Source: UniProtKB-KW
  • chloride channel activity Source: MGI
  • chloride ion binding Source: GO_Central
  • solute:proton antiporter activity Source: GO_Central
  • voltage-gated chloride channel activity Source: GO_Central

GO - Biological processi

Keywordsi

Biological processAntiport, Ion transport, Transport
LigandATP-binding, Chloride, Nucleotide-binding

Enzyme and pathway databases

ReactomeiR-HSA-2672351 Stimuli-sensing channels

Protein family/group databases

TCDBi2.A.49.2.8 the chloride carrier/channel (clc) family

Names & Taxonomyi

Protein namesi
Recommended name:
H(+)/Cl(-) exchange transporter 4
Alternative name(s):
Chloride channel protein 4
Short name:
ClC-4
Chloride transporter ClC-4
Gene namesi
Name:CLCN4
OrganismiHomo sapiens (Human)
Taxonomic identifieri9606 [NCBI]
Taxonomic lineageiEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresPrimatesHaplorrhiniCatarrhiniHominidaeHomo
Proteomesi
  • UP000005640 Componenti: Chromosome X

Organism-specific databases

EuPathDBiHostDB:ENSG00000073464.11
HGNCiHGNC:2022 CLCN4
MIMi302910 gene
neXtProtiNX_P51793

Subcellular locationi

Extracellular region or secreted Cytosol Plasma membrane Cytoskeleton Lysosome Endosome Peroxisome ER Golgi apparatus Nucleus Mitochondrion Manual annotation Automatic computational assertionGraphics by Christian Stolte; Source: COMPARTMENTS

Topology

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Topological domaini1 – 67CytoplasmicBy similarityAdd BLAST67
Transmembranei68 – 105HelicalBy similarityAdd BLAST38
Transmembranei151 – 174HelicalBy similarityAdd BLAST24
Intramembranei183 – 190HelicalBy similarity8
Transmembranei200 – 218HelicalBy similarityAdd BLAST19
Transmembranei224 – 243HelicalBy similarityAdd BLAST20
Intramembranei255 – 267HelicalBy similarityAdd BLAST13
Intramembranei271 – 279HelicalBy similarity9
Transmembranei291 – 309HelicalBy similarityAdd BLAST19
Transmembranei333 – 358HelicalBy similarityAdd BLAST26
Transmembranei365 – 385HelicalBy similarityAdd BLAST21
Transmembranei442 – 462HelicalBy similarityAdd BLAST21
Transmembranei467 – 486HelicalBy similarityAdd BLAST20
Intramembranei514 – 528HelicalBy similarityAdd BLAST15
Intramembranei532 – 543HelicalBy similarityAdd BLAST12
Intramembranei544 – 547Note=Loop between two helicesBy similarity4
Transmembranei548 – 566HelicalBy similarityAdd BLAST19
Topological domaini567 – 760CytoplasmicBy similarityAdd BLAST194

Keywords - Cellular componenti

Endoplasmic reticulum, Endosome, Membrane

Pathology & Biotechi

Involvement in diseasei

Mental retardation, X-linked 49 (MRX49)2 Publications
The disease is caused by mutations affecting the gene represented in this entry.
Disease descriptionA disorder characterized by significantly below average general intellectual functioning associated with impairments in adaptive behavior and manifested during the developmental period. Intellectual deficiency is the only primary symptom of non-syndromic X-linked mental retardation, while syndromic mental retardation presents with associated physical, neurological and/or psychiatric manifestations.
See also OMIM:300114
Feature keyPosition(s)DescriptionActionsGraphical viewLength
Natural variantiVAR_07781978G → S in MRX49; marked reduction in outwardly-rectifying currents. 1 Publication1
Natural variantiVAR_077820221L → V in MRX49; marked reduction in outwardly-rectifying currents. 1 Publication1
Natural variantiVAR_077821536V → M in MRX49; marked reduction in outwardly-rectifying currents. 1 Publication1
Natural variantiVAR_077822544G → R in MRX49; has normal localization to structures resembling endoplasmic reticulum membranes; almost abolishes the outwardly-rectifying currents. 1 PublicationCorresponds to variant dbSNP:rs587777161EnsemblClinVar.1
Natural variantiVAR_077823731G → R in MRX49; marked reduction in outwardly-rectifying currents. 1 Publication1

Mutagenesis

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Mutagenesisi224E → A: Restores chloride translocation, but not proton transport; when associated with A-281. 1 Publication1
Mutagenesisi281E → A: Abolishes translocation of protons and chloride ions. 1 Publication1

