#CFTR

Membrane Transportation

Which ion transporter is defective in cystic fibrosis?

Cystic fibrosis is monogenic disease caused by dysfunction of chloride and bicarbonate channel CFTR, ABCC7, not by Na+/K+ ATPase primary gradient generator nor by V-type proton pump acidifying organelles nor by ABCB1 drug efflux pump. CFTR localized apically in respiratory epithelium, pancreatic ductules, sweat duct, intestinal crypts and male reproductive tract mediates cAMP-activated Cl- secretion driving fluid movement and maintaining airway surface liquid hydration and mucus viscosity. Loss-of-function reduces chloride and bicarbonate secretion, leads to thickened secretions, obstructive l

Ref: Riordan et al., Annu Rev Biochem 2008, CFTR and cystic fibrosis; Davies et al., Science 2023.

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Membrane Transportation

The ABC transporter CFTR is unique because:

CFTR ABCC7 stands as atypical member of ABC superfamily because evolution transformed an active exporter scaffold into ATP-gated ion channel. Typical ABC exporters use ATP binding and hydrolysis to drive large TMD movements translocating substrate uphill. In CFTR, transmembrane domains create chloride-selective pore allowing passive flow down electrochemical gradient when open, while nucleotide-binding domains still bind ATP and regulate gating rather than transport solute stoichiometrically. Two ATP sites: NBD1 non-canonical hydrolyzes slowly, NBD2 drives channel closure upon hydrolysis. Addi

Ref: Gadsby et al., Nature 2006, Unique CFTR channel mechanism; Hwang & Sheppard, 2009.

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Membrane Transportation

The regulatory (R) domain of CFTR is phosphorylated by:

Regulatory R domain of CFTR spanning approximately residues 590 to 850 is an intrinsically disordered segment bridging NBD1 and TMD2 containing numerous consensus PKA and PKC phosphorylation sites. Phosphorylation is central to activation. Elevated intracellular cAMP activates protein kinase A which phosphorylates serines including Ser660, Ser737, Ser795, Ser813 and Ser768, neutralizing inhibitory interactions between R domain and NBDs and between NBD1-NBD2 interface. This conformational unblocking permits ATP binding to NBDs, dimer formation, and pore opening. Protein kinase C, Ca2+/calmoduli

Ref: Hwang & Sheppard, Trends Pharmacol Sci 2009, CFTR R domain regulation; Riordan, Annu Rev Biochem 2008.

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Membrane Transportation

The CFTR protein, which is defective in cystic fibrosis, is part of which transporter family?

Cystic fibrosis most common lethal autosomal recessive disorder in Caucasian populations results from mutations in CFTR gene on chromosome 7q31.2 encoding cystic fibrosis transmembrane conductance regulator. Biochemical classification places CFTR within C subfamily of ATP binding cassette transporters ABCC7 despite functional divergence. Topology includes two membrane spanning domains each six helices forming anion selective pore, two nucleotide binding domains NBD1 and NBD2 containing Walker motifs and LSGGQ signature dimerizing upon ATP binding, and unique regulatory R domain with multiple P

Ref: Riordan et al., Science 1989, CFTR Gene Identification - ABC Transporter Family Classification.

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