Rac1 gets fattier.

Since its description more than two decades ago as a substrate for botulinum C3 exoenzyme (Didsbury et al, 1989), Rac1 has been one of the most studied small GTPases of the Ras superfamily. Interest in Rac1 exploded in 1992 when Ridley and Hall published their seminal work showing that Rac1 regulates the actin cytoskeleton to promote lamellipodia formation (Ridley et al, 1992). Since that report, 44350 studies have been published on Rac1 and seemingly every detail of its regulation and biological function has been dissected, including its post-translational modifications. It therefore comes as somewhat of a surprise when del Pozo and colleagues (Navarro-Lérida et al, 2012) report for the first time in this issue of The EMBO Journal that Rac1 can be palmitoylated and that acylation directs its location in plasma membrane microdomains and modulates its signalling output. Palmitoylation is a common and reversible form of posttranslational modification that has received much attention recently because a long sought family of protein acyltransferases (PATs) have been described (Lobo et al, 2002) and because global proteomic analysis has revealed a great many substrates for PATs (Roth et al, 2006). No consensus aminoacid sequence for palmitoylation has been discerned such that genomic data cannot predict protein acylation. GTPases are no strangers to palmitoylation. Indeed, H-Ras is among the best studied of all palmitoylated proteins and N-Ras, K-Ras4A, RhoB, and TC10 are other examples of palmitoylated small GTPases. Small GTPases are directed to the plasma membrane as a consequence of a three-step post-translational modification of a C-terminal CAAX sequence that adds a farnesyl or geranylgeranyl lipid to the CAAX cysteine. Also required is a so-called second signal immediately upstream of the CAAX sequence that consists either of a polybasic region or one or more cysteines that serve as sites for palmitoylation (Choy et al, 1999). The prototypical polybasic region is that of K-Ras4B, which possesses a net charge of þ 8. Rac1 has a similar polybasic region with a net charge of þ 6 and this has been considered to be its functional second signal for plasma membrane targeting.