Keywords - Diseasei

Disease mutation, Mental retardation

Organism-specific databases

DisGeNETi1183
MalaCardsiCLCN4
MIMi300114 phenotype
OpenTargetsiENSG00000073464
Orphaneti485350 CLCN4-related X-linked intellectual disability syndrome
777 X-linked non-syndromic intellectual disability
PharmGKBiPA26549

Chemistry databases

GuidetoPHARMACOLOGYi703

Polymorphism and mutation databases

BioMutaiCLCN4
DMDMi20141247

PTM / Processingi

Molecule processing

Feature keyPosition(s)DescriptionActionsGraphical viewLength
ChainiPRO_00000944431 – 760H(+)/Cl(-) exchange transporter 4Add BLAST760

Proteomic databases

MaxQBiP51793
PaxDbiP51793
PeptideAtlasiP51793
PRIDEiP51793
ProteomicsDBi56390

PTM databases

iPTMnetiP51793
PhosphoSitePlusiP51793

Expressioni

Tissue specificityi

Abundant in skeletal muscle and also detectable in brain and heart.

Gene expression databases

BgeeiENSG00000073464 Expressed in 199 organ(s), highest expression level in Brodmann (1909) area 46
CleanExiHS_CLCN4
ExpressionAtlasiP51793 baseline and differential
GenevisibleiP51793 HS

Organism-specific databases

HPAiHPA031313
HPA063637

Interactioni

Protein-protein interaction databases

STRINGi9606.ENSP00000370213

Structurei

3D structure databases

ProteinModelPortaliP51793
SMRiP51793
ModBaseiSearch...
MobiDBiSearch...

Family & Domainsi

Domains and Repeats

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Domaini600 – 666CBS 1PROSITE-ProRule annotationAdd BLAST67
Domaini697 – 755CBS 2PROSITE-ProRule annotationAdd BLAST59

Region

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Regioni14 – 63Required for localization in the endoplasmic reticulum1 PublicationAdd BLAST50

Motif

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Motifi180 – 184Selectivity filter part_1By similarity5
Motifi222 – 226Selectivity filter part_2By similarity5
Motifi467 – 471Selectivity filter part_3By similarity5

Sequence similaritiesi

Keywords - Domaini

CBS domain, Repeat, Transmembrane, Transmembrane helix

Phylogenomic databases

eggNOGiKOG0475 Eukaryota
COG0038 LUCA
GeneTreeiENSGT00760000119109
HOGENOMiHOG000164493
HOVERGENiHBG050984
InParanoidiP51793
KOiK05012
OMAiWYSSFTS
OrthoDBiEOG091G01YH
PhylomeDBiP51793
TreeFamiTF313867

Family and domain databases

Gene3Di1.10.3080.10, 1 hit
InterProiView protein in InterPro
IPR000644 CBS_dom
IPR014743 Cl-channel_core
IPR001807 Cl-channel_volt-gated
IPR002246 Cl_channel-4
PANTHERiPTHR11689:SF18 PTHR11689:SF18, 1 hit
PfamiView protein in Pfam
PF00571 CBS, 2 hits
PF00654 Voltage_CLC, 1 hit
PRINTSiPR00762 CLCHANNEL
PR01115 CLCHANNEL4
SMARTiView protein in SMART
SM00116 CBS, 2 hits
SUPFAMiSSF81340 SSF81340, 1 hit
PROSITEiView protein in PROSITE
PS51371 CBS, 2 hits

Sequences (2+)i

Sequence statusi: Complete.

This entry describes 2 isoformsi produced by alternative splicing. AlignAdd to basket

This entry has 2 described isoforms and 2 potential isoforms that are computationally mapped.Show allAlign All

Isoform 1 (identifier: P51793-1) [UniParc]FASTAAdd to basket

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.

