Biomedical Engineering Reference
In-Depth Information
Fig. 3.7 Schematic
representation of Rab-GAP
cascades. Active/GTP-
bound Rab proteins are
shown in
green
, and
inactive/GDP-bound Rab
proteins are colored in
red
.
The effector proteins are
depicted in
dark blue
(RBD)
and in
light blue
(GAP
domain)
domain, a downstream Rab protein. Again, a positive feedback loop will ensure the
accumulation of this Rab protein on the membrane domain, which will then,
provided a certain threshold is reached, recruit an effector protein. This will
deactivate the first Rab protein, thereby ensuring its release from the membrane
domain.
3.5.2 Effector Coupling
Divalent and multivalent effectors directly participate in the coordination of Rab
function. To our knowledge, the first divalent Rab effector to be described was
Rabaptin-5, demonstrated to bind to both Rab4 and Rab5 (Vitale et al.
1998
). Later
on, the Rab4- and Rab5-binding sites were shown to interact with other Rab
GTPases (see above). Several other proteins that bind to both Rab4 and Rab5
through separate domains have been identified, such as Rabaptin-5 and Rabip4
0
(de Renzis et al.
2002
; Fouraux et al.
2004
). These effectors link Rab4- and Rab5-
regulated trafficking and signaling pathways. For instance, the overexpression of
Rabenosyn-5 increases the overlap between Rab4 and Rab5 domains on early
endosomes and stimulates transferrin recycling (de Renzis et al.
2002
).
Another example of a divalent effector is Rab6IP1/DENND5 that interacts with
Rab6 and Rab11 (Miserey-Lenkei et al.
2007
). Rab6IP1/DENND5 binds to Rab6a,
but not to Rab11a, via its C-terminal RUN domain whereas Rab11a recognition
required the full-length protein (Miserey-Lenkei et al.
2007
; Recacha et al.
2009
).
In addition, Rab6IP1/DENND5 shows a GEF activity in vitro towards Rab39,
indicating that it likely interacts in vivo with Rab39 via its N-terminal DENN
domain (Yoshimura et al.
2010
).
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