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Protein

H(+)/Cl(-) exchange transporter 5

Gene

CLCN5

Organism
Homo sapiens (Human)
Status
Reviewed-Annotation score: Annotation score: 5 out of 5-Experimental evidence at protein leveli

Functioni

Proton-coupled chloride transporter. Functions as antiport system and exchanges chloride ions against protons. Important for normal acidification of the endosome lumen. May play an important role in renal tubular function.

Sites

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Binding sitei168ChlorideBy similarity1
Sitei211Mediates proton transfer from the outer aqueous phase to the interior of the protein; involved in linking H(+) and Cl(-) transportBy similarity1
Sitei268Mediates proton transfer from the protein to the inner aqueous phaseBy similarity1
Binding sitei455Chloride; via amide nitrogenBy similarity1
Binding sitei558ChlorideBy similarity1
Binding sitei596ATP; via amide nitrogen and carbonyl oxygenCombined sources1 Publication1

Regions

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Nucleotide bindingi617 – 619ATPCombined sources1 Publication3
Nucleotide bindingi724 – 727ATPCombined sources1 Publication4

GO - Molecular functioni

GO - Biological processi

  • excretion Source: ProtInc
  • ion transmembrane transport Source: Reactome
  • transport Source: ProtInc
Complete GO annotation...

Keywords - Biological processi

Antiport, Ion transport, Transport

Keywords - Ligandi

ATP-binding, Chloride, Nucleotide-binding

Enzyme and pathway databases

BioCyciZFISH:ENSG00000171365-MONOMER.
ReactomeiR-HSA-2672351. Stimuli-sensing channels.

Names & Taxonomyi

Protein namesi
Recommended name:
H(+)/Cl(-) exchange transporter 5
Alternative name(s):
Chloride channel protein 5
Short name:
ClC-5
Chloride transporter ClC-5
Gene namesi
Name:CLCN5
Synonyms:CLCK2
OrganismiHomo sapiens (Human)
Taxonomic identifieri9606 [NCBI]
Taxonomic lineageiEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresPrimatesHaplorrhiniCatarrhiniHominidaeHomo
Proteomesi
  • UP000005640 Componenti: Chromosome X

Organism-specific databases

HGNCiHGNC:2023. CLCN5.

Subcellular locationi

  • Golgi apparatus membrane 1 Publication; Multi-pass membrane protein 1 Publication
  • Endosome membrane 1 Publication; Multi-pass membrane protein 1 Publication
  • Cell membrane 1 Publication; Multi-pass membrane protein 1 Publication

Topology

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Topological domaini1 – 54CytoplasmicBy similarityAdd BLAST54
Transmembranei55 – 92HelicalBy similarityAdd BLAST38
Transmembranei138 – 161HelicalBy similarityAdd BLAST24
Intramembranei170 – 177HelicalBy similarity8
Transmembranei186 – 205HelicalBy similarityAdd BLAST20
Transmembranei211 – 230HelicalBy similarityAdd BLAST20
Intramembranei242 – 254HelicalBy similarityAdd BLAST13
Intramembranei258 – 266HelicalBy similarity9
Transmembranei278 – 296HelicalBy similarityAdd BLAST19
Transmembranei319 – 345HelicalBy similarityAdd BLAST27
Transmembranei352 – 372HelicalBy similarityAdd BLAST21
Transmembranei428 – 448HelicalBy similarityAdd BLAST21
Transmembranei453 – 472HelicalBy similarityAdd BLAST20
Intramembranei500 – 514HelicalBy similarityAdd BLAST15
Intramembranei515 – 517Note=Loop between two helicesBy similarity3
Intramembranei518 – 529HelicalBy similarityAdd BLAST12
Intramembranei530 – 534Note=Loop between two helicesBy similarity5
Transmembranei535 – 552HelicalBy similarityAdd BLAST18
Topological domaini553 – 746CytoplasmicBy similarityAdd BLAST194

GO - Cellular componenti

  • apical part of cell Source: UniProtKB
  • endosome Source: GO_Central
  • endosome membrane Source: Reactome
  • Golgi membrane Source: UniProtKB-SubCell
  • integral component of plasma membrane Source: ProtInc
  • lysosomal membrane Source: UniProtKB
  • membrane Source: UniProtKB
Complete GO annotation...

