Ras hitchhikes on PDE6δ

Abstract

Ras GTPases are tethered to cellular membranes by a farnesyl lipid that modifies a C-terminal cysteine. Among the ways Ras traffics between membranes is via fluid phase diffusion, suggesting that a cytosolic chaperone might be needed to shield the farnesyl lipid during transport. PDE6δ is now revealed to be a farnesyl-binding Ras chaperone that facilitates its trafficking and signaling.

Figure 1

PDE6δ is a Ras chaperone that facilitates cytoplasmic trafficking. PDE6δ extracts Ras from a donor membrane and allows solubilization in the aqueous environment of the cytosol by sequestering the farnesyl chain in a hydrophobic pocket. Upon arrival by simple diffusion at the acceptor membrane, GTP-bound Arl2/3 binds to an allosteric site on PDE6δ causing it to release Ras onto the acceptor membrane where the farnesyl lipid can once again partition into phospholipid bilayer. In the case of H-Ras the donor membrane is the plasma membrane where H-Ras can be depalmitoylated and gain affinity for PDE6δ, and the acceptor membrane is the Golgi where H-Ras is re-acylated. In the case of K-Ras4B the donor membrane is endomembrane where the electrostatic interaction with its C-terminal polybasic region is relatively low and the acceptor membrane is the plasma membrane where that interaction is strong.