PXD055156-1

PXD055156 is an original dataset announced via ProteomeXchange.

Title	Proteostasis Landscapes of Selective versus Poorly Responsive CFTR Variants Reveals Structural Vulnerabilities to Correction
Description	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.
HostingRepository	PRIDE
AnnounceDate	2025-10-27
AnnouncementXML	Submission_2025-10-26_19:55:05.912.xml
DigitalObjectIdentifier	https://dx.doi.org/10.6019/PXD055156
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Supported dataset by repository
PrimarySubmitter	Minsoo Kim
SpeciesList	scientific name: Homo sapiens (Human); NCBI TaxID: NEWT:9606;
ModificationList	TMT6plex-126 reporter+balance reagent acylated residue; iodoacetamide derivatized residue
Instrument	Orbitrap Fusion

Revision	Datetime	Status	ChangeLog Entry
0	2024-08-23 15:12:59	ID requested
⏵ 1	2025-10-26 19:55:07	announced

McDonald EF, Kim M, Olson JA, Meiler J, Plate L, Proteostasis landscapes of cystic fibrosis variants reveal drug response vulnerability. Proc Natl Acad Sci U S A, 122(17):e2418407122(2025) [pubmed]

10.6019/PXD055156;

10.1073/pnas.2418407122;

submitter keyword: proteomics, CF, CFTR, interactomics,AP-MS, VX-445

Lars Plate
contact affiliation	Departments of Chemistry, Biological Sciences, Pathology, Microbiology and Immunology, Vanderbilt University
contact email	lars.plate@vanderbilt.edu
lab head
Minsoo Kim
contact affiliation	Vanderbilt University
contact email	min.soo.kim.1@vanderbilt.edu
dataset submitter

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PRIDE project URI

• PRIDE
  1. PXD055156
     1. Label: PRIDE project
     2. Name: Proteostasis Landscapes of Selective versus Poorly Responsive CFTR Variants Reveals Structural Vulnerabilities to Correction