The structural basis of RanGAP1 regulation and catalysis in nuclear transport

RanGAP1 promotes GTP hydrolysis of nuclear pore complex (NPC) transport at the cytoplasmic face. A disordered linker connects its catalytic GAP domain to the C-terminal sumoylation domain, anchoring into NPC’s cytoplasmic filaments. How these distinct functions are coordinated within a crowded cellular environment remains unclear. Our atomistic simulations suggest that RanGAP1 may adopt an autoinhibited conformation, where the C-terminal domain masks the catalytic GAP domain. Sumoylation allosterically weakens the interaction between the GAP and C-terminal domains, relieving the autoinhibition and promoting GTP-bound Ran access to the GAP domain. In the cytosol, Ran-GTP/RanBP1 may bind a less populated open conformation of RanGAP1, providing a complementary route for GTP hydrolysis. Importantly, our simulations show that Arg191 of human RanGAP1 inserts into the GTP-binding pocket of Ran and directly interacts with the γ-phosphate, adopting a conformation consistent with an arginine finger-like mechanism. This observation contrasts with earlier models derived from yeast RanGAP and suggests that human RanGAP1 may utilize a catalytic strategy analogous to that of classical small GTPase regulators like NF1. Together, these findings link autoinhibition, sumoylation, spatial organization at the NPC, and the GTPase-activation mechanisms. They also highlight how conformational regulation and post-translational modification coordinate GTP hydrolysis in Ran-dependent nuclear transport. RanGAP1’s role in GTP hydrolysis at the nuclear pore complex raises questions about the coordination of its distinct functions in crowded cellular environments. Here, the authors use atomistic MD simulations to propose RanGAP1 exists in an autoinhibited state, which could be allosterically relieved by C-terminal sumoylation and then promote Ran-GTP hydrolysis in an arginine-finger like mechanism.