A new structure of the guanine nucleotide exchange factor, Rab3GAP, offers insight into its activation of Rab18 GTPase and many essential cellular functions.
In a January 2025 publication in Nature Communications, Fairlie, Nguyen and colleagues discuss their high-resolution structure of the Rab3GAP catalytic core. One crucial observation lies in the elusive interaction of the two Rab3GAP subunits, which are both required for Rab3GTPase activation.
The 3.37 Å structure (PDB: 8VYB) shows the two Rab3GAP subunits nestled together with the N-terminal domain of Rab3GAP2 bound to Rab3GAP1 via “an extensive interface.” Electron micrographs from HRMEM demonstrate the binding of two subunits, and the resultant data from our Titan Krios supported the structure determination.
This discovery helps broaden our understanding of the activation of an essential enzyme as well as the pathophysiology of genetic diseases. Researchers found that known mutations for Warburg Micro Syndrome, a rare and debilitating genetic disorder, do not impact the overall structure of Rab3GAP but instead likely alter the binding pocket of crucial substrates, like Rab18.
This publication comes as a collaborative effort between the Burke Lab at the University of Victoria and the Yip Lab at the University of British Columbia. As it turns out, the best structural biology research, like Rab3GAP, comes in pairs.