PXD032836

PXD032836 is an original dataset announced via ProteomeXchange.

Title	Distinct proteostasis states drive pharmacologic chaperone susceptibility for Cystic Fibrosis Transmembrane Conductance Regulator misfolding mutants
Description	Pharmacological chaperones represent a class of therapeutic compounds for treating protein misfolding diseases. One of the most prominent examples is the FDA-approved pharmacological chaperone lumacaftor (VX-809), which has transformed cystic fibrosis (CF) therapy. CF is a fatal disease caused by mutations in the cystic fibrosis transmembrane conductance regulator (CFTR). VX-809 corrects folding of F508del CFTR, the most common patient mutation, yet F508del exhibits only mild VX-809 response. In contrast, rarer mutations P67L and L206W are hyper-responsive to VX-809, while G85E is non-responsive. Despite the clinical success of VX-809, the mechanistic origin for the distinct susceptibility of mutants remains unclear. Here, we use interactomics to characterize the impact of VX-809 on proteostasis interactions of P67L and L206W and compare these to F508del and G85E. We determine hyper-responsive mutations P67L and L206W exhibit decreased interactions with proteasomal, and autophagy degradation machinery compared to F508del and G85E. We then show inhibiting the proteasome attenuates P67L and L206W VX-809 response. Our data suggests a previously unidentified but required role for protein degradation in VX-809 correction. Furthermore, we present an approach for identifying proteostasis characteristics of mutant-specific therapeutic response to pharmacological chaperones.
HostingRepository	PRIDE
AnnounceDate	2022-05-04
AnnouncementXML	Submission_2022-05-04_05:31:38.423.xml
DigitalObjectIdentifier
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Unsupported dataset by repository
PrimarySubmitter	Eli McDonald
SpeciesList	scientific name: Homo sapiens (Human); NCBI TaxID: 9606;
ModificationList	TMT6plex-126 reporter+balance reagent acylated residue; monohydroxylated residue; iodoacetamide derivatized residue
Instrument	Orbitrap Exploris 480

Revision	Datetime	Status	ChangeLog Entry
0	2022-03-26 18:30:38	ID requested
⏵ 1	2022-05-04 05:31:38	announced

Dataset with its publication pending

submitter keyword: cystic fibrosis, corrector, theratype, affinity-purification mass spectrometry (AP-MS), interactomics, protein quality control, tandem mass tags

Lars Plate
contact affiliation	Vanderbilt University
contact email	lars.plate@vanderbilt.edu
lab head
Eli McDonald
contact affiliation	Vanderbilt University
contact email	eli.f.mcdonald@vanderbilt.edu
dataset submitter

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PRIDE project URI

• PRIDE
  1. PXD032836
     1. Label: PRIDE project
     2. Name: Distinct proteostasis states drive pharmacologic chaperone susceptibility for Cystic Fibrosis Transmembrane Conductance Regulator misfolding mutants