Effectors of Rab GTPases: Rab Binding Specificity and Their Role in Coordination of Rab Function and Localization - Ras Superfamily Small G Proteins: Biology and Mechanisms 2 - page 59

In addition to the effector proteins that comprise two Rab binding domains, there
are effectors that have the capacity to bind to even more Rabs through separate
domains. Among them are proteins of the Golgin family, which are large, mostly
coiled-coil proteins present on Golgi and TGN membranes (Goud and Gleeson
2010 ). They were proposed to act as tentacles to catch transport vesicles moving to
or through the Golgi complex (Sinka et al. 2008 ). For instance, the Drosophila
golgin-97, which is recruited to Golgi membranes by interaction of its GRIP
domain with Arl1, binds through different sites located across its entire length to
dRab6, dRab19, and dRab30 (Sinka et al. 2008 ). Similarly, the human golgin
GCC185/GCC2 was demonstrated to interact through five different sites with
Rab1a/b, Rab2a/b, Rab6a/b, Rab9a/b, Rab15, Rab27b, Rab30, Rab33b, Rab35,
and Rab36 (Hayes et al. 2009 ). The interaction with Rab6 may help in the
recruitment of GCC185 to Golgi membranes (Burguete et al. 2008 ), but this
remains to be confirmed (Houghton et al. 2009 ). In addition, the interactions
between Golgins and Rab GTPases located on adjacent compartments, such as
perinuclear recycling endosomes (Rab11) or pre-Golgi compartments (Rab1 and
Rab2), could play an important role in defining the spatial relationship between
Golgi/TGN membranes and membranes of these compartments as they would
bridge the different compartments (Goud and Gleeson 2010 ).
Another example of an effector that is likely involved in the coordination of Rab
function is the actin-based motor MyoVa recently shown to interact directly with
thirteen Rabs (including isoforms), i.e., Rab3, Rab6, Rab8, Rab10, Rab11, Rab14,
Rab25, and Rab39b (Lindsay et al. 2013 ) via three distinct Rab binding domains
(see above). The physiological role of multiple interactions between MyoVa/b and
Rab GTPases is still poorly understood. Only Rab10 and Rab11, dependent on the
MyoVa splice variant, are involved in MyoVa recruitment to intracellular mem-
branes. One tentative hypothesis is that MyoVa, once recruited to membranes by
Rab10 or Rab11, relieves a MyoVa autoinhibition to allow its participation in Rab
cascades involving the other Rab GTPases that interact with MyoVa. These cas-
cades could then regulate both remodeling and maturation of endocytic/recycling
compartments and post-Golgi secretory pathways (Lindsay et al. 2013 ).
Finally, one should mention the case where a direct interaction takes place between
two effectors of the same Rab GTPase. For instance, FIP2 can bind to Rab11a and to
MyoVb, and evidence exists that the tripartite association of Rab11 with FIP2 and
MyoVb is implicated in regulating the dynamics of Rab11-positive membranes and
recycling events (Hales et al. 2002 ;Wangetal. 2008 ; Gidon et al. 2012 ).
3.5.3 Effectors and the Localization of Rab GTPases
The mechanisms by which Rab GTPases are targeted to specific membranes are not
yet fully understood, although growing evidence indicates that GEFs are key
players in these processes (Schoebel et al. 2009 ; Wu et al. 2010 ; Blumer
et al. 2013 ). However, Rab effectors could also play a direct role. The first example