Functional and structural deficiencies of Gemin5 variants associated with neurological disorders
Entidad
UAM. Departamento de Biología MolecularEditor
EMBOpressFecha de edición
2022-04-07Cita
10.26508/lsa.202201403
Life Science Alliance 5.7 (2022): e202201403
ISSN
2575-1077DOI
10.26508/lsa.202201403Proyecto
Gobierno de España. BFU2017-84492-R; Gobierno de España. PID2020-115096RB-I00; Comunidad de Madrid. 2017/BMD-3770/RyPSEVersión del editor
https://doi.org/10.26508/lsa.202201403Materias
Gemin5; Neurological disorders; Survival of motor neurons (SMN); RNA-binding proteins (RBPs); Biología y Biomedicina / BiologíaDerechos
© 2022 Francisco-Velilla et al.Resumen
Dysfunction of RNA-binding proteins is often linked to a wide range of human disease, particularly with neurological conditions. Gemin5 is a member of the survival of the motor neurons (SMN) complex, a ribosome-binding protein and a translation reprogramming factor. Recently, pathogenic mutations in Gemin5 have been reported, but the functional consequences of these variants remain elusive. Here, we report functional and structural deficiencies associated with compound heterozygosity variants within the Gemin5 gene found in patients with neurodevelopmental disorders. These clinical variants are located in key domains of Gemin5, the tetratricopeptide repeat (TPR)-like dimerization module and the noncanonical RNA-binding site 1 (RBS1). We show that the TPR-like variants disrupt protein dimerization, whereas the RBS1 variant confers protein instability. All mutants are defective in the interaction with protein networks involved in translation and RNA-driven pathways. Importantly, the TPR-like variants fail to associate with native ribosomes, hampering its involvement in translation control and establishing a functional difference with the wild-type protein. Our study provides insights into the molecular basis of disease associated with malfunction of the Gemin5 protein
Lista de ficheros
Google Scholar:Francisco Velilla, María del Rosario
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Embarc Buh, Azman
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del Caño-Ochoa, Francisco
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Abellan, Salvador
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Vilar, Marçal
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Alvarez, Sara
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Fernández Jaén, Alberto
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Kour, Sukhleen
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Rajan, Deepa S.
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Pandey, Udai Bhan
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Ramón Maiques, Santiago
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Martínez Salas, Encarnación
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