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

ABSTRACT: Crosslinking MS of SR6-GEF1 construct of Human Trio. BS3 crosslinking of wild-type and three point mutants implicated in neurodevelopmental disorders (E883D, R1078Q, D1368V). Data acquired using FAIMS ion mobility source with each sample acquired at 4 different CVs (-40, -50, -60, -70V).

INSTRUMENT(S): Orbitrap Exploris 480

ORGANISM(S): Homo Sapiens (ncbitaxon:9606)

SUBMITTER: Anthony Koleske

PROVIDER: MSV000089621 | MassIVE | Wed Jun 08 14:44:00 BST 2022

REPOSITORIES: MassIVE

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Autoinhibition of the GEF activity of cytoskeletal regulatory protein Trio is disrupted in neurodevelopmental disorder-related genetic variants.

Bircher Josie E JE Corcoran Ellen E EE Lam TuKiet T TT Trnka Michael J MJ Koleske Anthony J AJ

The Journal of biological chemistry 20220810 9

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. Function-damaging variants in the TRIO gene are known to be enriched in individuals with neurodevelopmental disorders (NDDs). Disease variants in the GEF1 domain or the nine adjacent spectrin repeats (SRs) are enriched in NDDs, suggesting that dysregulated GEF1 activit ...[more]

PMID: 35963430

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

Project description: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.

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