RanGAPs

RanGAPs, or Ran GTPase-activating proteins, are enzymes that regulate the Ran GTPase, a central controller of nucleocytoplasmic transport. They accelerate the hydrolysis of GTP to GDP on Ran, converting Ran-GTP to Ran-GDP in the cytoplasm and thereby helping to establish and maintain the Ran gradient across the nuclear envelope. This gradient—high Ran-GTP in the nucleus and high Ran-GDP in the cytoplasm—provides energy and direction for cargo transport carried by karyopherins (importins and exportins).

Localization and mechanism: In many eukaryotes, RanGAP activity is concentrated at the cytoplasmic face of the nuclear pore complex (NPC). RanGAP1 frequently docks at the NPC through interactions involving SUMOylation and binding to nucleoporins such as Nup358/RanBP2, anchoring the GAP activity where translocation occurs. This positioning ensures rapid hydrolysis of Ran-GTP on cargo complexes that have traversed the NPC, promoting cargo release in the cytoplasm. Some organisms also express additional RanGAP family members that contribute to Ran regulation, expanding the regulatory network around nucleocytoplasmic transport.

Structure and genetics: RanGAP proteins typically carry a conserved GTPase-activating protein (GAP) domain in their C-terminal region, which stimulates Ran’s GTP hydrolysis. The N-terminal region of RanGAP1 contains a SUMOylation site that mediates docking to the NPC via interaction with SUMO-targeted partners like RanBP2.

Biological significance: Proper RanGAP function is essential for efficient nucleocytoplasmic transport and cell cycle progression. Disruption of RanGAP activity can impair cargo import and export, affecting cellular viability.