Keywords - Cellular componenti

Cell membrane, Endosome, Golgi apparatus, Membrane

Pathology & Biotechi

Involvement in diseasei

Hypophosphatemic rickets, X-linked recessive (XLRHR)1 Publication
The disease is caused by mutations affecting the gene represented in this entry.
Disease descriptionA renal disease belonging to the 'Dent disease complex', a group of disorders characterized by proximal renal tubular defect, hypercalciuria, nephrocalcinosis, and renal insufficiency. The spectrum of phenotypic features is remarkably similar in the various disorders, except for differences in the severity of bone deformities and renal impairment. XLRH patients present with rickets or osteomalacia, hypophosphatemia due to decreased renal tubular phosphate reabsorption, hypercalciuria, and low molecular weight proteinuria. Patients develop nephrocalcinosis with progressive renal failure in adulthood. Female carriers may have asymptomatic hypercalciuria or hypophosphatemia only.
See also OMIM:300554
Feature keyPosition(s)DescriptionActionsGraphical viewLength
Natural variantiVAR_001618244S → L in XLRHR; trafficks normally to the cell surface and to early endosomes; displays complex glycosylation at the cell surface like wild-type protein; exhibits reduced current. 6 PublicationsCorresponds to variant rs151340626dbSNPEnsembl.1
Nephrolithiasis 2 (NPHL2)12 Publications
The disease is caused by mutations affecting the gene represented in this entry.
Disease descriptionAn X-linked recessive renal disease belonging to the 'Dent disease complex', a group of disorders characterized by proximal renal tubular defect, hypercalciuria, nephrocalcinosis, and renal insufficiency. The spectrum of phenotypic features is remarkably similar in the various disorders, except for differences in the severity of bone deformities and renal impairment. Nephrolithiasis type 2 patients manifest hypercalciuria, hypophosphatemia, aminoaciduria, nephrocalcinosis and nephrolithiasis, renal insufficiency leading to renal failure in adulthood, rickets (33% of patients) and osteomalacia.
See also OMIM:300009
Feature keyPosition(s)DescriptionActionsGraphical viewLength
Natural variantiVAR_00161530R → RH in NPHL2. 1 Publication1
Natural variantiVAR_00161657G → V in NPHL2; alters targeting to endosomes. 3 PublicationsCorresponds to variant rs151340629dbSNPEnsembl.1
Natural variantiVAR_065591179G → D in NPHL2; retained in the endoplasmic reticulum; improperly N-glycosylated and non-functional. 1 Publication1
Natural variantiVAR_001617200L → R in NPHL2; retained in the endoplasmic reticulum; improperly N-glycosylated and non-functional. 2 PublicationsCorresponds to variant rs151340622dbSNPEnsembl.1
Natural variantiVAR_065592203S → L in NPHL2; retained in the endoplasmic reticulum; improperly N-glycosylated and non-functional. 1 Publication1
Natural variantiVAR_065593212G → A in NPHL2; trafficks normally to the cell surface and to early endosomes; endergoes complex glycosylation at the cell surface like wild-type protein but exhibits significant reductions in outwardly rectifying ion currents. 1 Publication1
Natural variantiVAR_065594219C → R in NPHL2; retained in the endoplasmic reticulum; improperly N-glycosylated and non-functional. 2 Publications1
Natural variantiVAR_065595221C → R in NPHL2; retained in the endoplasmic reticulum; improperly N-glycosylated and non-functional. 2 Publications1
Natural variantiVAR_065596225L → P in NPHL2; retained in the endoplasmic reticulum; improperly N-glycosylated and non-functional. 1 PublicationCorresponds to variant rs273585645dbSNPEnsembl.1
Natural variantiVAR_065597260G → V in NPHL2; delayed in processing of the protein and decrease in the stability of the mature complex glycosylated form causing lower cell surface expression; the early endosome distribution is normal; shows abolished current at the plasma membrane. 4 PublicationsCorresponds to variant rs151340630dbSNPEnsembl.1
Natural variantiVAR_065598267E → A in NPHL2. 1 Publication1
Natural variantiVAR_065599267Missing in NPHL2. 1 Publication1
Natural variantiVAR_065600270S → G in NPHL2. 1 Publication1
Natural variantiVAR_065601270S → R in NPHL2; retained in the endoplasmic reticulum; alters protein stability; associated with an abolition of chloride current. 2 Publications1
Natural variantiVAR_065602272Y → C in NPHL2; trafficks normally to the cell surface and to early endosomes and displays complex glycosylation at the cell surface like wild-type protein; exhibits no current. 2 PublicationsCorresponds to variant rs273585644dbSNPEnsembl.1
