Chloride directly interacts with the DDX3X helicase core, impairing its ATPase and RNA helicase activities and disrupting its condensation propensity in vitro.
Chloride binding regulates DDX3X functions, providing insights into the molecular pathophysiology of a neurodevelopmental disorder-linked mutation.
Cl − homeostasis is pivotal during neurodevelopment and in multiple processes in mature neurons, and its disruption is implicated in several neurodevelopmental disorders. Here, we investigated the role of Cl − in regulating DDX3X, an ATP-dependent RNA helicase that is associated with a neurodevelopmental disorder and is involved in stress granule assembly through biomolecular condensation. Cl − directly interacted with the DDX3X helicase core in the RNA binding region. This interaction impaired both ATPase and RNA helicase activities at physiologically relevant concentrations in a manner similar to inorganic phosphate and disrupted its condensation propensity in vitro. In neuroblastoma cells, Cl − efflux induced the formation of large, persistent DDX3X-containing stress granules. Furthermore, the R326H mutation, which is linked to a severe neurodevelopmental disorder, altered the chemical environment of the Cl − -binding site and impaired Cl − -sensitive functions. Together, our findings demonstrate that Cl − binding regulates DDX3X functions and provide insights into the molecular pathophysiology of a neurodevelopmental disorder–linked mutation in DDX3X.
Silva et al. (Tue,) conducted a other in Neurodevelopmental disorder. Chloride (Cl-) binding and efflux was evaluated on DDX3X ATPase and RNA helicase activities and stress granule formation. Chloride directly interacts with the DDX3X helicase core, impairing its ATPase and RNA helicase activities and disrupting its condensation propensity in vitro.