Summary: Cystic fibrosis TM conductance regulator (CFTR), regulator domain
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Cystic fibrosis transmembrane conductance regulator Edit Wikipedia article
|Cystic fibrosis transmembrane conductance regulator (ATP-binding cassette sub-family C, member 7)|
NBD1 of human CFTR complexed with ATP. PDB rendering based on 1xmi.
|External IDs||IUPHAR: ChEMBL: GeneCards:|
CFTR is an ABC transporter-class ion channel that transports chloride and thiocyanate ions across epithelial cell membranes. Mutations of the CFTR gene affect functioning of the chloride ion channels in these cell membranes, leading to cystic fibrosis and congenital absence of the vas deferens.
The gene that encodes the CFTR protein is found on the human chromosome 7, on the long arm at position q31.2. from base pair 116,907,253 to base pair 117,095,955. CFTR orthologs  have also been identified in all mammals for which complete genome data are available.
The CFTR gene has been used in animals as a nuclear DNA phylogenetic marker. Large genomic sequences of this gene have been used to explore the phylogeny of the major groups of mammals, and confirmed the grouping of placental orders into four major clades: Xenarthra, Afrotheria, Laurasiatheria, and Euarchonta plus Glires.
Well over one thousand mutations have been described that can affect the CFTR gene. Such mutations can cause two genetic disorders, congenital bilateral absence of vas deferens and the more widely known disorder cystic fibrosis. Both disorders arise from the blockage of the movement of ions and, therefore, water into and out of cells. In congenital bilateral absence of vas deferens, the protein may be still functional but not at normal efficiency, this leads to the production of thick mucus, which blocks the developing vas deferens. In people with mutations giving rise to cystic fibrosis, the blockage in ion transport occurs in epithelial cells that line the passageways of the lungs, pancreas, and other organs. This leads to chronic dysfunction, disability, and a reduced life expectancy.
The most common mutation, ÎF508 results from a deletion (Î) of three nucleotides which results in a loss of the amino acid phenylalanine (F) at the 508th position on the protein. As a result the protein does not fold normally and is more quickly degraded.
The vast majority of mutations are quite rare. The distribution and frequency of mutations varies among different populations which has implications for genetic screening and counseling.
Mutations consist of replacements, duplications, deletions or shortenings in the CFTR gene. This may result in proteins that may not function, work less effectively, are more quickly degraded, or are present in inadequate numbers.
It has been hypothesized that mutations in the CFTR gene may confer a selective advantage to heterozygous individuals. Cells expressing a mutant form of the CFTR protein are resistant to invasion by the Salmonella typhi bacterium, the agent of typhoid fever, and mice carrying a single copy of mutant CFTR are resistant to diarrhea caused by cholera toxin.Template:Pmid =11138935
 List of common mutations
The CFTR gene is approximately 189 kb in length, with 27 exons and 28 intons. CFTR is a glycoprotein with 1480 amino acids. The protein consists of five domains. There are two transmembrane domains, each with six spans of alpha helices. These are each connected to a nucleotide binding domain (NBD) in the cytoplasm. The first NBD is connected to the second transmembrane domain by a regulatory "R" domain that is a unique feature of CFTR, not present in other ABC transporters. The ion channel only opens when its R-domain has been phosphorylated by PKA and ATP is bound at the NBDs. The carboxyl terminal of the protein is anchored to the cytoskeleton by a PDZ-interacting domain.
 Location and function
CFTR functions as a cAMP-activated ATP-gated anion channel, increasing the conductance for certain anions (e.g. Clâ) to flow down their electrochemical gradient. ATP-driven conformational changes in CFTR open and close a gate to allow transmembrane flow of anions down their electrochemical gradient. This in contrast to other ABC proteins, in which ATP-driven conformational changes fuel uphill substrate transport across cellular membranes. Essentially, CFTR is an ion channel that evolved as a 'broken' ABC transporter that leaks when in open conformation.
The CFTR is found in the epithelial cells of many organs including the lung, liver, pancreas, digestive tract, reproductive tract, and skin. Normally, the protein moves chloride and thiocyanate ions (with a negative charge) out of an epithelial cell to the covering mucus. Positively charged sodium ions follow these anions out of the cell to maintain electrical balance. This increases the total electrolyte concentration in the mucus, resulting in the movement of water out of cell by osmosis.
