Restoration of the GTPase activity and cellular interactions of Gα_o mutants by Zn²⁺ in GNAO1 encephalopathy models.

ABSTRACT: De novo point mutations in GNAO1, gene encoding the major neuronal G protein Gα_o, have recently emerged in patients with pediatric encephalopathy having motor, developmental, and epileptic dysfunctions. Half of clinical cases affect codons Gly²⁰³, Arg²⁰⁹, or Glu²⁴⁶; we show that these mutations accelerate GTP uptake and inactivate GTP hydrolysis through displacement Gln²⁰⁵ critical for GTP hydrolysis, resulting in constitutive GTP binding by Gα_o. However, the mutants fail to adopt the activated conformation and display aberrant interactions with signaling partners. Through high-throughput screening of approved drugs, we identify zinc pyrithione and Zn²⁺ as agents restoring active conformation, GTPase activi

SUBMITTER: Larasati YA 

PROVIDER: S-EPMC9544338 | biostudies-literature | 2022 Oct

REPOSITORIES: biostudies-literature