Molecular annotation of G protein variants in a neurological disorder
Kevin M. Knight, Elizabeth G. Obarow, Wenyuan Wei, Sepehr Mani, Maria I. Esteller, Meng Cui, Ning Ma, Sarah A. Martin, Emily Brinson, Natalie Hewitt, Gaby M. Soden, Diomedes E. Logothetis, Nagarajan Vaidehi, Henrik Dohlman
Abstract
Heterotrimeric G proteins transduce extracellular chemical messages to generate appropriate intracellular responses. Point mutations in GNAO1 , encoding the G protein α o 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 Gα o 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.