Submitted on December 14, 2005
Revised on January 5, 2006
Accepted on January 9, 2006
Geranylgeranylation of Rab GTPases
Ka Fai Leung, Rudi Baron, and Miguel C. Seabra
Biomedical Sciences, Imperial College London, London, London SW7 2AZ
Corresponding Author: m.seabra{at}imperial.ac.uk
Rab GTPases require special machinery for protein prenylation, which include Rab Escort Protein (REP) and Rab Geranylgeranyl Transferase (RGGT). The current model of Rab geranylgeranylation proposes that the Rab protein must bind REP, which presents the Rab to RGGT. Following geranylgeranylation of C-terminal cysteines in Rab, REP delivers the prenylated protein to membranes. The REP-like protein, Rab GDP dissociation inhibitor (RabGDI) then recycles the prenylated Rab between the membrane and the cytosol. The recent solution of crystal structures of the Rab prenylation machinery have helped to refine this model and provide further insights. The hydrophobic prenyl binding site of RGGT is similar to that of geranylgeranyl transferase type-I (GGT-I) but differs from farnesyl transferase (FT). At the bottom of the hydrophobic isoprenyl-binding pocket, a bulky Trp residue in FT prevents binding of the longer geranylgeranyl pyrophosphate group whereas in GGT-I and RGGT this position is occupied by the smaller residues Thr and Ser, respectively. At the REP:RGGT interface, a highly conserved Phe in REP, which is absent in RabGDI, plays a critical role in the formation of the REP:RGGT complex and may explain the inability of RabGDI to complex with RGGT. A geranylgeranyl-binding site in REP and RabGDI has been identified within domain II. However, as most Rabs undergo double geranylgeranylation, it is still unclear how and where the second geranylgeranyl group is stabilised. The post-prenylation events, including the specific targeting of Rabs to target membranes and the requirement for single versus double-geranylgeranylation by different Rabs remain obscure and should be the object of future studies.
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