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UniProtKB - P51790 (CLCN3_HUMAN)

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Protein

H(+)/Cl(-) exchange transporter 3

Gene

CLCN3

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

Functioni

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.1 Publication

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).By similarity

Sites

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Binding sitei239ChlorideBy similarity1
Sitei282Mediates proton transfer from the outer aqueous phase to the interior of the protein; involved in linking H(+) and Cl(-) transportBy similarity1
Sitei339Mediates proton transfer from the protein to the inner aqueous phaseBy similarity1
Binding sitei527Chloride; via amide nitrogenBy similarity1
Binding sitei630ChlorideBy similarity1

Regions

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Nucleotide bindingi689 – 691ATPBy similarity3
Nucleotide bindingi796 – 799ATPBy similarity4

GO - Molecular functioni

  • antiporter activity Source: UniProtKB-KW
  • ATP binding Source: UniProtKB-KW
  • chloride channel activity Source: GO_Central
  • PDZ domain binding Source: UniProtKB
  • protein heterodimerization activity Source: UniProtKB
  • protein homodimerization activity Source: UniProtKB
  • voltage-gated chloride channel activity Source: GO_Central
  • volume-sensitive chloride channel activity Source: GO_Central
View the complete GO annotation on QuickGO ...

GO - Biological processi

  • chloride transmembrane transport Source: GO_Central
  • endosomal lumen acidification Source: UniProtKB
  • negative regulation of cell volume Source: GO_Central
  • regulation of pH Source: UniProtKB
View the complete GO annotation on QuickGO ...

Keywordsi

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

Enzyme and pathway databases

ReactomeiR-HSA-2672351 Stimuli-sensing channels

Names & Taxonomyi

Protein namesi
Recommended name:
H(+)/Cl(-) exchange transporter 3
Alternative name(s):
Chloride channel protein 3
Short name:
ClC-3
Chloride transporter ClC-3
Gene namesi
Name:CLCN3
OrganismiHomo sapiens (Human)
Taxonomic identifieri9606 [NCBI]
Taxonomic lineageiEukaryota › Metazoa › Chordata › Craniata › Vertebrata › Euteleostomi › Mammalia › Eutheria › Euarchontoglires › Primates › Haplorrhini › Catarrhini › Hominidae › Homo
Proteomesi
  • UP000005640 Componenti: Chromosome 4

Organism-specific databases

EuPathDBiHostDB:ENSG00000109572.13
HGNCiHGNC:2021 CLCN3
MIMi600580 gene
neXtProtiNX_P51790

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 – 125CytoplasmicBy similarityAdd BLAST125
Transmembranei126 – 163HelicalBy similarityAdd BLAST38
Transmembranei209 – 232HelicalBy similarityAdd BLAST24
Intramembranei241 – 248HelicalBy similarity8
Transmembranei258 – 276HelicalBy similarityAdd BLAST19
Transmembranei282 – 301HelicalBy similarityAdd BLAST20
Intramembranei313 – 325HelicalBy similarityAdd BLAST13
Intramembranei329 – 337HelicalBy similarity9
Transmembranei349 – 367HelicalBy similarityAdd BLAST19
Transmembranei391 – 416HelicalBy similarityAdd BLAST26
Transmembranei423 – 443HelicalBy similarityAdd BLAST21
Transmembranei500 – 520HelicalBy similarityAdd BLAST21
Transmembranei525 – 544HelicalBy similarityAdd BLAST20
Intramembranei572 – 586HelicalBy similarityAdd BLAST15
Intramembranei590 – 601HelicalBy similarityAdd BLAST12
Intramembranei602 – 605Note=Loop between two helicesBy similarity4
Transmembranei606 – 624HelicalBy similarityAdd BLAST19
Topological domaini625 – 818CytoplasmicBy similarityAdd BLAST194

Keywords - Cellular componenti

Cytoplasmic vesicle, Endosome, Golgi apparatus, Membrane

Pathology & Biotechi

Mutagenesis

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Mutagenesisi280G → E: Changes channel selectivity from I(-)>Cl(-) to Cl(-)>I(-). 1 Publication1

Organism-specific databases

DisGeNETi1182
OpenTargetsiENSG00000109572
PharmGKBiPA26548

Chemistry databases

ChEMBLiCHEMBL2401603
GuidetoPHARMACOLOGYi702

Polymorphism and mutation databases

BioMutaiCLCN3
DMDMi226693513

PTM / Processingi

Molecule processing

Feature keyPosition(s)DescriptionActionsGraphical viewLength
ChainiPRO_00000944381 – 818H(+)/Cl(-) exchange transporter 3Add BLAST818

Amino acid modifications

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Glycosylationi177N-linked (GlcNAc...) asparagineSequence analysis1
Glycosylationi451N-linked (GlcNAc...) asparagineSequence analysis1
Glycosylationi479N-linked (GlcNAc...) asparagineSequence analysis1

