Cystic fibrosis (CF), the most common fatal genetic disease in the US, results from loss- of-function mutations in the CFTR (Cystic Fibrosis Transmembrane conductance Regulator) gene. As a member of the ABC (ATP Binding Cassette) transporter superfamily, CFTR harbors two nucleotide binding domains (NBD1 and NBD2) characterized by the canonical Walker A and B motifs for ATP binding/hydrolysis, and a signature sequence (i.e., LSGGQ) that plays a critical role for the formation of a head-to- tail NBD dimer upon ATP binding. CFTR is unique in that, instead of being an active transporter, CFTR is a bona fide ion channel, which utilizes ATP to drive conformational changes in its gating transitions. Our studies in the past have provided novel insights into the gating mechanism of CFTR. Contrary to the prevailing view that ATP hydrolysis is strictly coupled to the gating cycle, an idea supported by the popular model depicting that each NBD/TMD complex moves synchronously as a rigid body for ABC transporters, our data support a provocative alternative that these two domains assume autonomy on its own but are coupled energetically. [This novel mechanism turns out to explain mechanistically how an FDA-approved drug for CF treatment, VX-770 (Ivacaftor), works by exploiting this apparently imperfect coupling between TMDs and NBDs.] Our recent biophysical studies of CFTR's ion permeation pathway also establish a solid foundation for us to ask fundamental questions such as (Aim 1): What make up the pore? Where is the gate of CFTR? How does CFTR select anions versus cations? Our mechanistic studies of the gating defects manifested in the disease-associated G551D mutation not only challenge data from a major pharmaceutical company, our results also suggest an intriguing and testable hypothesis that this glycine-to-aspartate mutation in the signature sequence converts the catalysis-competent ATP binding site to an inhibitory site (Aim 2). [We believe a clear understanding of the CFTR function to a molecular detail and of how drugs such as VX-770 affect different aspects of CFTR function (Aim 3) will aid in the design of therapeutic reagents for the treatment of CF, secretory diarrhea, and other CFTR-associated diseases.]

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By incorporating biophysical, molecular biological, mathematical modeling and computational/structural biological technologies, the current proposal is aimed to achieve a molecular and structural understanding of CFTR function. The mechanistic insight gained subsequently constitutes the foundation for further investigating how disease- associated mutations cause CFTR dysfunction and how clinically used drugs promote CFTR function.

National Institute of Health (NIH)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
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Biophysics of Neural Systems Study Section (BPNS)
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Eggerman, Thomas L
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University of Missouri-Columbia
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Jih, Kang-Yang; Lin, Wen-Ying; Sohma, Yoshiro et al. (2017) CFTR potentiators: from bench to bedside. Curr Opin Pharmacol 34:98-104
Zhang, Jingyao; Hwang, Tzyh-Chang (2017) Electrostatic tuning of the pre- and post-hydrolytic open states in CFTR. J Gen Physiol 149:355-372
Yeh, Han-I; Sohma, Yoshiro; Conrath, Katja et al. (2017) A common mechanism for CFTR potentiators. J Gen Physiol 149:1105-1118
Gao, Xiaolong; Hwang, Tzyh-Chang (2016) Spatial positioning of CFTR's pore-lining residues affirms an asymmetrical contribution of transmembrane segments to the anion permeation pathway. J Gen Physiol 147:407-22
Yu, Ying-Chun; Sohma, Yoshiro; Hwang, Tzyh-Chang (2016) On the mechanism of gating defects caused by the R117H mutation in cystic fibrosis transmembrane conductance regulator. J Physiol 594:3227-44
Lin, Wen-Ying; Sohma, Yoshiro; Hwang, Tzyh-Chang (2016) Synergistic Potentiation of Cystic Fibrosis Transmembrane Conductance Regulator Gating by Two Chemically Distinct Potentiators, Ivacaftor (VX-770) and 5-Nitro-2-(3-Phenylpropylamino) Benzoate. Mol Pharmacol 90:275-85
Yeh, Han-I; Yeh, Jiunn-Tyng; Hwang, Tzyh-Chang (2015) Modulation of CFTR gating by permeant ions. J Gen Physiol 145:47-60
Zhang, Jingyao; Hwang, Tzyh-Chang (2015) The Fifth Transmembrane Segment of Cystic Fibrosis Transmembrane Conductance Regulator Contributes to Its Anion Permeation Pathway. Biochemistry 54:3839-50
Gao, Xiaolong; Hwang, Tzyh-Chang (2015) Localizing a gate in CFTR. Proc Natl Acad Sci U S A 112:2461-6
Lin, Wen-Ying; Jih, Kang-Yang; Hwang, Tzyh-Chang (2014) A single amino acid substitution in CFTR converts ATP to an inhibitory ligand. J Gen Physiol 144:311-20

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