BRAG about (s)lots.

Mutations in IQSEC2/BRAG1 cause intellectual dysfunction by impairing ARF-GEF activity and long-term depression. In this issue, Bai et al. (https://doi.org/10.1083/jcb.202307117) discover how constitutive ARF-GEF activity is regulated by a closed conformation which opens in the presence of Ca2+. Two known pathogenic mutations cause "leaky" autoinhibition with reduced synaptic dynamic range and impaired cognitive performance.