Natural variantiVAR_065603273F → L in NPHL2. 1 Publication1
Natural variantiVAR_065604278L → F in NPHL2; associated with a marked reduction to about 30% of wild-type chloride currents; no significant differences between the expression of the mutated and wild-type protein. 2 PublicationsCorresponds to variant rs273585648dbSNPEnsembl.1
Natural variantiVAR_075519333G → R in NPHL2; unknown pathological significance. 1 Publication1
Natural variantiVAR_065605340N → K in NPHL2; retained in the endoplasmic reticulum; improperly N-glycosylated and non-functional. 2 PublicationsCorresponds to variant rs273585646dbSNPEnsembl.1
Natural variantiVAR_065606462G → D in NPHL2. 1 Publication1
Natural variantiVAR_065607469L → P in NPHL2; retained in the endoplasmic reticulum; improperly N-glycosylated and non-functional. 1 Publication1
Natural variantiVAR_001621512G → R in NPHL2; abolishes the chloride currents. 1 Publication1
Natural variantiVAR_065608513G → E in NPHL2; causes retention in the endoplasmic reticulum and alters protein stability; total loss of function. 1 Publication1
Natural variantiVAR_065609513G → R in NPHL2. 2 PublicationsCorresponds to variant rs273585647dbSNPEnsembl.1
Natural variantiVAR_065610516R → W in NPHL2; causes retention in the endoplasmic reticulum and alters protein stability; total loss of function. 2 Publications1
Natural variantiVAR_001622520S → P in NPHL2. 1 PublicationCorresponds to variant rs151340623dbSNPEnsembl.1
Natural variantiVAR_001623527E → D in NPHL2; abolishes the chloride currents; total loss of function. 2 Publications1
Natural variantiVAR_065612545S → N in NPHL2. 1 Publication1
Natural variantiVAR_065613546K → E in NPHL2; delayed in processing of the protein and decrease in the stability of the mature complex glycosylated form causing lower cell surface expression; the early endosome distribution is normal; shows abolished current at the plasma membrane. 2 Publications1
Natural variantiVAR_065614547W → G in NPHL2; delayed in processing of the protein and decrease in the stability of the mature complex glycosylated form causing lower cell surface expression; the early endosome distribution is normal; shows reduced current at the plasma membrane. 2 PublicationsCorresponds to variant rs273585650dbSNPEnsembl.1
Natural variantiVAR_065615657T → S in NPHL2. 1 PublicationCorresponds to variant rs144207967dbSNPEnsembl.1
Nephrolithiasis 1 (NPHL1)1 Publication
The disease is caused by mutations affecting the gene represented in this entry.
Disease descriptionAn X-linked recessive renal disease belonging to the 'Dent disease complex', a group of disorders characterized by proximal renal tubular defect, hypercalciuria, nephrocalcinosis and renal insufficiency. The spectrum of phenotypic features is remarkably similar in the various disorders, except for differences in the severity of bone deformities and renal impairment. Nephrolithiasis type 1 presents with hypercalciuria, nephrocalcinosis, renal stones and renal insufficiency. Patients lack urinary acidification defects, rickets, and osteomalacia.
See also OMIM:310468
Feature keyPosition(s)DescriptionActionsGraphical viewLength
Natural variantiVAR_001620506G → E in NPHL1. 1 PublicationCorresponds to variant rs151340625dbSNPEnsembl.1
Low molecular weight proteinuria with hypercalciuria and nephrocalcinosis (LMWPHN)2 Publications
The disease is caused by mutations affecting the gene represented in this entry.
Disease descriptionAn X-linked renal disease belonging to the 'Dent disease complex', a group of disorders characterized by proximal renal tubular defect, hypercalciuria, nephrocalcinosis, and renal insufficiency. The spectrum of phenotypic features is remarkably similar in the various disorders, except for differences in the severity of bone deformities and renal impairment. LMWPHN is a slowly progressive disorder. Patients tend to have hypercalciuric nephrocalcinosis without rickets or renal failure.
See also OMIM:308990
Feature keyPosition(s)DescriptionActionsGraphical viewLength
Natural variantiVAR_001619280R → P in LMWPHN; 70% reduction in chloride transport activity and alters targeting to endosomes. 2 PublicationsCorresponds to variant rs151340628dbSNPEnsembl.1
Natural variantiVAR_065611524I → K in LMWPHN; causes retention in the endoplasmic reticulum and alters protein stability; total loss of function. 2 Publications1

