Your browser doesn't support javascript.
loading
Autoinhibition of the GEF activity of cytoskeletal regulatory protein Trio is disrupted in neurodevelopmental disorder-related genetic variants.
Bircher, Josie E; Corcoran, Ellen E; Lam, TuKiet T; Trnka, Michael J; Koleske, Anthony J.
Afiliación
  • Bircher JE; Department of Molecular Biophysics and Biochemistry, Yale University, New Haven, Connecticut, USA.
  • Corcoran EE; Department of Molecular Biophysics and Biochemistry, Yale University, New Haven, Connecticut, USA.
  • Lam TT; Department of Molecular Biophysics and Biochemistry, Yale University, New Haven, Connecticut, USA; Keck MS & Proteomics Resource, Yale University, New Haven, Connecticut, USA.
  • Trnka MJ; Department of Pharmaceutical Chemistry, University of California at San Francisco, San Francisco, California, USA.
  • Koleske AJ; Department of Molecular Biophysics and Biochemistry, Yale University, New Haven, Connecticut, USA; Department of Neuroscience, Yale University, New Haven, Connecticut, USA. Electronic address: anthony.koleske@yale.edu.
J Biol Chem ; 298(9): 102361, 2022 09.
Article en En | MEDLINE | ID: mdl-35963430
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.
Asunto(s)
Palabras clave

Texto completo: 1 Bases de datos: MEDLINE Asunto principal: Proteínas de Unión al GTP Monoméricas / Trastornos del Neurodesarrollo Límite: Humans Idioma: En Revista: J Biol Chem Año: 2022 Tipo del documento: Article País de afiliación: Estados Unidos

Texto completo: 1 Bases de datos: MEDLINE Asunto principal: Proteínas de Unión al GTP Monoméricas / Trastornos del Neurodesarrollo Límite: Humans Idioma: En Revista: J Biol Chem Año: 2022 Tipo del documento: Article País de afiliación: Estados Unidos