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Protein

Cystic fibrosis transmembrane conductance regulator

Gene

CFTR

Organism
Ovis aries (Sheep)
Status
Reviewed-Annotation score: Annotation score: 5 out of 5-Experimental evidence at protein leveli

Functioni

Epithelial ion channel that plays an important role in the regulation of epithelial ion and water transport and fluid homeostasis. Mediates the transport of chloride ions across the cell membrane (By similarity). Channel activity is coupled to ATP hydrolysis. The ion channel is also permeable to HCO3-; selectivity depends on the extracellular chloride concentration. Exerts its function also by modulating the activity of other ion channels and transporters. Contributes to the regulation of the pH and the ion content of the epithelial fluid layer. Modulates the activity of the epithelial sodium channel (ENaC) complex, in part by regulating the cell surface expression of the ENaC complex. May regulate bicarbonate secretion and salvage in epithelial cells by regulating the transporter SLC4A7. Can inhibit the chloride channel activity of ANO1 (By similarity). Plays a role in the chloride and bicarbonate homeostasis during sperm epididymal maturation and capacitation (By similarity).By similarity

Catalytic activityi

ATP + H2O = ADP + phosphate.By similarity

Sites

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Binding sitei401ATP 1By similarity1
Binding sitei492ATP 1By similarity1
Binding sitei1220ATP 2By similarity1

Regions

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Nucleotide bindingi457 – 464ATP 1PROSITE-ProRule annotation8
Nucleotide bindingi1245 – 1252ATP 2PROSITE-ProRule annotation8

GO - Molecular functioni

GO - Biological processi

Keywordsi

Molecular functionChloride channel, Hydrolase, Ion channel
Biological processIon transport, Transport
LigandATP-binding, Chloride, Nucleotide-binding

Names & Taxonomyi

Protein namesi
Recommended name:
Cystic fibrosis transmembrane conductance regulator
Short name:
CFTR
Alternative name(s):
ATP-binding cassette sub-family C member 7
Channel conductance-controlling ATPase (EC:3.6.3.49By similarity)
cAMP-dependent chloride channel
Gene namesi
Name:CFTR
Synonyms:ABCC7
OrganismiOvis aries (Sheep)
Taxonomic identifieri9940 [NCBI]
Taxonomic lineageiEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaLaurasiatheriaCetartiodactylaRuminantiaPecoraBovidaeCaprinaeOvis
Proteomesi
  • UP000002356 Componenti: Chromosome 4

Subcellular locationi

  • Apical cell membrane By similarity; Multi-pass membrane protein By similarity
  • Early endosome membrane By similarity; Multi-pass membrane protein By similarity
  • Cell membrane By similarity; Multi-pass membrane protein By similarity
  • Recycling endosome membrane By similarity; Multi-pass membrane protein By similarity
  • Endoplasmic reticulum membrane By similarity; Multi-pass membrane protein By similarity

  • Note: The channel is internalized from the cell surface into an endosomal recycling compartment, from where it is recycled to the cell membrane. In the oviduct and bronchus, detected on the apical side of epithelial cells, but not associated with cilia.By similarity

Topology

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Topological domaini1 – 77CytoplasmicBy similarityAdd BLAST77
Transmembranei78 – 98Helical; Name=1By similarityAdd BLAST21
Topological domaini99 – 122ExtracellularBy similarityAdd BLAST24
Transmembranei123 – 146Helical; Name=2By similarityAdd BLAST24
Topological domaini147 – 195CytoplasmicBy similarityAdd BLAST49
Transmembranei196 – 216Helical; Name=3By similarityAdd BLAST21
Topological domaini217 – 222ExtracellularBy similarity6
Transmembranei223 – 243Helical; Name=4By similarityAdd BLAST21
Topological domaini244 – 298CytoplasmicBy similarityAdd BLAST55
Transmembranei299 – 319Helical; Name=5By similarityAdd BLAST21
Topological domaini320 – 339ExtracellularBy similarityAdd BLAST20
Transmembranei340 – 358Helical; Name=6By similarityAdd BLAST19
Topological domaini359 – 858CytoplasmicBy similarityAdd BLAST500
Transmembranei859 – 879Helical; Name=7By similarityAdd BLAST21
Topological domaini880 – 918ExtracellularBy similarityAdd BLAST39
Transmembranei919 – 939Discontinuously helical; Name=8By similarityAdd BLAST21
Topological domaini940 – 990CytoplasmicBy similarityAdd BLAST51
Transmembranei991 – 1011Helical; Name=9By similarityAdd BLAST21
Topological domaini1012 – 1013ExtracellularBy similarity2
Transmembranei1014 – 1034Helical; Name=10By similarityAdd BLAST21
Topological domaini1035 – 1095CytoplasmicBy similarityAdd BLAST61
Transmembranei1096 – 1116Helical; Name=11By similarityAdd BLAST21
Topological domaini1117 – 1130ExtracellularBy similarityAdd BLAST14
Transmembranei1131 – 1151Helical; Name=12By similarityAdd BLAST21
Topological domaini1152 – 1481CytoplasmicBy similarityAdd BLAST330