Mutagenesis

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Mutagenesisi211E → A: Abolishes proton transport, but not chloride transport. 1 Publication1
Mutagenesisi617Y → A: Strongly decreased affinity for ATP, but no effect on chloride transport. 1 Publication1
Mutagenesisi618S → A: No effect ATP binding or chloride transport. 1 Publication1
Mutagenesisi672Y → A: Abolishes interaction with NEDD4 and NEDD4L. 1 Publication1
Mutagenesisi727D → A: Strongly decreased affinity for ATP, but no effect on chloride transport. 1 Publication1

Keywords - Diseasei

Disease mutation

Organism-specific databases

DisGeNETi1184.
MalaCardsiCLCN5.
MIMi300009. phenotype.
300554. phenotype.
308990. phenotype.
310468. phenotype.
OpenTargetsiENSG00000171365.
Orphaneti93622. Dent disease type 1.
PharmGKBiPA26550.

PTM / Processingi

Molecule processing

Feature keyPosition(s)DescriptionActionsGraphical viewLength
ChainiPRO_00000944461 – 746H(+)/Cl(-) exchange transporter 5Add BLAST746

Post-translational modificationi

Ubiquitinated by NEDD4L in the presence of albumin; which promotes endocytosis and proteasomal degradation.1 Publication

Keywords - PTMi

Ubl conjugation

Proteomic databases

MaxQBiP51795.
PaxDbiP51795.
PeptideAtlasiP51795.
PRIDEiP51795.

PTM databases

iPTMnetiP51795.
PhosphoSitePlusiP51795.

Expressioni

Tissue specificityi

Kidney. Moderately expressed in aortic vascular smooth muscle and endothelial cells, and at a slightly higher level in the coronary vascular smooth muscle.1 Publication

Gene expression databases

BgeeiENSG00000171365.
CleanExiHS_CLCN5.
ExpressionAtlasiP51795. baseline and differential.
GenevisibleiP51795. HS.

Organism-specific databases

HPAiHPA000401.
HPA003213.

Interactioni

Subunit structurei

Interacts with NEDD4 and NEDD4L.1 Publication

Protein-protein interaction databases

BioGridi107598. 4 interactors.
DIPiDIP-29263N.
MINTiMINT-1524912.
STRINGi9606.ENSP00000365256.

Structurei

Secondary structure

1746
Legend: HelixTurnBeta strandPDB Structure known for this area
Show more details
Feature keyPosition(s)DescriptionActionsGraphical viewLength
Helixi582 – 585Combined sources4
Beta strandi586 – 588Combined sources3
Beta strandi598 – 601Combined sources4
Helixi605 – 614Combined sources10
Beta strandi618 – 624Combined sources7
Turni626 – 628Combined sources3
Beta strandi630 – 636Combined sources7
Helixi637 – 648Combined sources12
Beta strandi659 – 661Combined sources3
Beta strandi663 – 665Combined sources3
Helixi680 – 682Combined sources3
Beta strandi683 – 686Combined sources4
Beta strandi689 – 691Combined sources3
Helixi696 – 706Combined sources11
Beta strandi709 – 715Combined sources7
Beta strandi718 – 724Combined sources7
Helixi725 – 735Combined sources11

3D structure databases

Select the link destinations:
PDBei
RCSB PDBi
PDBji
Links Updated
PDB entryMethodResolution (Å)ChainPositionsPDBsum
2J9LX-ray2.30A/B/C/D/E/F571-746[»]
2JA3X-ray3.05A/B/C/D/E/F571-746[»]
ProteinModelPortaliP51795.
SMRiP51795.
ModBaseiSearch...
MobiDBiSearch...

Miscellaneous databases

EvolutionaryTraceiP51795.

Family & Domainsi

Domains and Repeats

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Domaini586 – 650CBS 1PROSITE-ProRule annotationAdd BLAST65
Domaini682 – 742CBS 2PROSITE-ProRule annotationAdd BLAST61

Motif

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Motifi167 – 171Selectivity filter part_1By similarity5
Motifi209 – 213Selectivity filter part_2By similarity5
Motifi453 – 457Selectivity filter part_3By similarity5

Sequence similaritiesi

Contains 2 CBS domains.PROSITE-ProRule annotation

Keywords - Domaini

CBS domain, Repeat, Transmembrane, Transmembrane helix

Phylogenomic databases

eggNOGiKOG0475. Eukaryota.
COG0038. LUCA.
GeneTreeiENSGT00760000119109.
HOGENOMiHOG000164493.
HOVERGENiHBG050984.
InParanoidiP51795.
KOiK05012.
OMAiLMDIPGT.
OrthoDBiEOG091G01YH.
PhylomeDBiP51795.
TreeFamiTF313867.

