Prenylation of RabGTPases, Their Delivery to Membranes, and Rab Recycling - Ras Superfamily Small G Proteins: Biology and Mechanisms 2 - page 11

Fig. 1.3 Substitution of the Rab HVD with different C-terminal structures. The CIM is
highlighted in yellow , the RILP interaction sequence of Rab7 in orange , while the basic residues
in Rab35 are in blue and the prenylatable cysteines are in red
the membrane or another membrane component). This is because in the heterote-
trameric complex there are four rather than two prenyl groups that interact with the
membrane. It is conceivable that this is the reason for the importance of the Rab7
effector interaction for membrane stabilization, as described above. This is perhaps
of more general significance, since several other Rab-effector interactions involve
this dimeric type of interaction, including Rab5:Rabaptin5 (Zhu et al. 2004 ), Rab6:
GCC185 (Burguete et al. 2008 ), Rab11:FIP2 (Jagoe et al. 2006 ), and Rab11:FIP3
(Eathiraj et al. 2006 ; Shiba et al. 2006 ). In the absence of additional interactions of
the effector with the membrane or other membrane-bound components, this cannot
be a targeting mechanism, but could be a mechanism to stabilize a Rab protein at a
specific membrane after the initial targeting step, in which GDP/GTP exchange by a
specifically localized GEF probably plays the most important role. Thus, a dimeric
or better divalent effector would be able both to stabilize the membrane-bound form
of the Rab protein and to interact with a further partner, for example, the dynein-
dynactin complex in the case of Rab7 (Tan et al. 2011 ). It will be of interest to
determine whether Rab effectors that also interact with the C-terminal region, but in
a monovalent manner, also contribute to Rab targeting. Known examples are Rab3:
Rabphilin (Ostermeier and Brunger 1999 ) and Rab27:melanophilin (Kukimoto-
Niino et al. 2008 ).
In the case of targeting of Rab27a to melanosomes, it has been shown that
impaired effector binding does not affect membrane localization, whereas the
nonredundant GEF activity of Rab3GEP/MADD is essential (Tarafder
et al. 2011 ). However, mutants of Rab27a were found that were substrates for the
GEF activity of Rab3GEP in vitro but were not correctly localized, suggesting that
an additional factor or activity (i.e., not just GEF activity) is required for targeting.
However, it is not clear what the effect of these mutations on Rab27 cycling is. In a
similar vein, it was recently shown that the Ypt7 GEF Mon1:Ccz1 is required for
correct localization of wild-type Ypt7, but not for a Ypt7 mutant that showed
facilitated (i.e., GEF-independent) nucleotide exchange (Cabrera and Ungermann
2013 ). This again suggests that an additional factor or factors are required for
targeting and even suggests that the exact site of the exchange reaction is not
important.