Background: Rab geranylgeranyltransferase (RabGGT) catalyzes the addition of two geranylgeranyl groups to the C-terminal cysteine residues of Rab proteins, which is crucial for membrane association and function of these proteins in intracellular vesicular trafficking. Unlike protein farnesyltransferase (FT) and type I geranylgeranyltransferase, which both prenylate monomeric small G proteins or short peptides, RabGGT can prenylate Rab only when Rab is in a complex with Rab escort protein (REP). Results: The crystal structure of rat RabGGT at 2.0 Å resolution reveals an assembly of four distinct structural modules. The β subunit forms an α-α barrel that contains most of the residues in the active site. The α subunit consists of a helical domain, an immunoglobulin (Ig)-like domain, and a leucine-rich repeat (LRR) domain. The N-terminal region of the α subunit binds to the active site in the β subunit; residue His2α directly coordinates a zinc ion. The prenyl-binding pocket of RabGGT is deeper than that in FT. Conclusions: LRR and Ig domains are often involved in protein-protein interactions; in RabGGT they might participate in the recognition and binding of REP. The binding of the N-terminal peptide of the α subunit to the active site suggests an autoinhibition mechanism that might contribute to the inability of RabGGT to recognize short peptides or Rab alone as its substrate. Replacement of residues Trp102β and Tyr154β in FT by Ser48β and Leu99β, respectively, in RabGGT largely determine the different lipid- binding specificities of the two enzymes.
- Crystal structure
- Geranylgeranyltransferase type II
- Leucine-rich repeats
- Post-translational modification
ASJC Scopus subject areas
- Structural Biology
- Molecular Biology