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3.A.1.202.1
Cystic fibrosis transmembrane conductance regulator (CFTR) (also called ABCC7); cyclic AMP-dependent chloride channel; also catalyzes nucleotide (ATP-ADP)-dependent glutathione and glutathione-conjugate flux (Kogan et al., 2003) (may also activate inward rectifying K+ channels). The underlying mechanism by which ATP hydrolysis controls channel opening is described by Gadsby et al., 2006. The most common cause of cystic fibrosis (CF) is defective folding of a cystic fibrosis transmembrane conductance regulator (CFTR) mutant lacking Phe508 (DeltaF508)(Riordan, 2008). The DeltaF508 protein appears to be trapped in a prefolded state with incomplete packing of the transmembrane segments, a defect that can be repaired by direct interaction with correctors such as corr-4a, VRT-325, and VRT-532 (Wang et al., 2007). CFTR interacts directly with MRP4 (3.A.1.208.7) to control Cl- secretion (Li et al., 2007). It has intrinsic adenylate kinase activity that may be of functional importance (Randak and Welsh, 2007). The intact CFTR protein mediates ATPase rather than adenylate kinase activity (Ramjeesingh et al., 2008). Regulated by Na+/H+ exchange regulatory cofactors (NHERF; O14745; TC #8.A.24.1.1) (Seidler et al., 2009). Regulated by protein kinase A and C phosphorylation (Csanády et al., 2010). It is also activated by membrane stretch induced by negative pressures (Zhang et al., 2010). TMS6 plays roles in gating and permeation (Bai et al., 2010; 2011). The 3-D structure revealed the probable location of the channel gate (Rosenberg et al., 2011). Conformational changes opening the CFTR chloride channel pore, coupled to ATP-dependent gating, have been studied (Wang and Linsdell, 2012). Alternating access to the transmembrane domain of CFTR has been demonstrated (Wang and Linsdell, 2012). MRP4 and CFTR function in the regulation of cAMP and beta-adrenergic contraction in cardiac myocytes (Sellers et al., 2012). An asymmetric hourglass, comprising a shallow outward-facing vestibule that tapers toward a narrow "bottleneck" linking the outer vestibule to a large inner cavity extending toward the cytoplasmic extent of the lipid bilayer has been proposed (Norimatsu et al., 2012). Small molecule CFTR potentiators and correctors that overcome the efects of deleterious mutations have been identified (Kym et al. 2018).  The intracellular processing, trafficking, apical membrane localization, and channel function of CFTR are regulated by dynamic protein-protein interactions in a complex network. Zhang et al. 2017 reviewed the macromolecular complex of CFTR, Na⁺/H⁺ exchanger regulatory factor 2 (NHERF2; TC# 8.A.24.1.2), and lysophosphatidic acids (LPA) receptor 2 (LPA2; see TC# 9.A.14.2.5) at the apical plasma membrane of airway and gut epithelial cells

Accession Number:P13569
Protein Name:CFTR aka ABCC7
Length:1480
Molecular Weight:168142.00
Species:Homo sapiens (Human) [9606]
Number of TMSs:11
Location1 / Topology2 / Orientation3: Early endosome membrane1 / Multi-pass membrane protein2
Substrate Cl-, Glutathione

Cross database links:

Genevestigator: P13569
eggNOG: prNOG15545
HEGENOM: HBG444760
DIP: DIP-32788N
RefSeq: NP_000483.3   
Entrez Gene ID: 1080   
Pfam: PF00664    PF00005   
Drugbank: Drugbank Link   
OMIM: 219700  phenotype
277180  phenotype
602421  gene
KEGG: hsa:1080   

Gene Ontology

GO:0016324 C:apical plasma membrane
GO:0016323 C:basolateral plasma membrane
GO:0034707 C:chloride channel complex
GO:0005769 C:early endosome
GO:0005524 F:ATP binding
GO:0005224 F:ATP-binding and phosphorylation-dependent c...
GO:0005260 F:channel-conductance-controlling ATPase acti...
