Key Points
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Rab proteins, which constitute the largest family of monomeric GTPases, and their effectors coordinate consecutive stages of transport, such as vesicle formation, vesicle and organelle motility, and tethering of vesicles with target membranes.
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The ability of Rabs to cycle regularly between GTP- and GDP-bound forms imposes temporal and spatial regulation to membrane transport.
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Rabs mediate the first specific tethering event between a vesicle and its target membrane, and so provide a complementary layer of regulation to that subsequently provided by SNARE pairing.
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Specific Rab effectors have been implicated in various membrane tethering events, including delivery of post-Golgi vesicles to the plasma membrane (for example, the exocyst complex), tethering of endosomes (EEA1) or vacuoles (the HOPS complex).
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Rabs have been implicated in regulating vesicle motility through interaction with both microtubules and actin filaments of the cytoskeleton.
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The structural heterogeneity shown by Rab effectors implies that these are highly specialized molecules whose activities are exclusively tailored for individual organelles and transport systems. Rab5 regulates the activity of several effectors and evidence indicates cooperativity between these molecules.
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There is increasing evidence that Rab proteins and their effectors are not randomly distributed but are enriched in membrane domains, termed here Rab domains. In the case of Rab5, effector cooperativity, protein-lipid interactions and oligomerization between effectors are central factors to the formation of a Rab5 domain. The Rab5 machinery can be viewed as a modular system, in which specific biochemical interactions between Rab5 effectors and regulators as well as other endosomal proteins create spatial segregation. Furthermore, the integration between GTPase and ATPase cycles ensures a dynamic state between assembly and disassembly of complexes and so confers a specific control on domain size.
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Direct interactions have been characterized between Rab effectors and SNAREs. The authors propose a model in which the selective incorporation of a cis-SNARE complex within a Rab domain is a prerequisite for trans-SNARES pairing, which brings two membranes into close proximity.
Abstract
Cellular organelles in the exocytic and endocytic pathways have a distinctive spatial distribution and communicate through an elaborate system of vesiculo-tubular transport. Rab proteins and their effectors coordinate consecutive stages of transport, such as vesicle formation, vesicle and organelle motility, and tethering of vesicles to their target compartment. These molecules are highly compartmentalized in organelle membranes, making them excellent candidates for determining transport specificity and organelle identity.
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Acknowledgements
We thank members of the Zerial lab, R. Lippe, M. Miaczynska and S. De Renzis, as well as our colleagues K. Simons, J. Gruenberg, G. Griffiths, J. Howard for their helpful comments and critical reading of the manuscript. We are grateful to I. Kaestner for superb secretarial help.
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HYPERLINKED FIGURE AND TABLES
FURTHER INFORMATION
Glossary
- COGNATE SNARES
-
SNAREs on opposite membranes that are destined to form trans-SNARE complexes to mediate fusion.
- NSF
-
Molecular chaperone involved in recycling SNAREs after one round of fusion.
- EFFECTOR
-
A protein or protein complex that binds the GTPase directly and in a GTP-dependent manner and is required for the downstream function determined by that GTPase.
- EEA1
-
The antigen involved in a human autoimmune disease.
- COPII VESICLES
-
Coated vesicles involved in transport from the endoplasmic reticulum to the Golgi.
- CCP
-
Area of the plasma membrane where receptors and the clathrin machinery are concentrated, preparing to form a vesicle.
- CCV
-
Coated vesicles involved in the endocytosis of receptors at the plasma membrane.
- LIPID RAFTS
-
Lipids including cholesterol and sphingomyelin aggregated laterally to form membrane microdomains.
- GREEN FLUORESCENT PROTEIN
-
Autofluorescent protein originally identified in the jellyfish Aequorea Victoria.
- RECYCLING ENDOSOME
-
About 90% of endocytosed receptors are recycled to the plasma membrane. At least part of this traffic occurs through recycling endosomes.
- TRANSFERRIN
-
Protein involved in ferric ion uptake into the cell. The pathway followed by transferrin bound to its receptor defines the recycling pathway.
- APICAL JUNCTIONAL COMPLEX
-
Desmosomes, adherens junctions and tight junctions make up the apical junctional complex.
- NEURITE
-
Process extended by a nerve cell that can give rise to an axon or a dendrite.
- CIS-SNARE COMPLEX
-
SNARE pairing occurring within the same membrane.
- SEC18P (Sec18p)
-
Saccharomyces cerevisiae homologue of NSF.
- HAEMAGGLUTININ
-
Spike protein of the influenza virus. HA is the best-understood fusion protein.
- TRANSCYTOSIS PATHWAYS
-
Transport of macromolecules across a cell, consisting of endocytosis of a macromolecule at one side of a monolayer and exocytosis at the other side.
- APICAL
-
Plasma membrane surface of an epithelial cell that faces the lumen.
- BASOLATERAL
-
Plasma membrane surface of an epithelial cell that adjoins underlying tissue.
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Zerial, M., McBride, H. Rab proteins as membrane organizers. Nat Rev Mol Cell Biol 2, 107–117 (2001). https://doi.org/10.1038/35052055
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DOI: https://doi.org/10.1038/35052055