The isoforms of the GTPase RAS have highly similar protein sequences, yet they localise to different subcellular membranes and consequently have distinct functions. The hypervariable region (HVR) – the only RAS domain for which the sequence differs significantly between isoforms – directs subcellular targeting, but how it does so is unclear. On page 421, Alex Laude and Ian Prior identify a series of targeting motifs within the HVR. By expressing GFP-tagged HVR constructs, the authors show that the HVRs of the monopalmitoylated N-RAS and K(A)-RAS isoforms both localise to the plasma membrane, just as the full-length proteins do. However, when the linker domain of the HVR is removed or replaced with alanine residues, both isoforms redistribute to the membranes of the ER and Golgi. Notably, the HVR of the doubly palmitoylated isoform H-RAS remains at the plasma membrane even when the linker domain is removed. The authors characterise motifs within the linker domain that cooperate to promote plasma-membrane binding. The HVR linker domain is therefore a key promoter of plasma-membrane association in mono-palmitoylated RAS isoforms, highlighting the diversity of signals that control subcellular RAS targeting.
- © The Company of Biologists Limited 2008