Biomedical Engineering Reference
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Fig. 1.1 The mechanism of Rab prenylation in the Rab:REP:RabGGTase complex. After an
initial relatively weak association of the globular domain of Rab with REP, interaction of the CIM
(C-terminal interaction motif) of Rab with the CBR (C-terminal binding region) of REP leads to
tightening of this interaction. This is followed by a high-affinity interaction of the Rab:REP
complex with RabGGTase and geranylgeranyl pyrophosphate (GGPP) to form the high-affinity
quaternary complex. The first geranylgeranyl group is transferred to the most C-terminal cysteine
of Rab with the help of a catalytic zinc ion. The second prenyl group is then transferred more
slowly (in the case of Rab7) to the preceding cysteine, after which the prenylated Rab:REP
complex is released under the influence of a further lipid substrate molecule. The constants
given apply to Rab7 and REP-1. Figure modified from the publication of Wu et al. (
2009
)
structural investigations on a complex between prenylated Rab proteins and REP
(Rak et al.
2004
) or GDI (GDP dissociation inhibitor) (Rak et al.
2003
). This short
motif, consisting of a polar residue sandwiched between two hydrophobic residues,
is essential for high-affinity binding to REP and for efficient prenylation. The
positioning of the cysteine groups with respect to this motif is critical. In wild-
type Rab7, there are 12 residues downstream of this motif before the first
prenylatable cysteine, and this can be shortened by a further 3 residues without
drastic effects on the prenylation reaction, but shortening to 7 residues leads to only
residual activity and with 6 residues or less there is no detectable activity
(Wu et al.
2009
). Interestingly, it has recently been shown that the region between
the CIM and the cysteines can be replaced by a non-peptidic structure and that
cysteine can be replaced by a simple thiol group and still retain full prenylation
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