In epithelial cells with motile cilia lining the bronchus and the oviduct, CFTR is located on cell membrane but not on cilia. In contrast to CFTR, ENaC is located along the entire length of the cilia. These findings contradict a previous hypothesis that CFTR normally downregulates ENaC by direct interaction and that in CF patients, CFTR cannot downregulate ENaC causing hyper-absorption in the lungs and recurrent lung infections.
In sweat glands, CFTR defects result in reduced transport of sodium chloride and sodium thiocyanate in the reabsorptive duct and saltier sweat. This was the basis of a clinically important sweat test for cystic fibrosis before genetic screening was available.
Cystic fibrosis transmembrane conductance regulator has been shown to interact with:
It is inhibited by the anti-diarrhoea drug crofelemer.
 Related conditions
- Congenital bilateral absence of vas deferens: Males with congenital bilateral absence of the vas deferens most often have a mild mutation (a change that allows partial function of the gene) in one copy of the CFTR gene and a cystic fibrosis-causing mutation in the other copy of CFTR. As a result of these mutations, the movement of water and salt into and out of cells is disrupted. This disturbance leads to the production of a large amount of thick mucus that blocks the developing vas deferens (a tube that carries sperm from the testes) and causes it to degenerate, resulting in infertility.
- Cystic fibrosis: More than 1,700 mutations in the CFTR gene have been found but the majority of these have not been associated with cystic fibrosis. Most of these mutations either substitute one amino acid (a building block of proteins) for another amino acid in the CFTR protein or delete a small amount of DNA in the CFTR gene. The most common mutation, called ÎF508, is a deletion (Î) of one amino acid (phenylalanine) at position 508 in the CFTR protein. This altered protein never reaches the cell membrane because it is degraded shortly after it is made. All disease-causing mutations in the CFTR gene prevent the channel from functioning properly, leading to a blockage of the movement of salt and water into and out of cells. As a result of this blockage, cells that line the passageways of the lungs, pancreas, and other organs produce abnormally thick, sticky mucus. This mucus obstructs the airways and glands, causing the characteristic signs and symptoms of cystic fibrosis. In addition, only thin mucus can be removed by cilia, thick mucus cannot, so it traps bacteria that give rise to chronic infections.
- Gadsby DC, Vergani P, CsanÃ¡dy L (March 2006). "The ABC protein turned chloride channel whose failure causes cystic fibrosis". Nature 440 (7083): 477â83. Bibcode:2006Natur.440..477G. doi:10.1038/nature04712. PMC 2720541. PMID 16554808.
- Rommens JM, Iannuzzi MC, Kerem B, Drumm ML, Melmer G, Dean M, Rozmahel R, Cole JL, Kennedy D, Hidaka N (September 1989). "Identification of the cystic fibrosis gene: chromosome walking and jumping". Science 245 (4922): 1059â65. Bibcode:1989Sci...245.1059R. doi:10.1126/science.2772657. PMID 2772657.
- Childers M, Eckel G, Himmel A, Caldwell J (2007). "A new model of cystic fibrosis pathology: lack of transport of glutathione and its thiocyanate conjugates". Med. Hypotheses 68 (1): 101â12. doi:10.1016/j.mehy.2006.06.020. PMID 16934416.
- "OrthoMaM phylogenetic marker: CFTR coding sequence".
- Prasad A. B., Allard M. W., NISC Comparative Sequencing Program & Green E. D. (2008). "Confirming the phylogeny of mammals by use of large comparative sequence data sets". Mol. Biol. Evol. 25 (9): 1795â1808. doi:10.1093/molbev/msn104. PMC 2515873. PMID 18453548.
- Rowe SM, Miller S, Sorscher EJ (May 2005). "Cystic fibrosis". N. Engl. J. Med. 352 (19): 1992â2001. doi:10.1056/NEJMra043184. PMID 15888700.
- AraÃºjo FG, Novaes FC, Santos NP, Martins VC, Souza SM, Santos SE, Ribeiro-dos-Santos AK (January 2005). "Prevalence of deltaF508, G551D, G542X, and R553X mutations among cystic fibrosis patients in the North of Brazil". Braz. J. Med. Biol. Res. 38 (1): 11â5. doi:10.1590/S0100-879X2005000100003. PMID 15665983.
- Cystic Fibrosis Mutation Database. Genomic DNA sequence.
- Sheppard DN, Welsh MJ (January 1999). "Structure and function of the CFTR chloride channel". Physiol. Rev. 79 (1 Suppl): S23â45. PMID 9922375.
