Abstract
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 REP binds Rab and presents it to RGGT. After geranylgeranylation of Rab C-terminal cysteines, 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 has helped to refine this model and provided further insights. The hydrophobic prenyl binding pocket of RGGT and geranylgeranyl transferase type-I (GGT-I) differs from that of farnesyl transferase (FT). A bulky tryptophan residue in FT restricts the size of the pocket, whereas in RGGT and GGT-I, this position is occupied by smaller residues. A highly conserved phenylalanine in REP, which is absent in RabGDI, is critical for the formation of the REP:RGGT complex. Finally, a geranylgeranyl binding site conserved in REP and RabGDI has been identified within helical domain II. The postprenylation 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 subject of future studies.
Highlights
Rab GTPases require special machinery for protein prenylation, which include Rab escort protein (REP) and Rab geranylgeranyl transferase (RGGT)
The crystal structure of Rab GDP dissociation inhibitor (RabGDI) in complex with prenylated Ypt1p revealed that the geranylgeranyl moiety is accommodated in a hydrophobic lipid binding site in domain II [48]
The most likely hypothesis at present is that REP works at the initial prenylation/membrane association event, whereas RabGDI works at a later stage in recycling Rabs on/off membranes [22]
Summary
Very little is known about potential enzyme regulation. One possible mechanism involves an intramolecular interaction [27]. Comparison of structural data from Rab7:REP-1 [44] and Ypt1:yGdi1p [48] complexes indicates that they are very similar in terms of hydrophobic and hydrophilic interactions between REP/GDI and Rab proteins; such data cannot explain why RabGDI preferentially binds prenylated proteins. The crystal structure of RabGDI in complex with prenylated Ypt1p revealed that the geranylgeranyl moiety is accommodated in a hydrophobic lipid binding site in domain II [48]. The issue of whether there are differences between REP and RabGDI in binding affinities toward unprenylated and prenylated Rabs remains to be addressed experimentally, this is often referred to as a known fact. The most likely hypothesis at present is that REP works at the initial prenylation/membrane association event, whereas RabGDI works at a later stage in recycling Rabs on/off membranes [22]
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