Post-translational modificationi

N-glycosylated.2 Publications

Keywords - PTMi

Glycoprotein

Proteomic databases

EPDiP51790
MaxQBiP51790
PaxDbiP51790
PeptideAtlasiP51790
PRIDEiP51790
ProteomicsDBi56388
56389 [P51790-2]

PTM databases

iPTMnetiP51790
PhosphoSitePlusiP51790
SwissPalmiP51790

Expressioni

Tissue specificityi

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).3 Publications

Gene expression databases

BgeeiENSG00000109572
CleanExiHS_CLCN3
ExpressionAtlasiP51790 baseline and differential
GenevisibleiP51790 HS

Organism-specific databases

HPAiHPA044723

Interactioni

Subunit structurei

Homo- or heterodimer. Isoform 2 interacts with GOPC, PDZK1 and SLC9A3R1/EBP50.2 Publications

GO - Molecular functioni

  • PDZ domain binding Source: UniProtKB
  • protein heterodimerization activity Source: UniProtKB
  • protein homodimerization activity Source: UniProtKB
View the complete GO annotation on QuickGO ...

Protein-protein interaction databases

BioGridi107596, 16 interactors
IntActiP51790, 6 interactors
STRINGi9606.ENSP00000261514

Structurei

3D structure databases

ProteinModelPortaliP51790
SMRiP51790
ModBaseiSearch...
MobiDBiSearch...

Family & Domainsi

Domains and Repeats

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Domaini658 – 722CBS 1PROSITE-ProRule annotationAdd BLAST65
Domaini755 – 812CBS 2PROSITE-ProRule annotationAdd BLAST58

Motif

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Motifi238 – 242Selectivity filter part_1By similarity5
Motifi280 – 284Selectivity filter part_2By similarity5
Motifi525 – 529Selectivity filter part_3By similarity5

Domaini

Isoform 2 contains a C-terminal PDZ-binding motif mediating the interaction with GOPC.1 Publication

Sequence similaritiesi

Belongs to the chloride channel (TC 2.A.49) family. ClC-3/CLCN3 subfamily. [View classification]Curated

Keywords - Domaini

CBS domain, Repeat, Transmembrane, Transmembrane helix

Phylogenomic databases

eggNOGiKOG0475 Eukaryota
COG0038 LUCA
GeneTreeiENSGT00760000119109
HOGENOMiHOG000164493
InParanoidiP51790
KOiK05012
OMAiYFCALVA
OrthoDBiEOG091G01YH
PhylomeDBiP51790
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
IPR002245 Cl_channel-3
PfamiView protein in Pfam
PF00571 CBS, 2 hits
PF00654 Voltage_CLC, 1 hit
PRINTSiPR00762 CLCHANNEL
PR01114 CLCHANNEL3
SMARTiView protein in SMART
SM00116 CBS, 2 hits
SUPFAMiSSF81340 SSF81340, 3 hits
PROSITEiView protein in PROSITE
PS51371 CBS, 2 hits

Sequences (4)i

Sequence statusi: Complete.

This entry describes 4 isoformsi produced by alternative splicing. AlignAdd to basket

Isoform 1 (identifier: P51790-1) [UniParc]FASTAAdd to basket
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.

« Hide

        10         20         30         40         50
MESEQLFHRG YYRNSYNSIT SASSDEELLD GAGVIMDFQT SEDDNLLDGD 
        60         70         80         90        100
TAVGTHYTMT NGGSINSSTH LLDLLDEPIP GVGTYDDFHT IDWVREKCKD 
       110        120        130        140        150
RERHRRINSK KKESAWEMTK SLYDAWSGWL VVTLTGLASG ALAGLIDIAA 
       160        170        180        190        200
DWMTDLKEGI CLSALWYNHE QCCWGSNETT FEERDKCPQW KTWAELIIGQ 
       210        220        230        240        250
AEGPGSYIMN YIMYIFWALS FAFLAVSLVK VFAPYACGSG IPEIKTILSG 
       260        270        280        290        300
FIIRGYLGKW TLMIKTITLV LAVASGLSLG KEGPLVHVAC CCGNIFSYLF 
       310        320        330        340        350
PKYSTNEAKK REVLSAASAA GVSVAFGAPI GGVLFSLEEV SYYFPLKTLW 
       360        370        380        390        400
RSFFAALVAA FVLRSINPFG NSRLVLFYVE YHTPWYLFEL FPFILLGVFG 
       410        420        430        440        450
GLWGAFFIRA NIAWCRRRKS TKFGKYPVLE VIIVAAITAV IAFPNPYTRL 
       460        470        480        490        500
NTSELIKELF TDCGPLESSS LCDYRNDMNA SKIVDDIPDR PAGIGVYSAI 
       510        520        530        540        550
WQLCLALIFK IIMTVFTFGI KVPSGLFIPS MAIGAIAGRI VGIAVEQLAY 
       560        570        580        590        600
YHHDWFIFKE WCEVGADCIT PGLYAMVGAA ACLGGVTRMT VSLVVIVFEL 
       610        620        630        640        650
TGGLEYIVPL MAAVMTSKWV GDAFGREGIY EAHIRLNGYP FLDAKEEFTH 
       660        670        680        690        700
TTLAADVMRP RRNDPPLAVL TQDNMTVDDI ENMINETSYN GFPVIMSKES 
       710        720        730        740        750
QRLVGFALRR DLTIAIESAR KKQEGIVGSS RVCFAQHTPS LPAESPRPLK 
       760        770        780        790        800
LRSILDMSPF TVTDHTPMEI VVDIFRKLGL RQCLVTHNGR LLGIITKKDI 
       810 
LRHMAQTANQ DPASIMFN
Length:818
Mass (Da):90,966
Last modified:April 14, 2009 - v2
Checksum:i30FF0A6A2D6EF3B8
GO
Isoform 2 (identifier: P51790-2) [UniParc]FASTAAdd to basket
Also known as: ClC-3B