GO - Cellular componenti

Keywords - Cellular componenti

Cell membrane, Endoplasmic reticulum, Endosome, Membrane

PTM / Processingi

Molecule processing

Feature keyPosition(s)DescriptionActionsGraphical viewLength
ChainiPRO_00000934291 – 1481Cystic fibrosis transmembrane conductance regulatorAdd BLAST1481

Amino acid modifications

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Lipidationi523S-palmitoyl cysteineBy similarity1
Modified residuei548PhosphoserineBy similarity1
Modified residuei659PhosphoserineBy similarity1
Modified residuei669Phosphoserine; by PKABy similarity1
Modified residuei685PhosphoserineBy similarity1
Cross-linki687Glycyl lysine isopeptide (Lys-Gly) (interchain with G-Cter in ubiquitin)By similarity
Modified residuei699PhosphoserineBy similarity1
Modified residuei711PhosphoserineBy similarity1
Modified residuei716PhosphothreonineBy similarity1
Modified residuei736PhosphoserineBy similarity1
Modified residuei767PhosphoserineBy similarity1
Modified residuei790PhosphoserineBy similarity1
Modified residuei795PhosphoserineBy similarity1
Modified residuei813PhosphoserineBy similarity1
Glycosylationi894N-linked (GlcNAc...) asparagineSequence analysis1
Glycosylationi898N-linked (GlcNAc...) asparagineSequence analysis1
Lipidationi1396S-palmitoyl cysteineBy similarity1
Modified residuei1457PhosphoserineBy similarity1

Post-translational modificationi

N-glycosylated.By similarity
Phosphorylated; cAMP treatment promotes phosphorylation and activates the channel. Dephosphorylation decreases the ATPase activity (in vitro). Phosphorylation at PKA sites activates the channel. Phosphorylation at PKC sites enhances the response to phosphorylation by PKA. Phosphorylated by AMPK; this inhibits channel activity.By similarity
Ubiquitinated, leading to its degradation in the lysosome. Deubiquitination by USP10 in early endosomes enhances its endocytic recycling to the cell membrane. Ubiquitinated by RNF185 during ER stress.By similarity

Keywords - PTMi

Glycoprotein, Isopeptide bond, Lipoprotein, Palmitate, Phosphoprotein, Ubl conjugation

Expressioni

Gene expression databases

ExpressionAtlasiQ00555. baseline.

Interactioni

Subunit structurei

Monomer; does not require oligomerization for channel activity. May form oligomers in the membrane (By similarity). Interacts with SLC26A3, SLC26A6 and SLC9A3R1 (By similarity). Interacts with SHANK2 (By similarity). Interacts with MYO6 (By similarity). Interacts (via C-terminus) with GOPC (via PDZ domain); this promotes CFTR internalization and thereby decreases channel activity. Interacts with SLC4A7 through SLC9A3R1. Found in a complex with MYO5B and RAB11A. Interacts with ANO1. Interacts with SLC26A8 (By similarity). Interacts with AHCYL1; the interaction increases CFTR activity (By similarity). Interacts with CSE1L (By similarity).By similarity

Structurei

Secondary structure

11481
Legend: HelixTurnBeta strandPDB Structure known for this area
Show more details
Feature keyPosition(s)DescriptionActionsGraphical viewLength
Helixi502 – 506Combined sources5
Helixi508 – 517Combined sources10

3D structure databases

Select the link destinations:
PDBei
RCSB PDBi
PDBji
Links Updated
PDB entryMethodResolution (Å)ChainPositionsPDBsum
1CKWNMR-A497-522[»]
1CKXNMR-A497-522[»]
1CKYNMR-A497-522[»]
1CKZNMR-A497-522[»]
ProteinModelPortaliQ00555.
SMRiQ00555.
ModBaseiSearch...
MobiDBiSearch...

Miscellaneous databases

EvolutionaryTraceiQ00555.