« Hide
        10         20         30         40         50
MVNAGAMSGS GNLMDFLDEP FPDVGTYEDF HTIDWLREKS RDTDRHRKIT
60 70 80 90 100
SKSKESIWEF IKSLLDAWSG WVVMLLIGLL AGTLAGVIDL AVDWMTDLKE
110 120 130 140 150
GVCLSAFWYS HEQCCWTSNE TTFEDRDKCP LWQKWSELLV NQSEGASAYI
160 170 180 190 200
LNYLMYILWA LLFAFLAVSL VRVFAPYACG SGIPEIKTIL SGFIIRGYLG
210 220 230 240 250
KWTLLIKTVT LVLVVSSGLS LGKEGPLVHV ACCCGNFFSS LFSKYSKNEG
260 270 280 290 300
KRREVLSAAA AAGVSVAFGA PIGGVLFSLE EVSYYFPLKT LWRSFFAALV
310 320 330 340 350
AAFTLRSINP FGNSRLVLFY VEYHTPWYMA ELFPFILLGV FGGLWGTLFI
360 370 380 390 400
RCNIAWCRRR KTTRLGKYPV LEVIVVTAIT AIIAYPNPYT RQSTSELISE
410 420 430 440 450
LFNDCGALES SQLCDYINDP NMTRPVDDIP DRPAGVGVYT AMWQLALALI
460 470 480 490 500
FKIVVTIFTF GMKIPSGLFI PSMAVGAIAG RMVGIGVEQL AYHHHDWIIF
510 520 530 540 550
RNWCRPGADC VTPGLYAMVG AAACLGGVTR MTVSLVVIMF ELTGGLEYIV
560 570 580 590 600
PLMAAAVTSK WVADAFGKEG IYEAHIHLNG YPFLDVKDEF THRTLATDVM
610 620 630 640 650
RPRRGEPPLS VLTQDSMTVE DVETLIKETD YNGFPVVVSR DSERLIGFAQ
660 670 680 690 700
RRELILAIKN ARQRQEGIVS NSIMYFTEEP PELPANSPHP LKLRRILNLS
710 720 730 740 750
PFTVTDHTPM ETVVDIFRKL GLRQCLVTRS GRLLGIITKK DVLRHMAQMA
760
NQDPESIMFN
Length:760
Mass (Da):84,917
Last modified:February 11, 2002 - v2
Checksum:i3A5A25D1FEF3F217
GO
Isoform 2 (identifier: P51793-2) [UniParc]FASTAAdd to basket

The sequence of this isoform differs from the canonical sequence as follows:
     1-94: Missing.

Note: No experimental confirmation available.
Show »
Length:666
Mass (Da):74,347
Checksum:i4A8ACB4F7865A5C8
GO

Computationally mapped potential isoform sequencesi

There are 2 potential isoforms mapped to this entry.BLASTAlignShow allAdd to basket
EntryEntry nameProtein names
Gene namesLengthAnnotation
G3XAG5G3XAG5_HUMAN
Chloride channel protein
CLCN4 hCG_401215
729Annotation score:
E9PFB5E9PFB5_HUMAN
H(+)/Cl(-) exchange transporter 4
CLCN4
152Annotation score:

Experimental Info

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Sequence conflicti178A → R in CAA54417 (PubMed:8069296).Curated1
Sequence conflicti498 – 499II → YY in CAA54417 (PubMed:8069296).Curated2
Sequence conflicti659K → N in CAA54417 (PubMed:8069296).Curated1

Natural variant

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Natural variantiVAR_07781978G → S in MRX49; marked reduction in outwardly-rectifying currents. 1 Publication1
Natural variantiVAR_077820221L → V in MRX49; marked reduction in outwardly-rectifying currents. 1 Publication1
Natural variantiVAR_077821536V → M in MRX49; marked reduction in outwardly-rectifying currents. 1 Publication1
Natural variantiVAR_077822544G → R in MRX49; has normal localization to structures resembling endoplasmic reticulum membranes; almost abolishes the outwardly-rectifying currents. 1 PublicationCorresponds to variant dbSNP:rs587777161EnsemblClinVar.1
Natural variantiVAR_077823731G → R in MRX49; marked reduction in outwardly-rectifying currents. 1 Publication1

Alternative sequence

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Alternative sequenceiVSP_0546581 – 94Missing in isoform 2. 1 PublicationAdd BLAST94

Sequence databases

Select the link destinations:
EMBLi
GenBanki
DDBJi
Links Updated
X77197 mRNA Translation: CAA54417.1
AB019432 mRNA Translation: BAA77327.1
AF170492 mRNA Translation: AAD50981.1
AK289564 mRNA Translation: BAF82253.1
AK299611 mRNA Translation: BAH13080.1
AC003666 Genomic DNA No translation available.
AC121345 Genomic DNA No translation available.
CH471074 Genomic DNA Translation: EAW98778.1
BC130278 mRNA Translation: AAI30279.1
CCDSiCCDS14137.1 [P51793-1]
CCDS59159.1 [P51793-2]
PIRiI37242
RefSeqiNP_001243873.1, NM_001256944.1 [P51793-2]
NP_001821.2, NM_001830.3 [P51793-1]
UniGeneiHs.495674

Genome annotation databases

EnsembliENST00000380833; ENSP00000370213; ENSG00000073464 [P51793-1]
ENST00000421085; ENSP00000405754; ENSG00000073464 [P51793-2]
GeneIDi1183
KEGGihsa:1183
UCSCiuc004csy.5 human [P51793-1]

