Structure basis of CFTR folding, function and pharmacology (2024)

Hwang, T.-C., Braakman, I., van der Sluijs, P., & Callebaut, I. (2023). Structure basis of CFTR folding, function and pharmacology. Journal of Cystic Fibrosis, 22(S1), S5-S11. https://doi.org/10.1016/j.jcf.2022.09.010

Hwang, Tzyh-Chang ; Braakman, Ineke ; van der Sluijs, Peter et al. / Structure basis of CFTR folding, function and pharmacology. In: Journal of Cystic Fibrosis. 2023 ; Vol. 22, No. S1. pp. S5-S11.

@article{b11af749542547aea288481b1c0e41da,

title = "Structure basis of CFTR folding, function and pharmacology",

abstract = "The root cause of cystic fibrosis (CF), the most common life-shortening genetic disease in the Caucasian population, is the loss of function of the CFTR protein, which serves as a phosphorylation-activated, ATP-gated anion channel in numerous epithelia-lining tissues. In the past decade, high-throughput drug screening has made a significant stride in developing highly effective CFTR modulators for the treatment of CF. Meanwhile, structural-biology studies have succeeded in solving the high-resolution three-dimensional (3D) structure of CFTR in different conformations. Here, we provide a brief overview of some striking features of CFTR folding, function and pharmacology, in light of its specific structural features within the ABC-transporter superfamily. A particular focus is given to CFTR's first nucleotide-binding domain (NBD1), because folding of NBD1 constitutes a bottleneck in the CFTR protein biogenesis pathway, and ATP binding to this domain plays a unique role in the functional stability of CFTR. Unraveling the molecular basis of CFTR folding, function, and pharmacology would inspire the development of next-generation mutation-specific CFTR modulators.",

keywords = "ABC transporter, CFTR, corrector, modulator, potentiator",

author = "Tzyh-Chang Hwang and Ineke Braakman and {van der Sluijs}, Peter and Isabelle Callebaut",

note = "Funding Information: The authors acknowledge funding from i) NIH (NIHR01:DK55835); the Cystic Fibrosis Foundation (grant Hwang19G0), Ministry of Science and Technology, Taiwan (109–2320-B-010–049-MY2), and Veterans General Hospitals and University System of Taiwan Joint Research Program, Taiwan (VGHUST111-G6–10–1) (to TCH), ii) Cystic Fibrosis Foundation (CFF; BRAAKM14XX0, BRAAKM18G0), the Dutch Research Council (NWO; 731.016.403), the Netherlands Cystic Fibrosis Foundation (HIT-CF 2.0), and Stichting Zeldzame Ziekte Fonds via Stichting Muco & Friends (to IB/PvdS), iii) the French association Vaincre La Mucoviscidose (to IC). Funding Information: The authors acknowledge funding from i) NIH (NIHR01:DK55835); the Cystic Fibrosis Foundation (grant Hwang19G0), Ministry of Science and Technology, Taiwan (109–2320-B-010–049-MY2), and Veterans General Hospitals and University System of Taiwan Joint Research Program, Taiwan (VGHUST111-G6–10–1) (to TCH), ii) Cystic Fibrosis Foundation (CFF; BRAAKM14XX0, BRAAKM18G0), the Dutch Research Council (NWO; 731.016.403), the Netherlands Cystic Fibrosis Foundation (HIT-CF 2.0), and Stichting Zeldzame Ziekte Fonds via Stichting Muco & Friends (to IB/PvdS), iii) the French association Vaincre La Mucoviscidose (to IC). This paper is part of a supplement supported by the European Cystic Fibrosis Society (ECFS). Publisher Copyright: {\textcopyright} 2022",

year = "2023",

month = mar,

doi = "10.1016/j.jcf.2022.09.010",

language = "English",

volume = "22",

pages = "S5--S11",

journal = "Journal of Cystic Fibrosis",

issn = "1569-1993",

publisher = "Elsevier bedrijfsinformatie b.v.",

number = "S1",

}

Hwang, T-C, Braakman, I, van der Sluijs, P & Callebaut, I 2023, 'Structure basis of CFTR folding, function and pharmacology', Journal of Cystic Fibrosis, vol. 22, no. S1, pp. S5-S11. https://doi.org/10.1016/j.jcf.2022.09.010

Structure basis of CFTR folding, function and pharmacology. / Hwang, Tzyh-Chang; Braakman, Ineke; van der Sluijs, Peter et al.
In: Journal of Cystic Fibrosis, Vol. 22, No. S1, 03.2023, p. S5-S11.