- Short DB, Trotter KW, Reczek D, Kreda SM, Bretscher A, Boucher RC, Stutts MJ, Milgram SL (July 1998). "An apical PDZ protein anchors the cystic fibrosis transmembrane conductance regulator to the cytoskeleton". J. Biol. Chem. 273 (31): 19797â801. doi:10.1074/jbc.273.31.19797. PMID 9677412.
- Gadsby, D.; Vergani, P.; CsanÃ¡dy, L. (2006). "The ABC protein turned chloride channel whose failure causes cystic fibrosis.". Nature 440 (7083): 477â483. Bibcode:2006Natur.440..477G. doi:10.1038/nature04712. PMC 2720541. PMID 16554808.
- Moskwa P, Lorentzen D, Excoffon KJ, Zabner J, McCray PB, Nauseef WM, Dupuy C, BÃ¡nfi B (January 2007). "A novel host defense system of airways is defective in cystic fibrosis". Am. J. Respir. Crit. Care Med. 175 (2): 174â83. doi:10.1164/rccm.200607-1029OC. PMC 2720149. PMID 17082494.
- Enuka Y, Hanukoglu I, Edelheit O, Vaknine H, Hanukoglu A (2011). "Epithelial sodium channels (ENaC) are uniformly distributed on motile cilia in the oviduct and the respiratory airways". Histochem Cell Biol [Epub ahead of print] 137 (3): 339â53. doi:10.1007/s00418-011-0904-1. PMID 22207244.
- Xu Y, SzÃ©p S, Lu Z (December 2009). "The antioxidant role of thiocyanate in the pathogenesis of cystic fibrosis and other inflammation-related diseases". Proc. Natl. Acad. Sci. U.S.A. 106 (48): 20515â9. Bibcode:2009PNAS..10620515X. doi:10.1073/pnas.0911412106. PMC 2777967. PMID 19918082.
- Yonei Y, Tanaka M, Ozawa Y, Miyazaki K, Tsukada N, Inada S, Inagaki Y, Miyamoto K, Suzuki O, Okawa H (April 1992). "Primary hepatocellular carcinoma with severe hypoglycemia: involvement of insulin-like growth factors". Liver 12 (2): 90â3. PMID 1320177.
- Zhang, Hui; Peters Kathryn W, Sun Fei, Marino Christopher R, Lang Jochen, Burgoyne Robert D, Frizzell Raymond A (August 2002). "Cysteine string protein interacts with and modulates the maturation of the cystic fibrosis transmembrane conductance regulator". J. Biol. Chem. (United States) 277 (32): 28948â58. doi:10.1074/jbc.M111706200. ISSN 0021-9258. PMID 12039948.
- Cheng, Jie; Moyer Bryan D, Milewski Michal, Loffing Johannes, Ikeda Masahiro, Mickle John E, Cutting Garry R, Li Min, Stanton Bruce A, Guggino William B (February 2002). "A Golgi-associated PDZ domain protein modulates cystic fibrosis transmembrane regulator plasma membrane expression". J. Biol. Chem. (United States) 277 (5): 3520â9. doi:10.1074/jbc.M110177200. ISSN 0021-9258. PMID 11707463.
- Gentzsch, Martina; Cui Liying, Mengos April, Chang Xiu-Bao, Chen Jey-Hsin, Riordan John R (February 2003). "The PDZ-binding chloride channel ClC-3B localizes to the Golgi and associates with cystic fibrosis transmembrane conductance regulator-interacting PDZ proteins". J. Biol. Chem. (United States) 278 (8): 6440â9. doi:10.1074/jbc.M211050200. ISSN 0021-9258. PMID 12471024.
- Wang, S; Yue H, Derin R B, Guggino W B, Li M (September 2000). "Accessory protein facilitated CFTR-CFTR interaction, a molecular mechanism to potentiate the chloride channel activity". Cell (UNITED STATES) 103 (1): 169â79. doi:10.1016/S0092-8674(00)00096-9. ISSN 0092-8674. PMID 11051556.
- Liedtke, Carole M; Yun C H Chris, Kyle Nicole, Wang Dandan (June 2002). "Protein kinase C epsilon-dependent regulation of cystic fibrosis transmembrane regulator involves binding to a receptor for activated C kinase (RACK1) and RACK1 binding to Na+/H+ exchange regulatory factor". J. Biol. Chem. (United States) 277 (25): 22925â33. doi:10.1074/jbc.M201917200. ISSN 0021-9258. PMID 11956211.