GO:0019899 F:enzyme binding
GO:0030165 F:PDZ domain binding
GO:0007585 P:respiratory gaseous exchange
GO:0055085 P:transmembrane transport

References (71)

[1] “Identification of the cystic fibrosis gene: cloning and characterization of complementary DNA.”  Riordan J.R.et.al.   2475911
[2] “Genomic DNA sequence of the cystic fibrosis transmembrane conductance regulator (CFTR) gene.”  Zielenski J.et.al.   1710598
[3] “The DNA sequence of human chromosome 7.”  Hillier L.W.et.al.   12853948
[4] “Human chromosome 7: DNA sequence and biology.”  Scherer S.W.et.al.   12690205
[5] “Phosphorylation of the cystic fibrosis transmembrane conductance regulator.”  Picciotto M.R.et.al.   1377674
[6] “Mapping of cystic fibrosis transmembrane conductance regulator membrane topology by glycosylation site insertion.”  Chang X.-B.et.al.   7518437
[7] “Evidence for phosphorylation of serine 753 in CFTR using a novel metal-ion affinity resin and matrix-assisted laser desorption mass spectrometry.”  Neville D.C.A.et.al.   9385646
[8] “Splicing factors induce cystic fibrosis transmembrane regulator exon 9 skipping through a nonevolutionary conserved intronic element.”  Pagani F.et.al.   10766763
[9] “A Golgi-associated PDZ domain protein modulates cystic fibrosis transmembrane regulator plasma membrane expression.”  Cheng J.et.al.   11707463
[10] “The cystic fibrosis transmembrane conductance regulator interacts with and regulates the activity of the HCO3- salvage transporter human Na+-HCO3-cotransport isoform 3.”  Park M.et.al.   12403779
[11] “Myosin VI regulates endocytosis of the cystic fibrosis transmembrane conductance regulator.”  Swiatecka-Urban A.et.al.   15247260
[12] “Cystic fibrosis transmembrane conductance regulator and the etiology and pathogenesis of cystic fibrosis.”  McIntosh I.et.al.   1378801
[13] “Characterization of disease-associated mutations affecting an exonic splicing enhancer and two cryptic splice sites in exon 13 of the cystic fibrosis transmembrane conductance regulator gene.”  Aznarez I.et.al.   12913074
[14] “Phosphorylation of protein kinase C sites in NBD1 and the R domain control CFTR channel activation by PKA.”  Chappe V.et.al.   12588899
[15] “Tyrosine phosphorylated Par3 regulates epithelial tight junction assembly promoted by EGFR signaling.”  Wang Y.et.al.   17053785
[16] “Lys-N and trypsin cover complementary parts of the phosphoproteome in a refined SCX-based approach.”  Gauci S.et.al.   19413330
[17] “The deubiquitinating enzyme USP10 regulates the post-endocytic sorting of cystic fibrosis transmembrane conductance regulator in airway epithelial cells.”  Bomberger J.M.et.al.   19398555
[18] “A model for the nucleotide-binding domains of ABC transporters based on the large domain of aspartate aminotransferase.”  Hoedemaeker F.J.et.al.   9517543
[19] “Structural basis of the Na+/H+ exchanger regulatory factor PDZ1 interaction with the carboxyl-terminal region of the cystic fibrosis transmembrane conductance regulator.”  Karthikeyan S.et.al.   11304524
[20] “Mutations and sequence variations detected in the cystic fibrosis transmembrane conductance regulator (CFTR) gene: a report from the Cystic Fibrosis Genetic Analysis Consortium.”  Tsui L.-C.et.al.   1284534
