Cystic Fibrosis Transmembrane Conductance Regulator
Cystic Fibrosis Transmembrane Conductance Regulator | ||
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Representation after 1xmi | ||
Existing structural data : 1NBD , 1XMI , 1XMJ , 2BBO , 2BBS , 2BBT , 2LOB , 2PZE , 2PZF , 2PZG , 3GD7 , 3ISW |
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Properties of human protein | ||
Mass / length primary structure | 1480 AS ; 168 kDa | |
Secondary to quaternary structure | multipass membrane protein | |
Isoforms | 3 | |
Identifier | ||
Gene names | CFTR ; ABC35; ABCC7; CF; CFTR / MRP; MRP7; TNR-CFTR; dJ760C5.1 | |
External IDs | ||
Transporter classification | ||
TCDB | 3.A.1.202.1 | |
designation | ABC superfamily | |
Occurrence | ||
Homology family | ABC transporter | |
Orthologue | ||
human | House mouse | |
Entrez | 1080 | 12638 |
Ensemble | ENSG00000001626 | ENSMUSG00000041301 |
UniProt | P13569 | P26361 |
Refseq (mRNA) | NM_000492 | NM_021050 |
Refseq (protein) | NP_000483 | NP_066388 |
Gene locus | Chr 7: 117.47 - 117.72 Mb | Chr 6: 18.17-18.32 Mb |
PubMed search | 1080 |
12638
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The Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) is a protein stuck to the surface of cells , a so-called chloride channel , which is mainly found in the cell membrane of epithelial cells of fish and terrestrial vertebrates . Mutations in the CFTR gene in humans result in the absence or limited function of the channel, which cause of cystic fibrosis (cystic fibrosis) and congenital aplasia of the vas deferens ( CAVD ) is.
biosynthesis
The CFTR gene is located on chromosome 7 in the q31.2 region. It is 250 kb long and consists of 27 exons. The transcribed mRNA has a length of 6,123 bases and after translation and post-translational modification the CFTR protein with 1,480 amino acids results .
Protein structure
The protein is an integral protein that belongs to the cAMP -regulated ion channels . It has two subunits, each with six transmembrane domains , which form the actual transport channel. In addition, the protein has two nucleotide binding domains (NBD 1 and 2) and a cytoplasmic (inside the cell) regulatory domain (R). This R-domain can be phosphorylated by protein kinase A and thus activated. CFTR also contains other binding domains for protein-protein interactions, thereby regulating the transport of bicarbonate and other channels, among other things . It is also a member of the ATP-binding ABC transporters .
Function and pathology
The CFTR protein regulates water and salt transport in the plasma membrane of epithelial cells.
CFTR mutations restrict or stop the transport of chloride ions out of the cell. As a result, there is a difference in concentration, since there are many ions in the cell, but only a few in the secretion. Due to the osmotic forces present in the cell, water is withdrawn from the secretion. The secretion becomes viscous, can therefore be poorly broken down and clogs fine ducts in the lungs or the vas deferens , for example .
Mutation classes
There are six mutation classes:
- 1st class: no protein synthesis, as mutation prevents proper splicing
- 2nd class: protein cannot mature in the endoplasmic reticulum
- 3rd class: Protein matures and reaches the target membrane, but does not function as a chloride channel
- 4th class: protein is built into the target membrane, but has abnormal conductive properties
- 5th class: formation of some functional proteins
- 6th class: Reduction of the half-life of proteins
Classes 1 to 3 are severe mutations, while 4 to 6 are mild mutations - the function of the channel is not completely inhibited here.
Whether the mutation leads to CF or CAVD depends on the severity of the mutations on both alleles.
Known mutations
ΔF508
In this mutation, the amino acid phenylalanine is missing because of a deletion of three nucleotides at position 508 . The protein cannot be folded correctly, which is why it is broken down by the protein quality control in the proteasome . ΔF508 thus belongs to the class 2 mutations.
R117H
Is a slightly milder but still common mutation, it belongs to the class 4 mutations that are often found in CBAVD patients. It is a missense mutation in which the amino acid arginine has been replaced by histidine in the 117th position. This mutation leads to a lower chloride ion conductivity.
Polymorphisms
In addition to mutations, polymorphisms are also frequently found in CAVD and CF patients. The polymorphisms belong to the class 5 mutations. It has been found that there are differences in the number of thymidines at the end of the 3 'splice before exon 9. A distinction is made between T5, T7 and T9. The less thymidine is present, the more the splicing efficiency for exon 9 drops. As a result, the CFTR proteins are not folded correctly and are therefore broken down. This is also referred to as partial penetrance, ie penetrating power. The partial penetrance can be explained by a genetic factor, the (TG) m polymorphism. This is because the efficiency of splicing at exon 9 depends, among other things, on the TG repeats. The more TG repeats there are in intron 8, the more inefficient the splicing.
literature
- M. Claustres: Molecular pathology of the CFTR locus in male infertility. In: Reproductive Biomedicine Online . Volume 10, Number 1, January 2005, pp. 14-41, ISSN 1472-6483 . PMID 15705292 . (Review).
- H. Cuppens, JJ Cassiman: CFTR mutations and polymorphisms in male infertility. In: International journal of andrology. Volume 27, Number 5, October 2004, pp. 251-256, ISSN 0105-6263 . doi : 10.1111 / j.1365-2605.2004.00485.x . PMID 15379964 . (Review).
- G. Phillipson: Cystic fibrosis and reproduction. In: Reproduction, fertility, and development. Volume 10, Number 1, 1998, pp. 113-119, ISSN 1031-3613 . PMID 9727601 . (Review).
- WB Guggino, BA Stanton: New insights into cystic fibrosis: molecular switches that regulate CFTR. In: Nature reviews. Molecular cell biology. Volume 7, Number 6, June 2006, pp. 426-436, ISSN 1471-0072 . doi : 10.1038 / nrm1949 . PMID 16723978 .