ABSTRACT
CF is an autosomal recessive genetic disorder aecting many epithelium-lining organ systems such as the lung, pancreas, liver, intestine, and sweat duct (Quinton 1999). Although CF is found in all ethnicities, it is most prevalent in people of Caucasian
Contents 42.1 Introduction 627 42.2 Brief history of cystic brosis 627 42.3 CFTR 628
42.3.1 Overview 628 42.3.2 Nucleotide-binding domain: Gating mechanism 630
42.3.2.1 Structures of NBDs and NBD dimer 630 42.3.2.2 ATP-dependent gating driven by NBD dimerization 630 42.3.2.3 Hidden states during ATP-dependent gating cycle 631 42.3.2.4 Coupling between NBDs and MSDs 633 42.3.2.5 Future perspectives 633
42.3.3 Regulatory domain 634 42.3.3.1 Mechanism of CFTR regulation by the R domain 635
42.3.4 Membrane-spanning domains: Channel pore and gating motions 636 42.3.4.1 Biophysical characteristics of the CFTR channel pore 636 42.3.4.2 Molecular structure of the CFTR channel pore 636 42.3.4.3 CFTR pore blockers and vestibules 638
42.4 Molecular pathophysiology and pharmacology of CFTR 639 42.4.1 CFTR biosynthesis and membrane tracking 639 42.4.2 Mutations that lead to CF 639 42.4.3 Mechanism of CFTR dysfunction 639 42.4.4 CFTR pharmacology 640
42.5 Concluding remarks 641 Acknowledgment 641 References 641
heritage (Bobadilla et al., 2002). Humans have died from CF since thousands of years ago. European folklore from the medieval time warned “woe is the child who tastes salty from a kiss on the brow, for he is cursed, and soon must die” as if infants with a salty skin were hexed or bewitched (Quinton, 1999). Although sporadic case reports for CF-like childhood diseases can be found in the literature before 1938, the rst systematic description of CF as a clinical entity was often credited to a landmark paper by Dorothy Andersen (Andersen, 1938), who reported the clinicopathological ndings in 49 children with the characteristic brocystic changes of the pancreas and associated this pancreatic pathology with neonatal meconium ileus, and respiratory complications.
