Dataset Information

Proteostasis Landscapes of Selective versus Poorly Responsive CFTR Variants Reveals Structural Vulnerabilities to Correction

ABSTRACT: Cystic Fibrosis (CF) is a lethal genetic disorder caused by variants in CF transmembrane conductance regulator (CFTR). Many disease variants are treatable with corrector compounds, which enhance the folding and trafficking of CFTR. However, correctors fail to elicit a response for every CFTR variant. Approximately 3% of persons with CF harbor poorly responsive CFTR variants. Here, we reveal that a group of poorly responsive variants overlap with selectively responsive variants in a critical domain interface (nucleotide-binding domain 1/intracellular loop 4 – NBD1/ICL4). Affinity purification mass spectrometry proteomics was used to profile the protein homeostasis (proteostasis) changes of CFTR variants during corrector treatment to assess modulated interactions with protein folding and maturation pathways. Responsive variant interactions converged on similar proteostasis pathways during correction. In contrast, poorly responsive variants subtly diverged, revealing a partial restoration of protein quality control surveillance and a capacity to correct some mutations. Computational structural modeling showed that corrector VX-445 failed to confer enough NBD1 stability to poorly responsive variants. NBD1 secondary stabilizing mutations rescued poorly responsive variants, revealing structural vulnerabilities in NBD1 required for treating poor responders. Our study provides a framework for discerning the underlying protein quality control and structural defects of CFTR variants not reached with existing drugs. These insights can help expand therapeutics to all susceptible CFTR variants to enhance personalized medicine efforts.

INSTRUMENT(S):

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Cell Culture

SUBMITTER: Minsoo Kim

LAB HEAD: Lars Plate

PROVIDER: PXD055156 | Pride | 2025-10-27

REPOSITORIES: Pride

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			Action	DRS
	20220722_EFM_1839_CFTR_16plex_0C_1.raw	Raw
	20220722_EFM_1839_CFTR_16plex_100C_7.raw	Raw
	20220722_EFM_1839_CFTR_16plex_10C_2.raw	Raw
	20220722_EFM_1839_CFTR_16plex_20C_3.raw	Raw
	20220722_EFM_1839_CFTR_16plex_40C_4.raw	Raw

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Publications

Proteostasis landscapes of cystic fibrosis variants reveal drug response vulnerability.

McDonald Eli Fritz EF Kim Minsoo M Olson John A JA Meiler Jens J Plate Lars L

Proceedings of the National Academy of Sciences of the United States of America 20250422 17

Cystic fibrosis (CF) is a lethal genetic disorder caused by variants in CF transmembrane conductance regulator (CFTR). Many variants are treatable with correctors, which enhance the folding and trafficking of CFTR. However, approximately 3% of persons with CF harbor poorly responsive variants. Here, we used affinity purification mass spectrometry proteomics to profile the protein homeostasis (proteostasis) changes of CFTR variants during correction to assess modulated interactions with protein f ...[more]

PMID: 40261935

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