ArticleThe Journal of biological chemistry2022
Autoinhibition of the GEF activity of cytoskeletal regulatory protein Trio is disrupted in neurodevelopmental disorder-related genetic variants.
Article in The Journal of biological chemistry, 2022. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 9 papers.
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Who cites it
9 citing papers in PubMed, 18 citations in OpenAlex.
- Identification and growth features of developmental delay with macrocephaly caused by a novel TRIO variant affecting the second SH3 domain.BMC medical genomics · 2026Article
- Clinical Exome Sequencing as a Key Diagnostic Tool: A Rare de novoMolecular syndromology · 2026Article
- Trio and CRMP2 regulate axon branching and Semaphorin3A signaling.Communications biology · 2025Article
- Oligodendrocyte myelin glycoprotein impairs dendritic arbors via schizophrenia risk gene Trio.Neurobiology of disease · 2025Article
- Article
- The Rho GEF Trio functions in contact inhibition of locomotion of neural crest cells by interacting with Ptk7.Development (Cambridge, England) · 2025Article
- New Mechanisms Underlying Oncogenesis in Dbl Family Rho Guanine Nucleotide Exchange Factors.Molecular pharmacology · 2024Review
- Sec7 regulatory domains scaffold autoinhibited and active conformations.Proceedings of the National Academy of Sciences of the United States of America · 2024Article
- Pathogenic TRIO variants associated with neurodevelopmental disorders perturb the molecular regulation of TRIO and axon pathfinding in vivo.Molecular psychiatry · 2023Article
Corrections and comments
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Authors and funding
5 authors at 3 institutions in 1 country.
Funding
Abstract
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 activity is linked to these disorders. We provide evidence here that the Trio SRs interact intramolecularly with the GEF1 domain to inhibit its enzymatic 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 bio-layer interferometry indicate that the SRs primarily contact the pleckstrin homology region of the GEF1 domain, reducing GEF1 binding to the small GTPase 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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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the Socratic graph.