Family and domain databases

Gene3Di1.10.3080.10. 3 hits.
InterProiIPR000644. CBS_dom.
IPR014743. Cl-channel_core.
IPR001807. Cl-channel_volt-gated.
IPR002247. Cl_channel-5.
[Graphical view]
PfamiPF00571. CBS. 2 hits.
PF00654. Voltage_CLC. 1 hit.
[Graphical view]
PRINTSiPR00762. CLCHANNEL.
PR01116. CLCHANNEL5.
SMARTiSM00116. CBS. 2 hits.
[Graphical view]
SUPFAMiSSF81340. SSF81340. 3 hits.
PROSITEiPS51371. CBS. 2 hits.
[Graphical view]

Sequences (2)i

Sequence statusi: Complete.

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

Isoform 1 (identifier: P51795-1) [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
MDFLEEPIPG VGTYDDFNTI DWVREKSRDR DRHREITNKS KESTWALIHS
60 70 80 90 100
VSDAFSGWLL MLLIGLLSGS LAGLIDISAH WMTDLKEGIC TGGFWFNHEH
110 120 130 140 150
CCWNSEHVTF EERDKCPEWN SWSQLIISTD EGAFAYIVNY FMYVLWALLF
160 170 180 190 200
AFLAVSLVKV FAPYACGSGI PEIKTILSGF IIRGYLGKWT LVIKTITLVL
210 220 230 240 250
AVSSGLSLGK EGPLVHVACC CGNILCHCFN KYRKNEAKRR EVLSAAAAAG
260 270 280 290 300
VSVAFGAPIG GVLFSLEEVS YYFPLKTLWR SFFAALVAAF TLRSINPFGN
310 320 330 340 350
SRLVLFYVEF HTPWHLFELV PFILLGIFGG LWGALFIRTN IAWCRKRKTT
360 370 380 390 400
QLGKYPVIEV LVVTAITAIL AFPNEYTRMS TSELISELFN DCGLLDSSKL
410 420 430 440 450
CDYENRFNTS KGGELPDRPA GVGVYSAMWQ LALTLILKIV ITIFTFGMKI
460 470 480 490 500
PSGLFIPSMA VGAIAGRLLG VGMEQLAYYH QEWTVFNSWC SQGADCITPG
510 520 530 540 550
LYAMVGAAAC LGGVTRMTVS LVVIMFELTG GLEYIVPLMA AAMTSKWVAD
560 570 580 590 600
ALGREGIYDA HIRLNGYPFL EAKEEFAHKT LAMDVMKPRR NDPLLTVLTQ
610 620 630 640 650
DSMTVEDVET IISETTYSGF PVVVSRESQR LVGFVLRRDL IISIENARKK
660 670 680 690 700
QDGVVSTSII YFTEHSPPLP PYTPPTLKLR NILDLSPFTV TDLTPMEIVV
710 720 730 740
DIFRKLGLRQ CLVTHNGRLL GIITKKDVLK HIAQMANQDP DSILFN
Length:746
Mass (Da):83,147
Last modified:October 1, 1996 - v1
Checksum:iEF913C5BA40C85D8
GO
Isoform 2 (identifier: P51795-2) [UniParc]FASTAAdd to basket

The sequence of this isoform differs from the canonical sequence as follows:
     1-1: M → MAMWQGAMDNRGFQQGSFSSFQNSSSDEDLMDIPATAMDFSMRDDVPPLDREVGEDKSYNGGGIGSSNRIM

Show »
Length:816
Mass (Da):90,785
Checksum:iC9C63CC222959F35
GO

Experimental Info

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Sequence conflicti732I → V in BAG51748 (PubMed:14702039).Curated1

