Cystic fibrosis transmembrane conductance regulator

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.
Available structures: 1xmi, 1xmj, 2bbo, 2bbs, 2bbt
Identifiers
Symbols	CFTR; ABC35; ABCC7; CF; CFTR/MRP; MRP7; TNR-CFTR; dJ760C5.1
External IDs	OMIM: 602421 MGI: 88388 HomoloGene: 55465
Gene ontology Molecular function: • nucleotide binding • ion channel activity • ATP-binding and phosphorylation-dependent chloride channel activity • chloride channel activity • channel-conductance-controlling ATPase activity • protein binding • ATP binding • ATPase activity • PDZ domain binding • chloride ion binding • ATPase activity, coupled to transmembrane movement of substances Cellular component: • membrane • integral to membrane • basolateral plasma membrane • apical plasma membrane Biological process: • ion transport • respiratory gaseous exchange
Orthologs
	Human	Mouse
Entrez	1080	12638
Ensembl	ENSG00000001626	ENSMUSG00000041301
Uniprot	P13569	Q8CC89
Refseq	NM_000492 (mRNA) NP_000483 (protein)	NM_021050 (mRNA) NP_066388 (protein)
Location	Chr 7: 116.91 - 117.1 Mb	Chr 6: 18.12 - 18.27 Mb
Pubmed search	[1]	[2]

Cystic fibrosis transmembrane conductance regulator (CFTR) is an ABC transporter-class protein and ion channel that transports chloride 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.

Structure

The gene that encodes for CFTR is found on the human chromosome 7, on the long arm at position q31.2. It contains about 170,000 base pairs. The encoded 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 proteins. The ion channel only opens when its R-domain has been phosphorylated by PKA and ATP is bound at the NBDs.^[1] The carboxyl terminal of the protein is anchored to the cytoskeleton by a PDZ-interacting domain.^[2]

Function

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 ions (with a negative charge) out of an epithelial cell to the covering mucus. This results in an electrical gradient being formed and in the movement of (positively charged) sodium ions in the same direction as the chloride via a paracellular pathway. Due to this movement, the water potential of the mucus is reduced, resulting in the movement of water here by osmosis and a more fluid mucus.

In sweat glands, CFTR defects result in reduced transport of sodium chloride 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 ( see The Relevance of Sweat Testing for the Diagnosis of Cystic Fibrosis in the Genomic Era).

Mutations

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, ΔF508 results from a deletion (Δ) of three nucleotides which results in a loss of the amino acid phenylalanine (F) at the 508th (508) 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..^[3]

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.^{[citation needed]}

List of common mutations

The most common mutations in a Caucasian population are: ^[4]

• ΔF508
• G542X
• G551D
• N1303K
• W1282X

Interactions

Cystic fibrosis transmembrane conductance regulator has been shown to interact with Sodium-hydrogen exchange regulatory cofactor 2,^[5] GOPC,^[6][7] SNAP23,^[8] Sodium-hydrogen antiporter 3 regulator 1,^{[9][10][11][7][12][13][14]} STX1A,^[15][8] SLC4A8,^[14] PRKCE,^[16] DNAJC5^[17] and PDZK1.^[7][18]

References

Further reading

External links

• 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)

v • d • e PDB Gallery 1xmi: Crystal structure of human F508A NBD1 domain with ATP   1xmj: Crystal structure of human deltaF508 human NBD1 domain with ATP   2bbo: Human NBD1 with Phe508   2bbs: Human deltaF508 NBD1 with three solubilizing mutations   2bbt: Human deltaF508 NBD1 with two solublizing mutations.