Keywords - Coding sequence diversityi

Alternative splicing

Similar proteinsi

Cross-referencesi

Sequence databases

Select the link destinations:
EMBLi
GenBanki
DDBJi
Links Updated
X77197 mRNA Translation: CAA54417.1
AB019432 mRNA Translation: BAA77327.1
AF170492 mRNA Translation: AAD50981.1
AK289564 mRNA Translation: BAF82253.1
AK299611 mRNA Translation: BAH13080.1
AC003666 Genomic DNA No translation available.
AC121345 Genomic DNA No translation available.
CH471074 Genomic DNA Translation: EAW98778.1
BC130278 mRNA Translation: AAI30279.1
CCDSiCCDS14137.1 [P51793-1]
CCDS59159.1 [P51793-2]
PIRiI37242
RefSeqiNP_001243873.1, NM_001256944.1 [P51793-2]
NP_001821.2, NM_001830.3 [P51793-1]
UniGeneiHs.495674

3D structure databases

ProteinModelPortaliP51793
SMRiP51793
ModBaseiSearch...
MobiDBiSearch...

Protein-protein interaction databases

STRINGi9606.ENSP00000370213

Chemistry databases

GuidetoPHARMACOLOGYi703

Protein family/group databases

TCDBi2.A.49.2.8 the chloride carrier/channel (clc) family

PTM databases

iPTMnetiP51793
PhosphoSitePlusiP51793

Polymorphism and mutation databases

BioMutaiCLCN4
DMDMi20141247

Proteomic databases

MaxQBiP51793
PaxDbiP51793
PeptideAtlasiP51793
PRIDEiP51793
ProteomicsDBi56390

Protocols and materials databases

DNASUi1183
Structural Biology KnowledgebaseSearch...

Genome annotation databases

EnsembliENST00000380833; ENSP00000370213; ENSG00000073464 [P51793-1]
ENST00000421085; ENSP00000405754; ENSG00000073464 [P51793-2]
GeneIDi1183
KEGGihsa:1183
UCSCiuc004csy.5 human [P51793-1]

Organism-specific databases

CTDi1183
DisGeNETi1183
EuPathDBiHostDB:ENSG00000073464.11
GeneCardsiCLCN4
H-InvDBiHIX0056096
HGNCiHGNC:2022 CLCN4
HPAiHPA031313
HPA063637
MalaCardsiCLCN4
MIMi300114 phenotype
302910 gene
neXtProtiNX_P51793
OpenTargetsiENSG00000073464
Orphaneti485350 CLCN4-related X-linked intellectual disability syndrome
777 X-linked non-syndromic intellectual disability
PharmGKBiPA26549
GenAtlasiSearch...

Phylogenomic databases

eggNOGiKOG0475 Eukaryota
COG0038 LUCA
GeneTreeiENSGT00760000119109
HOGENOMiHOG000164493
HOVERGENiHBG050984
InParanoidiP51793
KOiK05012
OMAiWYSSFTS
OrthoDBiEOG091G01YH
PhylomeDBiP51793
TreeFamiTF313867

Enzyme and pathway databases

ReactomeiR-HSA-2672351 Stimuli-sensing channels

Miscellaneous databases

ChiTaRSiCLCN4 human
GeneWikiiCLCN4
GenomeRNAii1183
PROiPR:P51793
SOURCEiSearch...

Gene expression databases

BgeeiENSG00000073464 Expressed in 199 organ(s), highest expression level in Brodmann (1909) area 46
CleanExiHS_CLCN4
ExpressionAtlasiP51793 baseline and differential
GenevisibleiP51793 HS

Family and domain databases

Gene3Di1.10.3080.10, 1 hit
InterProiView protein in InterPro
IPR000644 CBS_dom
IPR014743 Cl-channel_core
IPR001807 Cl-channel_volt-gated
IPR002246 Cl_channel-4
PANTHERiPTHR11689:SF18 PTHR11689:SF18, 1 hit
PfamiView protein in Pfam
PF00571 CBS, 2 hits
PF00654 Voltage_CLC, 1 hit
PRINTSiPR00762 CLCHANNEL
PR01115 CLCHANNEL4
SMARTiView protein in SMART
SM00116 CBS, 2 hits
SUPFAMiSSF81340 SSF81340, 1 hit
PROSITEiView protein in PROSITE
PS51371 CBS, 2 hits
ProtoNetiSearch...

Entry informationi

Entry nameiCLCN4_HUMAN
AccessioniPrimary (citable) accession number: P51793
Secondary accession number(s): A1L3U1, B7Z5Z4, Q9UBU1
Entry historyiIntegrated into UniProtKB/Swiss-Prot: October 1, 1996
Last sequence update: February 11, 2002
Last modified: November 7, 2018
This is version 162 of the entry and version 2 of the sequence. See 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

Complete proteome, Reference proteome

Documents

  1. SIMILARITY comments
    Index of protein domains and families
  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. Human chromosome X
    Human chromosome X: entries, gene names and cross-references to MIM
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Main funding by: National Institutes of Health

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