Genetics and Proteins

CFTR gene and CFTR protein

The CFTR gene was identified in 1989, and comprises 27 coding exons, spanning over 250 kb on chromosome 7. The transcript is 6.5 kb [Riordan et al., 1989]. The protein encoded by the CFTR gene is named CFTR and comprises 1480 amino acids. It is a chloride channel expressed at the apical membrane of many epithelial cells and there are direct relationships that are demonstrable between its expression in organs and cystic fibrosis pathology. It allows passive diffusion of chloride and bicarbonate ions down their electrochemical gradient and has many other regulatory roles, including inhibition of sodium transport through the epithelial sodium channel. The CFTR protein is a member of the ATP-binding cassette (ABC) protein superfamily, and is characterised by 2 transmembrane domains which anchor the protein in the plasma membrane. Each is conjoined to a nucleotide binding domain (NBD) which binds and hydrolyses ATP. Unique to CFTR is a regulatory domain which has to be phosphorylated by the cAMP-dependent protein kinase (PKA) for channel gating by ATP [Figure] [Itani et al., 2011; Kirk and Wang, 2011; Hwang and Kirk, 2013].

Figure shows conformational changes in the CFTR Cl− channel during channel gating.

Figure above shows conformational changes in the CFTR Cl channel during channel gating. The simplified model shows a CFTR Cl channel under quiescent (left) and activated (right) conditions.
Kay: ADP, adenosine diphosphate; ATP, adenosine triphosphate; CFTR, cystic fibrosis transmembrane regulator; MSD, membrane-spanning domain; NBD, nucleotide-binding domain; P, phosphorylation of RegD; Pi, inorganic phosphate; PKA, cAMP-dependent protein kinase; PPase, protein phosphatase; RegD, regulatory domain.
In and Out denote the intracellular and extracellular sides of the membrane, respectively [Chen J-H, et al., 2006; Vallieres & Elborn 2014].