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PXD034393

PXD034393 is an original dataset announced via ProteomeXchange.

Dataset Summary
TitleAutoinhibition of Trio guanine nucleotide exchange factor activity for Rac1 by its spectrin repeats is disrupted by neurodevelopmental disorder-related genetic variants.
DescriptionFunction-damaging variants in the TRIO gene are enriched in individuals with neurodevelopmental disorders (NDDs). TRIO encodes a cytoskeletal regulatory protein with three catalytic domains – two guanine exchange factor (GEF) domains, GEF1 and GEF2, and a kinase domain, as well as several accessory domains that have not been extensively studied. Disease variants in the GEF1 domain or the nine adjacent spectrin repeats (SRs) are enriched in NDDs, suggesting that dysregulated GEF1 activity is linked to these disorders. We provide evidence here that the Trio SRs interact intramolecularly with the GEF1 domain to inhibit its activity. We demonstrate that SRs 6-9 decrease GEF1 catalytic activity both in vitro and in cells and show that NDD-associated variants in the SR8 and GEF1 domains relieve this autoinhibitory constraint. Our results from chemical cross-linking and BioLayer Interferometry indicate that the SRs primarily contact the PH region of the GEF1 domain, reducing GEF1 binding to Rac1. Together, our findings reveal a key regulatory mechanism that is commonly disrupted in multiple NDDs and may offer a new target for therapeutic intervention for TRIO-associated NDDs.
HostingRepositoryPRIDE
AnnounceDate2023-11-14
AnnouncementXMLSubmission_2023-11-14_08:28:37.332.xml
DigitalObjectIdentifier
ReviewLevelPeer-reviewed dataset
DatasetOriginOriginal dataset
RepositorySupportUnsupported dataset by repository
PrimarySubmitterTuKiet Lam
SpeciesList scientific name: Drosophila melanogaster (Fruit fly); NCBI TaxID: 7227;
ModificationListS-carboxamidoethyl-L-cysteine; phosphorylated residue; monohydroxylated residue; deamidated residue; iodoacetamide derivatized residue
InstrumentQ Exactive Plus
Dataset History
RevisionDatetimeStatusChangeLog Entry
02022-06-07 01:14:06ID requested
12022-10-13 11:09:36announced
22023-11-14 08:28:38announced2023-11-14: Updated project metadata.
Publication List
Bircher JE, Corcoran EE, Lam TT, Trnka MJ, Koleske AJ, Autoinhibition of the GEF activity of cytoskeletal regulatory protein Trio is disrupted in neurodevelopmental disorder-related genetic variants. J Biol Chem, 298(9):102361(2022) [pubmed]
Keyword List
submitter keyword: limited proteolysis, neurodevelopment disorders,TRIO gene, crosslinking
Contact List
TuKiet Lam
contact affiliationKeck MS & Proteomics Resource at Yale University Dept. MBB, Yale University
contact emailtukiet.lam@yale.edu
lab head
TuKiet Lam
contact affiliationYale University
contact emailtukiet.lam@yale.edu
dataset submitter
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Dataset FTP location
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