Prenylation of RabGTPases, Their Delivery to Membranes, and Rab Recycling - Ras Superfamily Small G Proteins: Biology and Mechanisms 2 - page 7

Fig. 1.2 Model for Rab delivery to membranes without a GDF. Assuming that there is a certain
tendency for the lipid moieties at the C-terminus to dissociate from their binding site on Rab, this
state might be temporarily trapped by the proximity of a membrane. If a cognate GEF is present at
this membrane, membrane attachment will be made essentially irreversible because of generation
of the GTP bound state of the Rab protein, which reduces the affinity to GDI dramatically

properties are enhanced by the influence of concerted or sequential GDP/GTP
exchange on the Rab:GDI affinity.
A hint towards a possible active role of membranes is suggested by comparing
the properties of Rab:GDI or Rho:GDI complexes with those of complexes of
farnesylated Ras family proteins with PDE

(Ismail et al. 2011 ). In this case, the
interaction appears to be almost exclusively with the prenyl group, and the structure
of farnesylated Rheb:GDP in complex with PDE

δ

complex confirms that there is

δ

little or no interaction between PDE and the body of the GTPase. In the case of

Rab or Rho complexes with GDI, the main contribution to affinity and therefore
specificity appears to come from the specific interaction of GDI with the GTPase
domain. The idea therefore arises that whereas there is a relatively strong interac-
tion of the farnesyl group with the lipid binding site of PDE

δ

, the interaction of
geranylgeranyl groups with the lipid binding site of GDI or REP is weak, leading to
a dynamic equilibrium between a state in which both the GTPase domain and lipid
are bound to GDI, and a state in which the lipid group is transiently free (see
Fig. 1.2 ). If this occurs in close proximity to a membrane, insertion of the lipid
group could then lead to complete dissociation of Rab:GDP from GDI, which
would again be reversible, unless a membrane-localized GEF can facilitate GDP
replacement by GTP, thus preventing the reverse reaction (i.e., rebinding of Rab to
GDI). These arguments are summarized in Fig. 1.2 .
Interestingly, a genuine GDF-type mechanism appears to operate in the case of
interaction of farnesylated proteins with PDE

δ

(Chandra et al. 2012 ; Ismail
et al. 2011 ). This protein binds farnesyl groups in a manner that is independent of
the GTPase core domain of Ras-family members, as already discussed. It appears to
act as a chaperone for farnesylated proteins in a similar manner to Rab and Rho
GDIs, with the important exception that there is no dependence of the interaction on
the nucleotide state of the GTPases. Intriguingly, PDE

δ

interacts with other

δ