Research output: Contribution to journal › Article › Academic › peer-review

TY - JOUR

T1 - Structure basis of CFTR folding, function and pharmacology

AU - Hwang, Tzyh-Chang

AU - Braakman, Ineke

AU - van der Sluijs, Peter

AU - Callebaut, Isabelle

N1 - Funding Information:The authors acknowledge funding from i) NIH (NIHR01:DK55835); the Cystic Fibrosis Foundation (grant Hwang19G0), Ministry of Science and Technology, Taiwan (109–2320-B-010–049-MY2), and Veterans General Hospitals and University System of Taiwan Joint Research Program, Taiwan (VGHUST111-G6–10–1) (to TCH), ii) Cystic Fibrosis Foundation (CFF; BRAAKM14XX0, BRAAKM18G0), the Dutch Research Council (NWO; 731.016.403), the Netherlands Cystic Fibrosis Foundation (HIT-CF 2.0), and Stichting Zeldzame Ziekte Fonds via Stichting Muco & Friends (to IB/PvdS), iii) the French association Vaincre La Mucoviscidose (to IC).Funding Information:The authors acknowledge funding from i) NIH (NIHR01:DK55835); the Cystic Fibrosis Foundation (grant Hwang19G0), Ministry of Science and Technology, Taiwan (109–2320-B-010–049-MY2), and Veterans General Hospitals and University System of Taiwan Joint Research Program, Taiwan (VGHUST111-G6–10–1) (to TCH), ii) Cystic Fibrosis Foundation (CFF; BRAAKM14XX0, BRAAKM18G0), the Dutch Research Council (NWO; 731.016.403), the Netherlands Cystic Fibrosis Foundation (HIT-CF 2.0), and Stichting Zeldzame Ziekte Fonds via Stichting Muco & Friends (to IB/PvdS), iii) the French association Vaincre La Mucoviscidose (to IC). This paper is part of a supplement supported by the European Cystic Fibrosis Society (ECFS).Publisher Copyright:© 2022

PY - 2023/3

Y1 - 2023/3

N2 - The root cause of cystic fibrosis (CF), the most common life-shortening genetic disease in the Caucasian population, is the loss of function of the CFTR protein, which serves as a phosphorylation-activated, ATP-gated anion channel in numerous epithelia-lining tissues. In the past decade, high-throughput drug screening has made a significant stride in developing highly effective CFTR modulators for the treatment of CF. Meanwhile, structural-biology studies have succeeded in solving the high-resolution three-dimensional (3D) structure of CFTR in different conformations. Here, we provide a brief overview of some striking features of CFTR folding, function and pharmacology, in light of its specific structural features within the ABC-transporter superfamily. A particular focus is given to CFTR's first nucleotide-binding domain (NBD1), because folding of NBD1 constitutes a bottleneck in the CFTR protein biogenesis pathway, and ATP binding to this domain plays a unique role in the functional stability of CFTR. Unraveling the molecular basis of CFTR folding, function, and pharmacology would inspire the development of next-generation mutation-specific CFTR modulators.

AB - The root cause of cystic fibrosis (CF), the most common life-shortening genetic disease in the Caucasian population, is the loss of function of the CFTR protein, which serves as a phosphorylation-activated, ATP-gated anion channel in numerous epithelia-lining tissues. In the past decade, high-throughput drug screening has made a significant stride in developing highly effective CFTR modulators for the treatment of CF. Meanwhile, structural-biology studies have succeeded in solving the high-resolution three-dimensional (3D) structure of CFTR in different conformations. Here, we provide a brief overview of some striking features of CFTR folding, function and pharmacology, in light of its specific structural features within the ABC-transporter superfamily. A particular focus is given to CFTR's first nucleotide-binding domain (NBD1), because folding of NBD1 constitutes a bottleneck in the CFTR protein biogenesis pathway, and ATP binding to this domain plays a unique role in the functional stability of CFTR. Unraveling the molecular basis of CFTR folding, function, and pharmacology would inspire the development of next-generation mutation-specific CFTR modulators.

KW - ABC transporter

KW - CFTR

KW - corrector

KW - modulator

KW - potentiator

UR - http://www.scopus.com/inward/record.url?scp=85139710599&partnerID=8YFLogxK

U2 - 10.1016/j.jcf.2022.09.010

DO - 10.1016/j.jcf.2022.09.010

M3 - Article

C2 - 36216744

SN - 1569-1993

VL - 22

SP - S5-S11

JO - Journal of Cystic Fibrosis

JF - Journal of Cystic Fibrosis

IS - S1

ER -

Hwang TC, Braakman I, van der Sluijs P, Callebaut I. Structure basis of CFTR folding, function and pharmacology. Journal of Cystic Fibrosis. 2023 Mar;22(S1):S5-S11. Epub 2022 Oct 7. doi: 10.1016/j.jcf.2022.09.010