- Park, Meeyoung; Ko Shigeru B H, Choi Joo Young, Muallem Gaia, Thomas Philip J, Pushkin Alexander, Lee Myeong-Sok, Kim Joo Young, Lee Min Goo, Muallem Shmuel, Kurtz Ira (December 2002). "The cystic fibrosis transmembrane conductance regulator interacts with and regulates the activity of the HCO3- salvage transporter human Na+-HCO3- cotransport isoform 3". J. Biol. Chem. (United States) 277 (52): 50503â9. doi:10.1074/jbc.M201862200. ISSN 0021-9258. PMID 12403779.
- Cormet-Boyaka, Estelle; Di Anke, Chang Steven Y, Naren Anjaparavanda P, Tousson Albert, Nelson Deborah J, Kirk Kevin L (September 2002). "CFTR chloride channels are regulated by a SNAP-23/syntaxin 1A complex". Proc. Natl. Acad. Sci. U.S.A. (United States) 99 (19): 12477â82. Bibcode:2002PNAS...9912477C. doi:10.1073/pnas.192203899. ISSN 0027-8424. PMC 129470. PMID 12209004.
- HegedÃ¼s, TamÃ¡s; Sessler TamÃ¡s, Scott Robert, Thelin William, Bakos Eva, VÃ¡radi AndrÃ¡s, SzabÃ³ Katalin, Homolya LÃ¡szlÃ³, Milgram Sharon L, Sarkadi BalÃ¡zs (March 2003). "C-terminal phosphorylation of MRP2 modulates its interaction with PDZ proteins". Biochem. Biophys. Res. Commun. (United States) 302 (3): 454â61. doi:10.1016/S0006-291X(03)00196-7. ISSN 0006-291X. PMID 12615054.
- Wang, S; Raab R W, Schatz P J, Guggino W B, Li M (May. 1998). "Peptide binding consensus of the NHE-RF-PDZ1 domain matches the C-terminal sequence of cystic fibrosis transmembrane conductance regulator (CFTR)". FEBS Lett. (NETHERLANDS) 427 (1): 103â8. doi:10.1016/S0014-5793(98)00402-5. ISSN 0014-5793. PMID 9613608.
- Moyer, B D; Duhaime M, Shaw C, Denton J, Reynolds D, Karlson K H, Pfeiffer J, Wang S, Mickle J E, Milewski M, Cutting G R, Guggino W B, Li M, Stanton B A (September 2000). "The PDZ-interacting domain of cystic fibrosis transmembrane conductance regulator is required for functional expression in the apical plasma membrane". J. Biol. Chem. (UNITED STATES) 275 (35): 27069â74. doi:10.1074/jbc.M004951200. ISSN 0021-9258. PMID 10852925.
- Hall, R A; Ostedgaard L S, Premont R T, Blitzer J T, Rahman N, Welsh M J, Lefkowitz R J (July 1998). "A C-terminal motif found in the beta2-adrenergic receptor, P2Y1 receptor and cystic fibrosis transmembrane conductance regulator determines binding to the Na+/H+ exchanger regulatory factor family of PDZ proteins". Proc. Natl. Acad. Sci. U.S.A. (UNITED STATES) 95 (15): 8496â501. Bibcode:1998PNAS...95.8496H. doi:10.1073/pnas.95.15.8496. ISSN 0027-8424. PMC 21104. PMID 9671706.
- Sun, F; Hug M J, Lewarchik C M, Yun C H, Bradbury N A, Frizzell R A (September 2000). "E3KARP mediates the association of ezrin and protein kinase A with the cystic fibrosis transmembrane conductance regulator in airway cells". J. Biol. Chem. (UNITED STATES) 275 (38): 29539â46. doi:10.1074/jbc.M004961200. ISSN 0021-9258. PMID 10893422.
- Naren, A P; Nelson D J, Xie W, Jovov B, Pevsner J, Bennett M K, Benos D J, Quick M W, Kirk K L (November 1997). "Regulation of CFTR chloride channels by syntaxin and Munc18 isoforms". Nature (ENGLAND) 390 (6657): 302â5. Bibcode:1997Natur.390..302N. doi:10.1038/36882. ISSN 0028-0836. PMID 9384384.
