Folding correctors can restore CFTR posttranslational folding landscape by allosteric domain–domain coupling

Naoto Soya, Haijin Xu, Ariel Roldan, Zhengrong Yang, Haoxin Ye, Fan Jiang, Aiswarya Premchandar, Guido Veit, Susan P. C. Cole, John Kappes, Tamás Hegedüs and Gergely L. Lukacs ()
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Naoto Soya: McGill University
Haijin Xu: McGill University
Ariel Roldan: McGill University
Zhengrong Yang: University of Alabama School of Medicine
Haoxin Ye: McGill University
Fan Jiang: University of Alabama School of Medicine
Aiswarya Premchandar: McGill University
Guido Veit: McGill University
Susan P. C. Cole: Queen’s University Cancer Research Institute
John Kappes: University of Alabama School of Medicine
Tamás Hegedüs: Semmelweis University
Gergely L. Lukacs: McGill University

Nature Communications, 2023, vol. 14, issue 1, 1-21

Abstract: Abstract The folding/misfolding and pharmacological rescue of multidomain ATP-binding cassette (ABC) C-subfamily transporters, essential for organismal health, remain incompletely understood. The ABCC transporters core consists of two nucleotide binding domains (NBD1,2) and transmembrane domains (TMD1,2). Using molecular dynamic simulations, biochemical and hydrogen deuterium exchange approaches, we show that the mutational uncoupling or stabilization of NBD1-TMD1/2 interfaces can compromise or facilitate the CFTR(ABCC7)-, MRP1(ABCC1)-, and ABCC6-transporters posttranslational coupled domain-folding in the endoplasmic reticulum. Allosteric or orthosteric binding of VX-809 and/or VX-445 folding correctors to TMD1/2 can rescue kinetically trapped CFTR posttranslational folding intermediates of cystic fibrosis (CF) mutants of NBD1 or TMD1 by global rewiring inter-domain allosteric-networks. We propose that dynamic allosteric domain-domain communications not only regulate ABCC-transporters function but are indispensable to tune the folding landscape of their posttranslational intermediates. These allosteric networks can be compromised by CF-mutations, and reinstated by correctors, offering a framework for mechanistic understanding of ABCC-transporters (mis)folding.

Date: 2023
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DOI: 10.1038/s41467-023-42586-8

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