Natural variant

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Natural variantiVAR_00161530R → RH in NPHL2. 1 Publication1
Natural variantiVAR_00161657G → V in NPHL2; alters targeting to endosomes. 3 PublicationsCorresponds to variant rs151340629dbSNPEnsembl.1
Natural variantiVAR_048694142M → I.Corresponds to variant rs34800648dbSNPEnsembl.1
Natural variantiVAR_065591179G → D in NPHL2; retained in the endoplasmic reticulum; improperly N-glycosylated and non-functional. 1 Publication1
Natural variantiVAR_001617200L → R in NPHL2; retained in the endoplasmic reticulum; improperly N-glycosylated and non-functional. 2 PublicationsCorresponds to variant rs151340622dbSNPEnsembl.1
Natural variantiVAR_065592203S → L in NPHL2; retained in the endoplasmic reticulum; improperly N-glycosylated and non-functional. 1 Publication1
Natural variantiVAR_065593212G → A in NPHL2; trafficks normally to the cell surface and to early endosomes; endergoes complex glycosylation at the cell surface like wild-type protein but exhibits significant reductions in outwardly rectifying ion currents. 1 Publication1
Natural variantiVAR_065594219C → R in NPHL2; retained in the endoplasmic reticulum; improperly N-glycosylated and non-functional. 2 Publications1
Natural variantiVAR_065595221C → R in NPHL2; retained in the endoplasmic reticulum; improperly N-glycosylated and non-functional. 2 Publications1
Natural variantiVAR_065596225L → P in NPHL2; retained in the endoplasmic reticulum; improperly N-glycosylated and non-functional. 1 PublicationCorresponds to variant rs273585645dbSNPEnsembl.1
Natural variantiVAR_001618244S → L in XLRHR; trafficks normally to the cell surface and to early endosomes; displays complex glycosylation at the cell surface like wild-type protein; exhibits reduced current. 6 PublicationsCorresponds to variant rs151340626dbSNPEnsembl.1
Natural variantiVAR_065597260G → V in NPHL2; delayed in processing of the protein and decrease in the stability of the mature complex glycosylated form causing lower cell surface expression; the early endosome distribution is normal; shows abolished current at the plasma membrane. 4 PublicationsCorresponds to variant rs151340630dbSNPEnsembl.1
Natural variantiVAR_065598267E → A in NPHL2. 1 Publication1
Natural variantiVAR_065599267Missing in NPHL2. 1 Publication1
Natural variantiVAR_065600270S → G in NPHL2. 1 Publication1
Natural variantiVAR_065601270S → R in NPHL2; retained in the endoplasmic reticulum; alters protein stability; associated with an abolition of chloride current. 2 Publications1
Natural variantiVAR_065602272Y → C in NPHL2; trafficks normally to the cell surface and to early endosomes and displays complex glycosylation at the cell surface like wild-type protein; exhibits no current. 2 PublicationsCorresponds to variant rs273585644dbSNPEnsembl.1
Natural variantiVAR_065603273F → L in NPHL2. 1 Publication1
Natural variantiVAR_065604278L → F in NPHL2; associated with a marked reduction to about 30% of wild-type chloride currents; no significant differences between the expression of the mutated and wild-type protein. 2 PublicationsCorresponds to variant rs273585648dbSNPEnsembl.1
Natural variantiVAR_001619280R → P in LMWPHN; 70% reduction in chloride transport activity and alters targeting to endosomes. 2 PublicationsCorresponds to variant rs151340628dbSNPEnsembl.1
Natural variantiVAR_075519333G → R in NPHL2; unknown pathological significance. 1 Publication1
Natural variantiVAR_065605340N → K in NPHL2; retained in the endoplasmic reticulum; improperly N-glycosylated and non-functional. 2 PublicationsCorresponds to variant rs273585646dbSNPEnsembl.1
Natural variantiVAR_065606462G → D in NPHL2. 1 Publication1
Natural variantiVAR_065607469L → P in NPHL2; retained in the endoplasmic reticulum; improperly N-glycosylated and non-functional. 1 Publication1
Natural variantiVAR_001620506G → E in NPHL1. 1 PublicationCorresponds to variant rs151340625dbSNPEnsembl.1
Natural variantiVAR_001621512G → R in NPHL2; abolishes the chloride currents. 1 Publication1
Natural variantiVAR_065608513G → E in NPHL2; causes retention in the endoplasmic reticulum and alters protein stability; total loss of function. 1 Publication1
Natural variantiVAR_065609513G → R in NPHL2. 2 PublicationsCorresponds to variant rs273585647dbSNPEnsembl.1
Natural variantiVAR_065610516R → W in NPHL2; causes retention in the endoplasmic reticulum and alters protein stability; total loss of function. 2 Publications1
Natural variantiVAR_001622520S → P in NPHL2. 1 PublicationCorresponds to variant rs151340623dbSNPEnsembl.1
Natural variantiVAR_065611524I → K in LMWPHN; causes retention in the endoplasmic reticulum and alters protein stability; total loss of function. 2 Publications1
Natural variantiVAR_001623527E → D in NPHL2; abolishes the chloride currents; total loss of function. 2 Publications1
Natural variantiVAR_065612545S → N in NPHL2. 1 Publication1
Natural variantiVAR_065613546K → E in NPHL2; delayed in processing of the protein and decrease in the stability of the mature complex glycosylated form causing lower cell surface expression; the early endosome distribution is normal; shows abolished current at the plasma membrane. 2 Publications1
Natural variantiVAR_065614547W → G in NPHL2; delayed in processing of the protein and decrease in the stability of the mature complex glycosylated form causing lower cell surface expression; the early endosome distribution is normal; shows reduced current at the plasma membrane. 2 PublicationsCorresponds to variant rs273585650dbSNPEnsembl.1
Natural variantiVAR_065615657T → S in NPHL2. 1 PublicationCorresponds to variant rs144207967dbSNPEnsembl.1

