Link to bioRxiv paper:
http://biorxiv.org/cgi/content/short/2023.03.27.534359v1?rss=1

Authors: Solis, G. P., Koval, A., Valnohova, J., Savitsky, M., Katanaev, V. L.

Abstract:
GNAO1 mutated in pediatric encephalopathies encodes the major neuronal G-protein G alpha o. Of greater than 40 pathogenic mutations, most are single amino acid substitutions spreading across G alpha o sequence. We perform extensive characterization of G alpha o mutants showing abnormal GTP uptake and hydrolysis, and deficiencies to bind G beta gamma and RGS19. Plasma membrane localization of G alpha o is decreased for a subset of mutations that leads to epileptic manifestations. Pathogenic mutants massively gain interaction with Ric8A/B proteins, delocalizing them from cytoplasm to Golgi. Being general G alpha-subunit chaperones and binding multiple other proteins, Ric8A/B likely mediate the disease dominance when engaging in neomorphic interactions with pathogenic G alpha o. As the strength of G alpha o-Ric8B interactions correlates with disease severity, our study further identifies an efficient biomarker and predictor for clinical manifestations in GNAO1 encephalopathies.

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