Autoinhibition of Trio guanine nucleotide exchange factor activity for Rac1 by its spectrin repeats is disrupted by neurodevelopmental disorder-related genetic variants.

ABSTRACT: Function-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.

INSTRUMENT(S): Q Exactive Plus

ORGANISM(S): Drosophila Melanogaster (fruit Fly)

SUBMITTER: TuKiet Lam  

LAB HEAD: TuKiet Lam

PROVIDER: PXD034393 | Pride | 2022-10-13

REPOSITORIES: Pride