17.8:
Rab Cascades
Each membrane-bound organelle and its associated transport vesicles have a specific set of Rab proteins.
Rabs act in a series where they switch between a cytosolic, GDP-bound inactive state and a membrane-associated, GTP-bound active state with the help of Guanine nucleotide exchange factors or GEFs and GTPase activating proteins or GAPs .
An activated Rab recruits the GEF to activate the next Rab, which can recruit the GAP to deactivate the previous Rab.
This sequential activation and deactivation of Rabs creates a cascade that builds a specialized Rab domain on the target membrane to guide a vesicle to the correct spot for fusion.
Cytosolic Rab5 is activated by its GEF present on the endosome membrane. The active Rab5 binds Rab effectors, such as tethering proteins and Rabaptin5.
Rabaptin5 binding stimulates additional GEFs to recruit Rab5 in a cascade, forming a Rab5 domain on the endosome membrane.
This helps concentrate the tethering proteins that coordinate with SNARE complexes to capture incoming vesicles and enable membrane fusion.
17.8:
Rab Cascades
Rab GTPases act in a regulated cascade during membrane fusion, helping the lipid bilayers mix. The Rab family of proteins are active when bound to GTP, and inactive when bound to GDP. Hence, they act as guanine nucleotide-dependent molecular switches. Rab-GTP recognizes and binds to long or short-range tethering proteins to capture the target vesicle. These tethers coordinate with SNAREs on the vesicle and the target membrane to assemble the trans SNARE complex that locks the mixing bilayers.
Rabs recruit a unique set of peripheral proteins called Rab effectors that mediate vesicle movement and regulate membrane traffic in their associated compartments, thus establishing a distinctive subcellular localization pattern. One Rab recruits the corresponding GEF that sequentially activates the next Rab along a Rab cascade pathway in its GTP-bound active state. In the cascade, Rab GAPs work in a fashion countering the Rab GEFs to complete the Rab conversions. Scientists describe this hypothesis that in a pathway, the activation of one Rab will recruit the GAP that inactivates the preceding Rab, thus reducing the overlap between adjacent Rab domains in a pathway.
Rab cascades establish the order of compartments during cargo progression between the organelles in the secretory pathway. Rab domains contact their effectors in a sequence, generating directional Rab cascades. The discovery of Rab cascades in the Golgi and the possible homotypic fusion of all membrane-bound Golgi compartments have led to a new model for protein transport in the Golgi.
Suggested Reading
- Rivera-Molina, F. E., & Novick, P. J. (2009). A Rab GAP cascade defines the boundary between two Rab GTPases on the secretory pathway. Proceedings of the National Academy of Sciences, 106(34), 14408-14413.