Molecular annotation of G protein variants in a neurological disorder

Heterotrimeric G proteins transduce extracellular chemical messages to generate appropriate intracellular responses. Point mutations in GNAO1, encoding the G protein αo subunit, have been implicated in a pathogenic condition characterized by seizures, movement disorders, intellectual disability, and developmental delay (GNAO1 disorder). However, the effects of these mutations on G protein structure and function are unclear. Here, we report the effects of 55 mutations on Gαo conformation, thermostability, nucleotide binding, and hydrolysis, as well as interaction with Gβγ subunits, receptors, and effectors. Our effort reveals four functionally distinct groups of mutants, including one group that sequesters receptors and another that sequesters Gβγ, both acting in a genetically dominant manner. These findings provide a more comprehensive understanding of disease-relevant mutations and reveal that GNAO1 disorder is likely composed of multiple mechanistically distinct disorders that will likely require multiple therapeutic strategies. [Display omitted] •Mutations in G proteins are linked to epilepsy and movement disorders•Many occur in regions that have no obvious role in G protein function•Mutations have distinct effects on signaling, catalysis, protein stability, and interactions•At least four mechanistically distinct groups will likely require distinct treatments In recent years, de novo mutations in cell signaling proteins have been linked to neurodevelopmental disorders. Knight et al. examine dozens of unique mutations in Gαo, representing the most abundant G protein in the brain, and determine that they fall into at least four mechanistically distinct groups.