[21] “A cluster of cystic fibrosis mutations in the first nucleotide-binding fold of the cystic fibrosis conductance regulator protein.”  Cutting G.R.et.al.   1695717
[22] “Identification of mutations in regions corresponding to the two putative nucleotide (ATP)-binding folds of the cystic fibrosis gene.”  Kerem B.-S.et.al.   2236053
[23] “Detection of three rare frameshift mutations in the cystic fibrosis gene in an African-American (CF444delA), an Italian (CF2522insC), and a Soviet (CF3821delT).”  White M.B.et.al.   1710600
[24] “Three novel mutations in the cystic fibrosis gene detected by chemical cleavage: analysis of variant splicing and a nonsense mutation.”  Jones C.T.et.al.   1284466
[25] “A new missense mutation (R1283M) in exon 20 of the cystic fibrosis transmembrane conductance regulator gene.”  Cheadle J.P.et.al.   1284468
[26] “A serine to proline substitution (S1255P) in the second nucleotide binding fold of the cystic fibrosis gene.”  Lissens W.et.al.   1284530
[27] “Detection of novel and rare mutations in exon 4 of the cystic fibrosis gene by SSCP.”  Shackleton S.et.al.   1284529
[28] “Identification of the M1101K mutation in the cystic fibrosis transmembrane conductance regulator (CFTR) gene and complete detection of cystic fibrosis mutations in the Hutterite population.”  Zielenski J.et.al.   7680525
[29] “Identification of eight novel mutations in a collaborative analysis of a part of the second transmembrane domain of the CFTR gene.”  Mercier B.et.al.   7683628
[30] “A new missense mutation (E92K) in the first transmembrane domain of the CFTR gene causes a benign cystic fibrosis phenotype.”  Nunes V.et.al.   7683954
[31] “Identification of a new missense mutation (P205S) in the first transmembrane domain of the CFTR gene associated with a mild cystic fibrosis phenotype.”  Chillon M.et.al.   7505694
[32] “Screening of 62 mutations in a cohort of cystic fibrosis patients from north eastern Italy: their incidence and clinical features of defined genotypes.”  Gasparini P.et.al.   7504969
[33] “Identification of eight mutations and three sequence variations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene.”  Ghaneb N.et.al.   7522211
[34] “Novel cystic fibrosis mutation associated with mild disease in Cypriot patients.”  Boteva K.et.al.   7513296
[35] “Detection of more than 50 different CFTR mutations in a large group of German cystic fibrosis patients.”  Doerk T.et.al.   7525450
[36] “A new missense mutation G1249E in exon 20 of the cystic fibrosis transmembrane conductance regulator (CFTR) gene.”  Greil I.et.al.   7520022
[37] “Identification of two new mutations (711 +3A-->G and V1397E) in CF chromosomes of Albanian and Macedonian origin.”  Petreska L.et.al.   7524913
[38] “A novel cystic fibrosis mutation, Y109C, in the first transmembrane domain of CFTR.”  Schaedel C.et.al.   7524909
[39] “Analysis of the CFTR gene in the Spanish population: SSCP-screening for 60 known mutations and identification of four new mutations (Q30X, A120T, 1812-1 G-->A, and 3667del4).”  Chillon M.et.al.   7517264
[40] “A missense mutation (F87L) in exon 3 of the cystic fibrosis transmembrane conductance regulator gene.”  Bienvenu T.et.al.   8081395
[41] “Is congenital bilateral absence of vas deferens a primary form of cystic fibrosis? Analyses of the CFTR gene in 67 patients.”  Mercier B.et.al.   7529962