Family & Domainsi

Domains and Repeats

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Domaini81 – 365ABC transmembrane type-1 1PROSITE-ProRule annotationAdd BLAST285
Domaini421 – 645ABC transporter 1PROSITE-ProRule annotationAdd BLAST225
Domaini859 – 1155ABC transmembrane type-1 2PROSITE-ProRule annotationAdd BLAST297
Domaini1211 – 1444ABC transporter 2PROSITE-ProRule annotationAdd BLAST234

Region

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Regioni653 – 831Intrinsically disordered R regionBy similarityAdd BLAST179

Motif

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Motifi1479 – 1481PDZ-bindingBy similarity3

Domaini

Binds and hydrolyzes ATP via the two cytoplasmic ABC transporter nucleotide-binding domains. The two ATP-binding domains interact with each other, forming a head-to-tail dimer. Normal ATPase activity requires interaction between the two domains. The first ABC transporter nucleotide-binding domain has no ATPase activity by itself.By similarity
The PDZ-binding motif mediates interactions with GOPC and with the SLC4A7, SLC9A3R1/EBP50 complex.By similarity
The R region is intrinsically disordered. It mediates channel activation when it is phosphorylated, but not in the absence of phosphorylation.By similarity

Sequence similaritiesi

Keywords - Domaini

Repeat, Transmembrane, Transmembrane helix

Phylogenomic databases

GeneTreeiENSGT00880000137856.
HOVERGENiHBG004169.
KOiK05031.

Family and domain databases

InterProiView protein in InterPro
IPR003593. AAA+_ATPase.
IPR011527. ABC1_TM_dom.
IPR003439. ABC_transporter-like.
IPR017871. ABC_transporter_CS.
IPR009147. CFTR/ABCC7.
IPR025837. CFTR_reg_dom.
IPR027417. P-loop_NTPase.
PANTHERiPTHR24223:SF273. PTHR24223:SF273. 1 hit.
PfamiView protein in Pfam
PF00664. ABC_membrane. 2 hits.
PF00005. ABC_tran. 2 hits.
PF14396. CFTR_R. 1 hit.
PRINTSiPR01851. CYSFIBREGLTR.
SMARTiView protein in SMART
SM00382. AAA. 2 hits.
SUPFAMiSSF52540. SSF52540. 2 hits.
SSF90123. SSF90123. 2 hits.
TIGRFAMsiTIGR01271. CFTR_protein. 1 hit.
PROSITEiView protein in PROSITE
PS50929. ABC_TM1F. 2 hits.
PS00211. ABC_TRANSPORTER_1. 1 hit.
PS50893. ABC_TRANSPORTER_2. 2 hits.

Sequencei

Sequence statusi: Complete.