- Cuppens H, Cassiman JJ (2004). "CFTR mutations and polymorphisms in male infertility". Int J Androl 27 (5): 251â6. doi:10.1111/j.1365-2605.2004.00485.x. PMID 15379964.
In Cholera, the CFTR channel is up-regulated by cAMP. Cholera toxin permanently activates adenylyl cyclase, resulting in increased cAMP, resulting in oversecretion of Cl-. Na+ and H2O follow Cl- resulting in dehydration and loss of electrolytes. Treatment: Oral Rehydration Therapy (ORT) = hydration (normal saline) and glucose.
 Further reading
- Kulczycki LL, Kostuch M, Bellanti JA (2003). "A clinical perspective of cystic fibrosis and new genetic findings: relationship of CFTR mutations to genotype-phenotype manifestations". Am J Med Genet A 116 (3): 262â7. doi:10.1002/ajmg.a.10886. PMID 12503104.
- Vankeerberghen A, Cuppens H, Cassiman JJ (2002). "The cystic fibrosis transmembrane conductance regulator: an intriguing protein with pleiotropic functions". J Cyst Fibros 1 (1): 13â29. doi:10.1016/S1569-1993(01)00003-0. PMID 15463806.
- Tsui LC (1993). "Mutations and sequence variations detected in the cystic fibrosis transmembrane conductance regulator (CFTR) gene: a report from the Cystic Fibrosis Genetic Analysis Consortium". Hum. Mutat. 1 (3): 197â203. doi:10.1002/humu.1380010304. PMID 1284534.
- McIntosh I, Cutting GR (1992). "Cystic fibrosis transmembrane conductance regulator and the etiology and pathogenesis of cystic fibrosis". FASEB J. 6 (10): 2775â82. PMID 1378801.
- Drumm ML, Collins FS (1993). "Molecular biology of cystic fibrosis". Mol. Genet. Med. 3: 33â68. PMID 7693108.
- Kerem B, Kerem E (1996). "The molecular basis for disease variability in cystic fibrosis". Eur. J. Hum. Genet. 4 (2): 65â73. PMID 8744024.
- Devidas S, Guggino WB (1998). "CFTR: domains, structure, and function". J. Bioenerg. Biomembr. 29 (5): 443â51. doi:10.1023/A:1022430906284. PMID 9511929.
- Nagel G (2000). "Differential function of the two nucleotide binding domains on cystic fibrosis transmembrane conductance regulator". Biochim. Biophys. Acta 1461 (2): 263â74. doi:10.1016/S0005-2736(99)00162-5. PMID 10581360.
- Boyle MP (2003). "Unique presentations and chronic complications in adult cystic fibrosis: do they teach us anything about CFTR?". Respir. Res. 1 (3): 133â5. doi:10.1186/rr23. PMC 59552. PMID 11667976.
- Greger R, Schreiber R, Mall M, et al. (2002). "Cystic fibrosis and CFTR". Pflugers Arch. 443 Suppl 1: S3â7. doi:10.1007/s004240100635. PMID 11845294.
- Bradbury NA (2002). "cAMP signaling cascades and CFTR: is there more to learn?". Pflugers Arch. 443 Suppl 1: S85â91. doi:10.1007/s004240100651. PMID 11845310.
- Dahan D, Evagelidis A, Hanrahan JW, et al. (2002). "Regulation of the CFTR channel by phosphorylation". Pflugers Arch. 443 Suppl 1: S92â6. doi:10.1007/s004240100652. PMID 11845311.
- Cohn JA, Noone PG, Jowell PS (2002). "Idiopathic pancreatitis related to CFTR: complex inheritance and identification of a modifier gene". J. Investig. Med. 50 (5): 247Sâ255S. PMID 12227654.
- Schwartz M (2003). "[Cystic fibrosis transmembrane conductance regulator (CFTR) gene: mutations and clinical phenotypes]". Ugeskr. Laeg. 165 (9): 912â6. PMID 12661515.
- Wong LJ, Alper OM, Wang BT, et al. (2004). "Two novel null mutations in a Taiwanese cystic fibrosis patient and a survey of East Asian CFTR mutations". Am. J. Med. Genet. A 120 (2): 296â8. doi:10.1002/ajmg.a.20039. PMID 12833420.
- Cuppens, Harry; Cassiman, Jean- Jacques (2005). "CFTR mutations and polymorphisms in male infertility". Int. J. Androl. 27 (5): 251â6. doi:10.1111/j.1365-2605.2004.00485.x. PMID 15379964.
