Structure basis of CFTR folding, function and pharmacology

Tzyh-Chang Hwang; Ineke Braakman; Peter van der Sluijs; Isabelle Callebaut

doi:10.1016/j.jcf.2022.09.010

Structure basis of CFTR folding, function and pharmacology

Tzyh-Chang Hwang, Ineke Braakman, Peter van der Sluijs, Isabelle Callebaut

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

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.

Original language	English
Pages (from-to)	S5-S11
Number of pages	7
Journal	Journal of Cystic Fibrosis
Volume	22
Issue number	S1
Early online date	7 Oct 2022
DOIs	https://doi.org/10.1016/j.jcf.2022.09.010
Publication status	Published - Mar 2023

Bibliographical 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:
© 2022

Keywords

ABC transporter
CFTR
corrector
modulator
potentiator

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10.1016/j.jcf.2022.09.010

1-s2.0-S1569199322006889Final published version, 1.05 MBLicence: Taverne

Cite this

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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",

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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

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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

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DO - 10.1016/j.jcf.2022.09.010

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SN - 1569-1993

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JO - Journal of Cystic Fibrosis

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ER -

Structure basis of CFTR folding, function and pharmacology

Abstract

Bibliographical note

Keywords

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