[42] “Structural analysis of CFTR gene in congenital bilateral absence of vas deferens.”  Jezequel P.et.al.   7539342
[43] “Search for mutations in pancreatic sufficient cystic fibrosis Italian patients: detection of 90% of molecular defects and identification of three novel mutations.”  Brancolini V.et.al.   7544319
[44] “Four adult patients with the missense mutation L206W and a mild cystic fibrosis phenotype.”  Desgeorges M.et.al.   8522333
[45] “Identification of six mutations (R31L, 441delA, 681delC, 1461ins4, W1089R, E1104X) in the cystic fibrosis transmembrane conductance regulator (CFTR) gene.”  Zielenski J.et.al.   7537150
[46] “Complete screening of mutations in the coding sequence of the CFTR gene in a sample of CF patients from Russia: identification of three novel alleles.”  Verlingue C.et.al.   7541273
[47] “Novel missense mutation in the first transmembrane segment of the CFTR gene (Q98R) identified in a male adult.”  Romey M.-C.et.al.   7581407
[48] “A specific cystic fibrosis mutation (T338I) associated with the phenotype of isolated hypotonic dehydration.”  Leoni G.B.et.al.   7543567
[49] “Identification of six novel CFTR mutations in a sample of Italian cystic fibrosis patients.”  Ferec C.et.al.   7541510
[50] “Distribution of CFTR mutations in cystic fibrosis patients of Tunisian origin: identification of two novel mutations.”  Messaoud T.et.al.   8800923
[51] “Novel missense mutation (G314R) in a cystic fibrosis patient with hepatic failure.”  Nasr S.Z.et.al.   8829633
[52] “A novel mutation in exon 12 (Y569C) of the CFTR gene identified in a patient of Croatian origin.”  Petreska L.et.al.   8723693
[53] “Identification of three novel mutations in the cystic fibrosis transmembrane conductance regulator gene in Argentinian CF patients.”  Bienvenu T.et.al.   8723695
[54] “Mutation characterization of CFTR gene in 206 Northern Irish CF families: thirty mutations, including two novel, account for approximately 94% of CF chromosomes.”  Hughes D.J.et.al.   8956039
[55] “Identification of two mutations (S50Y and 4173delC) in the CFTR gene from patients with congenital bilateral absence of vas deferens (CBAVD).”  Zielenski J.et.al.   9067761
[56] “Identification of four novel mutations in the cystic fibrosis transmembrane conductance regulator gene: E664X, 2113delA, 306delTAGA, and delta M1140.”  Clavel C.et.al.   9101301
[57] “Novel mutation (A141D) in exon 4 of the CFTR gene identified in an Algerian patient.”  Gouya L.et.al.   9222768
[58] “Missense mutation R1066C in the second transmembrane domain of CFTR causes a severe cystic fibrosis phenotype: study of 19 heterozygous and 2 homozygous patients.”  Casals T.et.al.   9375855
[59] “Cystic fibrosis mutation frequencies in upstate New York.”  Shrimpton A.E.et.al.   9401006
[60] “Cystic fibrosis transmembrane-conductance regulator mutations among African Americans.”  Friedman K.J.et.al.   9443874
[61] “Analysis of the CFTR gene in Turkish cystic fibrosis patients: identification of three novel mutations (3172delAC, P1013L and M1028I).”  Onay T.et.al.   9521595
[62] “Complete mutational screening of the CFTR gene in 120 patients with pulmonary disease.”  Bombieri C.et.al.   9921909
[63] “Characterization of 19 disease-associated missense mutations in the regulatory domain of the cystic fibrosis transmembrane conductance regulator.”  Vankeerberghen A.et.al.   9736778