Q00555-1 [UniParc]FASTAAdd to basket

« Hide

        10         20         30         40         50
MQRSPLEKAS VVSKLFFSWT RPILKKGYRQ RLELSDIYHI SSSDSADNLS
60 70 80 90 100
EKLEREWDRE LASKKNPKLI NALRRCFFWR FMFYGIILYL GEVTKAVQPL
110 120 130 140 150
LLGRIIASYD PDNKVERSIA IYLGIGLCLL FIVRTLLLHP AIFGLHHIGM
160 170 180 190 200
QMRIAMFSLI YKKTLKLSSR VLDKISIGQL VSLLSNNLNK FDEGLALAHF
210 220 230 240 250
VWIAPLQVTL LMGLLWDLLQ AFTFCGLAFL VVLALLQAGL GKMMMKYRDQ
260 270 280 290 300
RAGKINERLV ITSEMIENIQ SVKAYCWEEA MEKIIENLRQ TELKLTRKAA
310 320 330 340 350
YVRYLNSSAF FFSGFFVVFL SVLPYALLKG IILRKIFTTI SFCIVLRMAV
360 370 380 390 400
TRQFPWAVQT WYDSLGAINK IQDFLQKQEY KTLEYNLTTT DVVMENVTAF
410 420 430 440 450
WEEGFSKLFE KAKENNNNRK ISNCDTSLFF SNLLLGTPVL KDISFKIERG
460 470 480 490 500
QLLAVAGSTG AGKTSLLMMI MGELEPSEGK IKHSGRISFC SQYSWIMPGT
510 520 530 540 550
IKDNIIFGVS YDEYRYRSVI KACQLEEDIS KFSEKDNIVL GEGGITLSGG
560 570 580 590 600
QRARISLARA VYKDADLYLL DSPFGYLDVL TEKEIFESCV CKLMANKTRI
610 620 630 640 650
LVTSKMEHLK KADKILILHE GSVYFYGTFS ELQNQRPDFS SKLMGCDTFD
660 670 680 690 700
QFTAERRNSI ITETLRRFSL EGDTSVSWNE TKKPSFKQTG EFGEKRKNSI
710 720 730 740 750
LNSINSIRKF SVVQKTSLQM NGIDGASDEP LERRLSLVPH SEPGEGILPR
760 770 780 790 800
SNAVNSGPTF LGGRRQSVLN LMTCSSVNQG QSIHRKTATS TRKMSLAPQA
810 820 830 840 850
SLAEIDIYSR RLSQDTGLEI SEEINEEDLR DCFFDDVENI PAVTTWNTYL
860 870 880 890 900
RYITVHKSLM FVLIWCLVVF LVEVAASLVV LCLFPKILLQ DKGNSTKNAS
910 920 930 940 950
NSYAVIITST SSYYIFYIYV GVADTLLALG LFRGLPLVHT LITVSKTLHH
960 970 980 990 1000
KMLQSVLQAP MSTLNTLKTG GILNRFSKDI AVLDDLLPLT IFDFIQLLLI
1010 1020 1030 1040 1050
VIGAVVVVSV LQPYIFLATV PVIAAFILLR GYFLHTSQQL KQLESEGRSP
1060 1070 1080 1090 1100
IFTHLVTSLK GLWTLRAFGR QPYFETLFHK ALNLHTANWF LYLSTLRWFQ
1110 1120 1130 1140 1150
MRIEMIFVIF FIAVTFISIL TTGEGEGRVG IILTLAMNIM GTLQWAVNSS
1160 1170 1180 1190 1200
IDVDSLMRSV SRVFKFIDMP TEDGKPNNSF RPSKDSQPSK VMIIENQHVK
1210 1220 1230 1240 1250
KDDIWPSGGQ MTVKDLTAKY IDGGNAILEN ISFSISPGQR VGLLGRTGSG
1260 1270 1280 1290 1300
KSTLLLAFLR LLNTKGEIQI DGVSWDSITL QQWRKAFGVI PQKVFIFSGT
1310 1320 1330 1340 1350
FRKNLDPYEQ WSDQEIWKVA DEVGLRSVIE QFPGKLDFVL VDGGCVLSHG
1360 1370 1380 1390 1400
HKQLMCLARS VLSKAKILLL DEPSAHLDPI TYQIIRRTLK QAFADCTVIL
1410 1420 1430 1440 1450
SEHRIEAMLE CQRFLVIEEN KVRQYDSIQR MLSEKSLFRQ AISPADRLKL
1460 1470 1480
LPHRNSSRQR SRANIAALKE ETEEEVQETK L
Length:1,481
Mass (Da):167,927
Last modified:November 1, 1997 - v2
Checksum:iFCAB69E8205B6E32
GO

Experimental Info

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Sequence conflicti600 – 602ILV → TTL in AAA31514 (PubMed:1719001).Curated3
Sequence conflicti668F → L in AAA31514 (PubMed:1719001).Curated1

Natural variant

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Natural varianti297R → Q1 Publication1

Sequence databases

Select the link destinations:
EMBLi
GenBanki
DDBJi
Links Updated
U20418 mRNA. Translation: AAA68600.1.
DP000179 Genomic DNA. Translation: ABI75298.1.
M96682 Genomic DNA. Translation: AAA31514.1.
PIRiB39323.
RefSeqiNP_001009781.1. NM_001009781.1.
UniGeneiOar.402.

Genome annotation databases

EnsembliENSOART00000019744; ENSOARP00000019473; ENSOARG00000018133.
GeneIDi443347.
KEGGioas:443347.

Keywords - Coding sequence diversityi

Polymorphism

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.

Entry informationi

Entry nameiCFTR_SHEEP
AccessioniPrimary (citable) accession number: Q00555
Secondary accession number(s): Q09YI2, Q28544
Entry historyiIntegrated into UniProtKB/Swiss-Prot: February 1, 1994
Last sequence update: November 1, 1997
Last modified: June 7, 2017
This is version 137 of the entry and version 2 of the sequence. See complete history.
Entry statusiReviewed (UniProtKB/Swiss-Prot)
Annotation programChordata Protein Annotation Program

Miscellaneousi

Keywords - Technical termi

3D-structure, Complete proteome, Reference proteome

Documents

  1. PDB cross-references
    Index of Protein Data Bank (PDB) cross-references
  2. SIMILARITY comments
    Index of protein domains and families