- Cohn JA, Mitchell RM, Jowell PS (2005). "The impact of cystic fibrosis and PSTI/SPINK1 gene mutations on susceptibility to chronic pancreatitis". Clin. Lab. Med. 25 (1): 79â100. doi:10.1016/j.cll.2004.12.007. PMID 15749233.
- Southern KW, Peckham D (2005). "Establishing a diagnosis of cystic fibrosis". Chronic respiratory disease 1 (4): 205â10. doi:10.1191/1479972304cd044rs. PMID 16281647.
- Kandula L, Whitcomb DC, Lowe ME (2006). "Genetic issues in pediatric pancreatitis". Current gastroenterology reports 8 (3): 248â53. doi:10.1007/s11894-006-0083-8. PMID 16764792.
- Marcet B, Boeynaems JM (2007). "Relationships between cystic fibrosis transmembrane conductance regulator, extracellular nucleotides and cystic fibrosis". Pharmacol. Ther. 112 (3): 719â32. doi:10.1016/j.pharmthera.2006.05.010. PMID 16828872.
- Wilschanski M, Durie PR (2007). "Patterns of GI disease in adulthood associated with mutations in the CFTR gene". Gut 56 (8): 1153â63. doi:10.1136/gut.2004.062786. PMC 1955522. PMID 17446304.
- GeneReviews/NCBI/NIH/UW entry on CFTR-Related Disorders - Cystic Fibrosis (CF, Mucoviscidosis) and Congenital Absence of the Vas Deferens (CAVD)
- The Cystic Fibrosis Transmembrane Conductance Regulator Protein
- The Human Gene Mutation Database - CFTR Records
- Cystic Fibrosis Mutation Database
- Oak Ridge National Laboratory CFTR Information
- CFTR at OMIM (National Center for Biotechnology Information)
This tab holds the annotation information that is stored in the Pfam database. As we move to using Wikipedia as our main source of annotation, the contents of this tab will be gradually replaced by the Wikipedia tab.
Cystic fibrosis TM conductance regulator (CFTR), regulator domain Provide feedback
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This tab holds annotation information from the InterPro database.
InterPro entry IPR025837
Cystic fibrosis transmembrane conductance regulator (CFTR) that belongs to the ATP-binding cassette (ABC) transporter superfamily. It is a member of the ABC-C subfamily, which also contains the SUR receptors and the multidrug- resistance associated proteins (MRP) [PUBMED:11435397]. The CFTR protein encodes a chloride ion channel, which is controlled by phosphorylation. It has a major role in electrolyte and fluid secretion. CFTR is important in the determination of fluid flow, ion concentration and transepithelial salt transport. Dysfunction of the CFTR channel causes the life-threatening disease, cystic fibrosis, in which trans-epithelial ion transport is disrupted [PUBMED:9922375].
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|Number in seed:||9|
|Number in full:||137|
|Average length of the domain:||200.10 aa|
|Average identity of full alignment:||67 %|
|Average coverage of the sequence by the domain:||15.53 %|
|HMM build commands:||
build method: hmmbuild -o /dev/null HMM SEED
search method: hmmsearch -Z 23193494 -E 1000 --cpu 4 HMM pfamseq
|Family (HMM) version:||1|
|Download:||download the raw HMM for this family|
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This visualisation provides a simple graphical representation of the distribution of this family across species. You can find the original interactive tree in the More....
This chart is a modified "sunburst" visualisation of the species tree for this family. It shows each node in the tree as a separate arc, arranged radially with the superkingdoms at the centre and the species arrayed around the outermost ring.
How the sunburst is generated
The tree is built by considering the taxonomic lineage of each sequence that has a match to this family. For each node in the resulting tree, we draw an arc in the sunburst. The radius of the arc, its distance from the root node at the centre of the sunburst, shows the taxonomic level ("superkingdom", "kingdom", etc). The length of the arc represents either the number of sequences represented at a given level, or the number of species that are found beneath the node in the tree. The weighting scheme can be changed using the sunburst controls.
In order to reduce the complexity of the representation, we reduce the number of taxonomic levels that we show. We consider only the following eight major taxonomic levels:
Colouring and labels
Segments of the tree are coloured approximately according to their superkingdom. For example, archeal branches are coloured with shades of orange, eukaryotes in shades of purple, etc. The colour assignments are shown under the sunburst controls. Where space allows, the name of the taxonomic level will be written on the arc itself.