[64] “Detection of five novel mutations of the cystic fibrosis transmembrane regulator (CFTR) gene in Pakistani patients with cystic fibrosis: Y569D, Q98X, 296+12(T>C), 1161delC and 621+2(T>C).”  Malone G.et.al.   9482579
[65] “Identification of a novel mutation (S13F) in the CFTR gene in a CF patient of Sardinian origin.”  Leoni G.B.et.al.   9554753
[66] “Identification of three novel mutations in the CFTR gene, R117P, deltaD192, and 3121+1G-->A in four French patients.”  Feldmann D.et.al.   9452048
[67] “Paternal origin of a de novo novel CFTR mutation (L1065R) causing cystic fibrosis.”  Casals T.et.al.   9452054
[68] “A 2-amino acid insertion mutation (1243insACAAAA) in exon 7 of the CFTR gene.”  Shackleton S.et.al.   9452073
[69] “A novel missense mutation D513G in exon 10 of the cystic fibrosis transmembrane conductance regulator (CFTR) gene identified in a French CBAVD patient.”  Bienvenu T.et.al.   10651488
[70] “Identification of a D579G homozygote cystic fibrosis patient with pancreatic sufficiency and minor lung involvement.”  Picci L.et.al.   10094564
[71] “DNA sequencing of a cytogenetically normal acute myeloid leukaemia genome.”  Ley T.J.et.al.   18987736
Structure:
1NBD   1XMI   1XMJ   2BBO   2BBS   2BBT   2PZE   2PZF   2PZG   3GD7   [...more]

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Predict TMSs (Predict number of transmembrane segments)
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FASTA formatted sequence
1:	MQRSPLEKAS VVSKLFFSWT RPILRKGYRQ RLELSDIYQI PSVDSADNLS EKLEREWDRE 
61:	LASKKNPKLI NALRRCFFWR FMFYGIFLYL GEVTKAVQPL LLGRIIASYD PDNKEERSIA 
121:	IYLGIGLCLL FIVRTLLLHP AIFGLHHIGM QMRIAMFSLI YKKTLKLSSR VLDKISIGQL 
181:	VSLLSNNLNK FDEGLALAHF VWIAPLQVAL LMGLIWELLQ ASAFCGLGFL IVLALFQAGL 
241:	GRMMMKYRDQ RAGKISERLV ITSEMIENIQ SVKAYCWEEA MEKMIENLRQ TELKLTRKAA 
301:	YVRYFNSSAF FFSGFFVVFL SVLPYALIKG IILRKIFTTI SFCIVLRMAV TRQFPWAVQT 
361:	WYDSLGAINK IQDFLQKQEY KTLEYNLTTT EVVMENVTAF WEEGFGELFE KAKQNNNNRK 
421:	TSNGDDSLFF SNFSLLGTPV LKDINFKIER GQLLAVAGST GAGKTSLLMV IMGELEPSEG 
481:	KIKHSGRISF CSQFSWIMPG TIKENIIFGV SYDEYRYRSV IKACQLEEDI SKFAEKDNIV 
541:	LGEGGITLSG GQRARISLAR AVYKDADLYL LDSPFGYLDV LTEKEIFESC VCKLMANKTR 
601:	ILVTSKMEHL KKADKILILH EGSSYFYGTF SELQNLQPDF SSKLMGCDSF DQFSAERRNS 
661:	ILTETLHRFS LEGDAPVSWT ETKKQSFKQT GEFGEKRKNS ILNPINSIRK FSIVQKTPLQ 
721:	MNGIEEDSDE PLERRLSLVP DSEQGEAILP RISVISTGPT LQARRRQSVL NLMTHSVNQG 
781:	QNIHRKTTAS TRKVSLAPQA NLTELDIYSR RLSQETGLEI SEEINEEDLK ECFFDDMESI 
841:	PAVTTWNTYL RYITVHKSLI FVLIWCLVIF LAEVAASLVV LWLLGNTPLQ DKGNSTHSRN 
901:	NSYAVIITST SSYYVFYIYV GVADTLLAMG FFRGLPLVHT LITVSKILHH KMLHSVLQAP 
961:	MSTLNTLKAG GILNRFSKDI AILDDLLPLT IFDFIQLLLI VIGAIAVVAV LQPYIFVATV 
1021:	PVIVAFIMLR AYFLQTSQQL KQLESEGRSP IFTHLVTSLK GLWTLRAFGR QPYFETLFHK 
1081:	ALNLHTANWF LYLSTLRWFQ MRIEMIFVIF FIAVTFISIL TTGEGEGRVG IILTLAMNIM 
1141:	STLQWAVNSS IDVDSLMRSV SRVFKFIDMP TEGKPTKSTK PYKNGQLSKV MIIENSHVKK 
1201:	DDIWPSGGQM TVKDLTAKYT EGGNAILENI SFSISPGQRV GLLGRTGSGK STLLSAFLRL 
1261:	LNTEGEIQID GVSWDSITLQ QWRKAFGVIP QKVFIFSGTF RKNLDPYEQW SDQEIWKVAD 
1321:	EVGLRSVIEQ FPGKLDFVLV DGGCVLSHGH KQLMCLARSV LSKAKILLLD EPSAHLDPVT 
1381:	YQIIRRTLKQ AFADCTVILC EHRIEAMLEC QQFLVIEENK VRQYDSIQKL LNERSLFRQA 
1441:	ISPSDRVKLF PHRNSSKCKS KPQIAALKEE TEEEVQDTRL