Proteomics

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Folding correctors can retore CFTR post-translational folding landscape by allosteric domain-domain coupling

ABSTRACT: Numerous missense mutations cause misfolding and premature degradation of ATP-binding cassette (ABC)-transporters-transporters, accounting for several human conformational diseases with poorly under-stood molecular mechanisms. Recent breakthroughs in small molecule combination therapy led transformative improvement of patients’ outlook in cystic fibrosis (CF), caused by several mutations, including the most prevalent deletion of the F508 (delF508) in the cystic fibrosis transmembrane conductance regulator (CFTR) chloride channel, a member of the large ABC-transporter superfamily. By relying on hydrogen deuterium exchange mass spectrometry (HDX-MS), molecular dynamic simulations and biochemical techniques, we demonstrate that the recently approved pharmacophores (VX-445 [elexacaftor] and/or VX-809 [lumacaftor]) mechanism of action relies on a complex network of dynamic inter-domain allosteric interactions to restore the post-translational coupled domain folding and the final fold stability of mutant CFTRs.

INSTRUMENT(S): LTQ Orbitrap, Orbitrap Eclipse

ORGANISM(S): Homo Sapiens (human)

DISEASE(S): Cystic Fibrosis

SUBMITTER: Naoto Soya  

LAB HEAD: Gergely L. Lukacs

PROVIDER: PXD042481 | Pride | 2024-01-26

REPOSITORIES: Pride

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Dataset's files

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Action DRS
ABCC6_NBD1-WT_MSMS.msf Msf
ABCC6_NBD1_F713G.zip Other
ABCC6_NBD1_F713G_MSMS.msf Msf
ABCC6_NBD1_WT.zip Other
CFTR_NBD1_6SS-WT_Nep2-Pep_digestion.zip Other
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Folding correctors can restore CFTR posttranslational folding landscape by allosteric domain-domain coupling.

Soya Naoto N   Xu Haijin H   Roldan Ariel A   Yang Zhengrong Z   Ye Haoxin H   Jiang Fan F   Premchandar Aiswarya A   Veit Guido G   Cole Susan P C SPC   Kappes John J   Hegedüs Tamás T   Lukacs Gergely L GL  

Nature communications 20231027 1

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 facilitat  ...[more]

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