#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 lung disease with chronic Pseudomonas infection, pancreatic insufficiency, meconium ileus, and elevated sweat chloride above 60 mmol/L diagnostic hallmark. More than 2000 mutations including F508del, G551D, R117H impair trafficking, gating or conductance. Therapeutic correctors and potentiators target CFTR directly. Na+/K+ ATPase generates electrochemical gradient consumed by secondary transporters, V-ATPase acidifies lysosomes, ABCB1 effluxes xenobiotics, none cause hallmark multisystem chloride transport defect seen in cystic fibrosis. Such detailed mechanistic insight is frequently examined in competitive tests including NEET, CUET, CSIR-NET and GATE where transporter classification, energetics and disease linkage are integrated into problem-solving questions.

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. Additionally R domain phosphorylation by protein kinase A is required to permit NBD dimerization and opening. Thus transport is not solute-coupled uphill pumping but gated diffusion of Cl- and HCO3-, regulating airway surface liquid volume. This unique adaptation explains why potentiators like ivacaftor increase open probability and correctors assist folding, strategies distinct from inhibitors targeting classical ABC efflux pumps that expel hydrophobic drugs. Such detailed mechanistic insight is frequently examined in competitive tests including NEET, CUET, CSIR-NET and GATE where transporter classification, energetics and disease linkage are integrated into problem-solving questions.

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+/calmodulin kinase and Src kinases provide modulatory phosphorylation but PKA is obligatory; non-phosphorylated CFTR remains closed even with ATP present. Dephosphorylation by PP2A and PP2C closes channel. Disease variants lacking PKA sites or with R domain deletions show reduced open probability. Potentiator ivacaftor enhances gating after phosphorylation, illustrating therapeutic relevance of understanding kinase regulation of this atypical ABC channel in epithelial fluid secretion and electrolyte homeostasis. Such detailed mechanistic insight is frequently examined in competitive tests including NEET, CUET, CSIR-NET and GATE where transporter classification, energetics and disease linkage are integrated into problem-solving questions.

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 PKA phosphorylation sites controlling gating. Unlike typical ABC exporter that alternates access to pump substrates, CFTR functions as low conductance chloride channel allowing passive efflux of Cl- and HCO3- down electrochemical gradient when phosphorylated R domain permits NBD dimerization and ATP binding opens pore. Most common mutation deletion Phe508 in NBD1 impairs folding trafficking degraded by ER quality control. Potentiators ivacaftor increase open probability, correctors lumacaftor aid folding. Hence defective protein belongs to ABC transporter family.

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

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