Alternative sequence

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Alternative sequenceiVSP_0420461M → MAMWQGAMDNRGFQQGSFSS FQNSSSDEDLMDIPATAMDF SMRDDVPPLDREVGEDKSYN GGGIGSSNRIM in isoform 2. 1 Publication1

Sequence databases

Select the link destinations:
EMBLi
GenBanki
DDBJi
Links Updated
X91906 mRNA. Translation: CAA63000.1.
AK056560 mRNA. Translation: BAG51748.1.
FO393402 Genomic DNA. No translation available.
BC130429 mRNA. Translation: AAI30430.1.
BC130431 mRNA. Translation: AAI30432.1.
X81836 mRNA. Translation: CAA57430.1.
BK000969 mRNA. Translation: DAA01544.1.
CCDSiCCDS14328.1. [P51795-1]
CCDS48115.1. [P51795-2]
PIRiI37277.
RefSeqiNP_000075.1. NM_000084.4. [P51795-1]
NP_001121370.1. NM_001127898.3. [P51795-2]
NP_001121371.1. NM_001127899.3. [P51795-2]
NP_001269092.1. NM_001282163.1.
UniGeneiHs.166486.
Hs.745501.

Genome annotation databases

EnsembliENST00000307367; ENSP00000304257; ENSG00000171365. [P51795-1]
ENST00000376088; ENSP00000365256; ENSG00000171365. [P51795-2]
ENST00000376091; ENSP00000365259; ENSG00000171365. [P51795-2]
ENST00000376108; ENSP00000365276; ENSG00000171365. [P51795-1]
GeneIDi1184.
KEGGihsa:1184.
UCSCiuc004doq.2. human. [P51795-1]

Keywords - Coding sequence diversityi

Alternative splicing, Polymorphism

Cross-referencesi

Sequence databases

Select the link destinations:
EMBLi
GenBanki
DDBJi
Links Updated
X91906 mRNA. Translation: CAA63000.1.
AK056560 mRNA. Translation: BAG51748.1.
FO393402 Genomic DNA. No translation available.
BC130429 mRNA. Translation: AAI30430.1.
BC130431 mRNA. Translation: AAI30432.1.
X81836 mRNA. Translation: CAA57430.1.
BK000969 mRNA. Translation: DAA01544.1.
CCDSiCCDS14328.1. [P51795-1]
CCDS48115.1. [P51795-2]
PIRiI37277.
RefSeqiNP_000075.1. NM_000084.4. [P51795-1]
NP_001121370.1. NM_001127898.3. [P51795-2]
NP_001121371.1. NM_001127899.3. [P51795-2]
NP_001269092.1. NM_001282163.1.
UniGeneiHs.166486.
Hs.745501.

3D structure databases

Select the link destinations:
PDBei
RCSB PDBi
PDBji
Links Updated
PDB entryMethodResolution (Å)ChainPositionsPDBsum
2J9LX-ray2.30A/B/C/D/E/F571-746[»]
2JA3X-ray3.05A/B/C/D/E/F571-746[»]
ProteinModelPortaliP51795.
SMRiP51795.
ModBaseiSearch...
MobiDBiSearch...

Protein-protein interaction databases

BioGridi107598. 4 interactors.
DIPiDIP-29263N.
MINTiMINT-1524912.
STRINGi9606.ENSP00000365256.

PTM databases

iPTMnetiP51795.
PhosphoSitePlusiP51795.

Proteomic databases

MaxQBiP51795.
PaxDbiP51795.
PeptideAtlasiP51795.
PRIDEiP51795.