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

Show »
Length:866
Mass (Da):96,733
Checksum:i1B2C8D0CC47CF592
GO
Isoform 3 (identifier: P51790-4) [UniParc]FASTAAdd to basket

The sequence of this isoform differs from the canonical sequence as follows:
     312-338: Missing.

Show »
Length:791
Mass (Da):88,464
Checksum:i3C8F08C71A73D3AF
GO
Isoform 4 (identifier: P51790-5) [UniParc]FASTAAdd to basket

The sequence of this isoform differs from the canonical sequence as follows:
     1-53: MESEQLFHRG...DNLLDGDTAV → MVTLQLGESH...ALASQVAEIT

Note: No experimental confirmation available.
Show »
Length:801
Mass (Da):88,781
Checksum:i2A7951DA858393D4
GO

Sequence cautioni

The sequence BAC54560 differs from that shown. Reason: Erroneous initiation. Translation N-terminally extended.Curated
The sequence CAA55281 differs from that shown. Reason: Erroneous initiation. Translation N-terminally extended.Curated

Experimental Info

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Sequence conflicti209M → T in BX647119 (PubMed:17974005).Curated1
Sequence conflicti551Y → C in BX647119 (PubMed:17974005).Curated1
Sequence conflicti570T → A in BX647119 (PubMed:17974005).Curated1
Sequence conflicti646E → EEF in CAA55280 (PubMed:7665160).Curated1
Sequence conflicti646E → EEF in CAA55281 (PubMed:7665160).Curated1
Sequence conflicti646E → EEF in BAC54560 (PubMed:11967229).Curated1
Sequence conflicti723Q → R in BX647119 (PubMed:17974005).Curated1

Alternative sequence

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Alternative sequenceiVSP_0544151 – 53MESEQ…GDTAV → MVTLQLGESHYVVQAGLQLL GSSNPPALASQVAEIT in isoform 4. 1 PublicationAdd BLAST53
Alternative sequenceiVSP_045105312 – 338Missing in isoform 3. 1 PublicationAdd BLAST27
Alternative sequenceiVSP_016073790 – 818RLLGI…SIMFN → IVLGIITKKNILEHLEQLKQ HVEPLAPPWHYNKKRYPPAY GPDGKPRPRFNNVQLNLTDE EREETEEEVYLLNSTTL in isoform 2. 1 PublicationAdd BLAST29

Sequence databases

Select the link destinations:
EMBLi
GenBanki
DDBJi
Links Updated
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.
AK304362 mRNA Translation: BAH14168.1
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
BC136510 mRNA Translation: AAI36511.1
CCDSiCCDS34100.1 [P51790-2]
CCDS34101.1 [P51790-1]
CCDS58932.1 [P51790-4]
PIRiI37240
RefSeqiNP_001230301.1, NM_001243372.1 [P51790-4]
NP_001230303.1, NM_001243374.1
NP_001820.2, NM_001829.3 [P51790-1]
NP_776297.2, NM_173872.3 [P51790-2]
UniGeneiHs.481186
Hs.736017

Genome annotation databases

EnsembliENST00000347613; ENSP00000261514; ENSG00000109572 [P51790-2]
ENST00000360642; ENSP00000353857; ENSG00000109572 [P51790-4]
ENST00000513761; ENSP00000424603; ENSG00000109572 [P51790-1]
GeneIDi1182
KEGGihsa:1182
UCSCiuc003ish.4 human [P51790-1]

Keywords - Coding sequence diversityi

Alternative splicing

Similar proteinsi

Entry informationi

Entry nameiCLCN3_HUMAN
AccessioniPrimary (citable) accession number: P51790
Secondary accession number(s): B7Z932
, B9EGJ9, D3DP34, E9PB97, O14918, Q86Z21
Entry historyiIntegrated into UniProtKB/Swiss-Prot: October 1, 1996
Last sequence update: April 14, 2009
Last modified: July 18, 2018
This is version 170 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. Human chromosome 4
    Human chromosome 4: entries, gene names and cross-references to MIM
  2. MIM cross-references
    Online Mendelian Inheritance in Man (MIM) cross-references in UniProtKB/Swiss-Prot
  3. SIMILARITY comments
    Index of protein domains and families

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