As you move your mouse across the sunburst, the current node will be highlighted. In the top section of the controls panel we show a summary of the lineage of the currently highlighed node. If you pause over an arc, a tooltip will be shown, giving the name of the taxonomic level in the title and a summary of the number of sequences and species below that node in the tree.
Anomalies in the taxonomy tree
There are some situations that the sunburst tree cannot easily handle and for which we have work-arounds in place.
Missing taxonomic levels
Some species in the taxonomic tree may not have one or more of the main eight levels that we display. For example, Bos taurus is not assigned an order in the NCBI taxonomic tree. In such cases we mark the omitted level with, for example, "No order", in both the tooltip and the lineage summary.
Unmapped species names
The tree is built by looking at each sequence in the full alignment for the family. We take the name of the species given by UniProt and try to map that to the full taxonomic tree from NCBI. In some cases, the name chosen by UniProt does not map to any node in the NCBI tree, perhaps because the chosen name is listed as a synonym or a misspelling in the NCBI taxonomy.
So that these nodes are not simply omitted from the sunburst tree, we group them together in a separate branch (or segment of the sunburst tree). Since we cannot determine the lineage for these unmapped species, we show all levels between the superkingdom and the species as "uncategorised".
Since we reduce the species tree to only the eight main taxonomic levels, sequences that are mapped to the sub-species level in the tree would not normally be shown. Rather than leave out these species, we map them instead to their parent species. So, for example, for sequences belonging to one of the Vibrio cholerae sub-species in the NCBI taxonomy, we show them instead as belonging to the species Vibrio cholerae.
Too many species/sequences
For large species trees, you may see blank regions in the outer layers of the sunburst. These occur when there are large numbers of arcs to be drawn in a small space. If an arc is less than approximately one pixel wide, it will not be drawn and the space will be left blank. You may still be able to get some information about the species in that region by moving your mouse across the area, but since each arc will be very small, it will be difficult to accurately locate a particular species.
The tree shows the occurrence of this domain across different species. More...
We show the species tree in one of two ways. For smaller trees we try to show an interactive representation, which allows you to select specific nodes in the tree and view them as an alignment or as a set of Pfam domain graphics.
Unfortunately we have found that there are problems viewing the interactive tree when the it becomes larger than a certain limit. Furthermore, we have found that Internet Explorer can become unresponsive when viewing some trees, regardless of their size. We therefore show a text representation of the species tree when the size is above a certain limit or if you are using Internet Explorer to view the site.
If you are using IE you can still load the interactive tree by clicking the "Generate interactive tree" button, but please be aware of the potential problems that the interactive species tree can cause.
For all of the domain matches in a full alignment, we count the number that are found on all sequences in the alignment. This total is shown in the purple box.
We also count the number of unique sequences on which each domain is found, which is shown in green. Note that a domain may appear multiple times on the same sequence, leading to the difference between these two numbers.
Finally, we group sequences from the same organism according to the NCBI code that is assigned by UniProt, allowing us to count the number of distinct sequences on which the domain is found. This value is shown in the pink boxes.
We use the NCBI species tree to group organisms according to their taxonomy and this forms the structure of the displayed tree. Note that in some cases the trees are too large (have too many nodes) to allow us to build an interactive tree, but in most cases you can still view the tree in a plain text, non-interactive representation. Those species which are represented in the seed alignment for this domain are highlighted.
You can use the tree controls to manipulate how the interactive tree is displayed:
- show/hide the summary boxes
- highlight species that are represented in the seed alignment
- expand/collapse the tree or expand it to a given depth
- select a sub-tree or a set of species within the tree and view them graphically or as an alignment
- save a plain text representation of the tree
Please note: for large trees this can take some time. While the tree is loading, you can safely switch away from this tab but if you browse away from the family page entirely, the tree will not be loaded.
For those sequences which have a structure in the Protein DataBank, we use the mapping between UniProt, PDB and Pfam coordinate systems from the PDBe group, to allow us to map Pfam domains onto UniProt sequences and three-dimensional protein structures. The table below shows the structures on which the CFTR_R domain has been found. There are 46 instances of this domain found in the PDB. Note that there may be multiple copies of the domain in a single PDB structure, since many structures contain multiple copies of the same protein seqence.
Loading structure mapping...