Protocols and materials databases

DNASUi1184.
Structural Biology KnowledgebaseSearch...

Genome annotation databases

EnsembliENST00000307367; ENSP00000304257; ENSG00000171365. [P51795-1]
ENST00000376088; ENSP00000365256; ENSG00000171365. [P51795-2]
ENST00000376091; ENSP00000365259; ENSG00000171365. [P51795-2]
ENST00000376108; ENSP00000365276; ENSG00000171365. [P51795-1]
GeneIDi1184.
KEGGihsa:1184.
UCSCiuc004doq.2. human. [P51795-1]

Organism-specific databases

CTDi1184.
DisGeNETi1184.
GeneCardsiCLCN5.
GeneReviewsiCLCN5.
HGNCiHGNC:2023. CLCN5.
HPAiHPA000401.
HPA003213.
MalaCardsiCLCN5.
MIMi300008. gene.
300009. phenotype.
300554. phenotype.
308990. phenotype.
310468. phenotype.
neXtProtiNX_P51795.
OpenTargetsiENSG00000171365.
Orphaneti93622. Dent disease type 1.
PharmGKBiPA26550.
GenAtlasiSearch...

Phylogenomic databases

eggNOGiKOG0475. Eukaryota.
COG0038. LUCA.
GeneTreeiENSGT00760000119109.
HOGENOMiHOG000164493.
HOVERGENiHBG050984.
InParanoidiP51795.
KOiK05012.
OMAiLMDIPGT.
OrthoDBiEOG091G01YH.
PhylomeDBiP51795.
TreeFamiTF313867.

Enzyme and pathway databases

BioCyciZFISH:ENSG00000171365-MONOMER.
ReactomeiR-HSA-2672351. Stimuli-sensing channels.

Miscellaneous databases

ChiTaRSiCLCN5. human.
EvolutionaryTraceiP51795.
GeneWikiiCLCN5.
GenomeRNAii1184.
PROiP51795.
SOURCEiSearch...

Gene expression databases

BgeeiENSG00000171365.
CleanExiHS_CLCN5.
ExpressionAtlasiP51795. baseline and differential.
GenevisibleiP51795. HS.

Family and domain databases

Gene3Di1.10.3080.10. 3 hits.
InterProiIPR000644. CBS_dom.
IPR014743. Cl-channel_core.
IPR001807. Cl-channel_volt-gated.
IPR002247. Cl_channel-5.
[Graphical view]
PfamiPF00571. CBS. 2 hits.
PF00654. Voltage_CLC. 1 hit.
[Graphical view]
PRINTSiPR00762. CLCHANNEL.
PR01116. CLCHANNEL5.
SMARTiSM00116. CBS. 2 hits.
[Graphical view]
SUPFAMiSSF81340. SSF81340. 3 hits.
PROSITEiPS51371. CBS. 2 hits.
[Graphical view]
ProtoNetiSearch...

Entry informationi

Entry nameiCLCN5_HUMAN
AccessioniPrimary (citable) accession number: P51795
Secondary accession number(s): A1L475
, B3KPN6, Q5JQD5, Q7RTN8
Entry historyi
Integrated into UniProtKB/Swiss-Prot: October 1, 1996
Last sequence update: October 1, 1996
Last modified: November 2, 2016
This is version 163 of the entry and version 1 of the sequence. [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

Miscellaneous

The CLC channel family contains both chloride channels and proton-coupled anion transporters that exchange chloride or another anion for protons. The absence of conserved gating glutamate residues is typical for family members that function as channels.

Keywords - Technical termi

3D-structure, Complete proteome, Reference proteome

Documents

  1. Human chromosome X
    Human chromosome X: entries, gene names and cross-references to MIM
  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. PDB cross-references
    Index of Protein Data Bank (PDB) cross-references
  6. SIMILARITY comments
    Index of protein domains and families

Similar proteinsi

Links to similar proteins from the UniProt Reference Clusters (UniRef) at 100%, 90% and 50% sequence identity:
100%UniRef100 combines identical sequences and sub-fragments with 11 or more residues from any organism into one UniRef entry.
90%UniRef90 is built by clustering UniRef100 sequences that have at least 90% sequence identity to, and 80% overlap with, the longest sequence (a.k.a seed sequence).
50%UniRef50 is built by clustering UniRef90 seed sequences that have at least 50% sequence identity to, and 80% overlap with, the longest sequence in the cluster.