Structure of a Ran-binding domain complexed with Ran bound to a GTP analogue: implications for nuclear transport

The protein Ran is a small GTP-binding protein that binds to two types of e ffector inside the cell: Ran-binding proteins, which have a role in termina ting export processes from the nucleus to the cytoplasm, and importin-beta- like molecules that bind cargo proteins during nuclear transport. The Ran-b inding domain is a conserved sequence motif found in several proteins that participate in these transport processes. The Ran-binding protein RanBP2 co ntains four of these domains and constitutes a large part of the cytoplasmi c fibrils that extend from the nuclear-pore complex. The structure of Ran b ound to a non-hydrolysable GTP analogue (Ran.GppNHp) in oomplex with the fi rst Ran-binding domain (RanBD1) of human RanRP2 reveals not only that RanBD 1 has a pleckstrin-homology domain fold, but also that the switch-I region of Ran.GppNHp resembles the canonical Ras.GppNHp structure and that the car boxy terminus of Ran is wrapped around RanBD1, contacting a basic patch on RanBD1 through its acidic end. This molecular 'embrace' enables RanBDs to s equester the Ran carboxy terminus, triggering the dissociation of Ran.GTP f rom importin-beta-related transport factors and facilitating GTP hydrolysis by the GTPase-activating protein ranGAP. Such a mechanism represents a new type of switch mechanism and regulatory protein-protein interaction for a Ras-related protein.