Structural Mechanisms for Regulation of Membrane Traffic by Rab GTPases

Program in Molecular Medicine and Department of Biochemistry & Molecular Pharmacology, University of Massachusetts Medical School, Worcester, MA 01605, USA.
Traffic (Impact Factor: 4.35). 06/2009; 10(10):1377-89. DOI: 10.1111/j.1600-0854.2009.00942.x
Source: PubMed


In all eukaryotic organisms, Rab GTPases function as critical regulators of membrane traffic, organelle biogenesis and maturation, and related cellular processes. The numerous Rab proteins have distinctive yet overlapping subcellular distributions throughout the endomembrane system. Intensive investigation has clarified the underlying molecular and structural mechanisms for several ubiquitous Rab proteins that control membrane traffic between tubular-vesicular organelles in the exocytic, endocytic and recycling pathways. In this review, we focus on structural insights that inform our current understanding of the organization of the Rab family as well as the mechanisms for membrane targeting and activation, interaction with effectors, deactivation and specificity determination.

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    • "The switch 1/2 region of Rab8a is predominantly positive and provides a favorable binding surface for the negatively charged C-terminal domain of αS (Fig. 3E). Notably, the major structural change between the two nucleotide-bound states of Rab proteins occurs in this region with the GTP-bound state being more rigid (Itzen and Goody, 2011; Lee et al., 2009). Thus, different conformations of the switch region and in particular the G2 loop of Rab8a might contribute to the higher affinity of αS towards Rab8a(GDP) (Fig. 2). "
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    ABSTRACT: Alpha-Synuclein (αS) misfolding is associated with Parkinson's disease (PD) but little is known about the mechanisms underlying αS toxicity. Increasing evidence suggests that defects in membrane transport play an important role in neuronal dysfunction. Here we demonstrate that the GTPase Rab8a interacts with αS in rodent brain. NMR spectroscopy reveals that the C-terminus of αS binds to the functionally important switch region as well as the C-terminal tail of Rab8a. In line with a direct Rab8a/αS interaction, Rab8a enhanced αS aggregation and reduced αS-induced cellular toxicity. In addition, Rab8 - the Drosophila ortholog of Rab8a - ameliorated αS-oligomer specific locomotor impairment and neuron loss in fruit flies. In support of the pathogenic relevance of the αS-Rab8a interaction, phosphorylation of αS at S129 enhanced binding to Rab8a, increased formation of insoluble αS aggregates and reduced cellular toxicity. Our study provides novel mechanistic insights into the interplay of the GTPase Rab8a and αS cytotoxicity, and underscores the therapeutic potential of targeting this interaction.
    Full-text · Article · Jun 2014 · Neurobiology of Disease
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    • "Conversely, a Drosophila mutant in HPS4, a component of the BLOC-3 machinery that catalyzes the fusion of MVBs with lysosomes (Suzuki et al, 2002; Li et al, 2004), leads to an increase in miRNA-or siRNAmediated RNA silencing (Lee et al, 2009). In fact, hps4 mutant extracts exhibit faster RISC loading in vitro (Lee et al, 2009). "
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    ABSTRACT: microRNAs (miRNAs) and small interfering RNAs (siRNAs) are small RNAs that repress gene expression at the post-transcriptional level in plants and animals. Small RNAs guide Argonaute-containing RNA-induced silencing complexes to target RNAs in a sequence-specific manner, resulting in mRNA deadenylation followed by exonucleolytic decay, mRNA endonucleolytic cleavage, or translational inhibition. Although our knowledge of small RNA biogenesis, turnover, and mechanisms of action has dramatically expanded in the past decade, the subcellular location of small RNA-mediated RNA silencing still needs to be defined. In contrast to the prevalent presumption that RNA silencing occurs in the cytosol, emerging evidence reveals connections between the endomembrane system and small RNA activities in plants and animals. Here, we summarize the work that uncovered this link between small RNAs and endomembrane compartments and present an overview of the involvement of the endomembrane system in various aspects of RNA silencing. We propose that the endomembrane system is an integral component of RNA silencing that has been long overlooked and predict that a marriage between cell biology and RNA biology holds the key to a full understanding of post-transcriptional gene regulation by small RNAs.
    Full-text · Article · May 2014 · The EMBO Journal
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    • "They are typically anchored to the bilayer by a long flexible hypervariable domain that ends in a prenylated C terminus. In the GTP-bound form, Rabs bind effectors, but when the GTP is hydrolyzed through the action of a GTPase activating protein (GAP), they are extracted from the bilayer by a carrier protein called GDP dissociation inhibitor (GDI) [11,12]. Thus the activating exchange factors (GEFs) and GAPs of Rabs act in concert to establish a restricted subcellular distribution for each particular Rab-GTP form, and this GTP form then serves as a landmark for the recruitment of those proteins that need to act in that location. "
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    ABSTRACT: Membrane-bound organelles are a defining feature of eukaryotic cells, and play a central role in most of their fundamental processes. The Rab G proteins are the single largest family of proteins that participate in the traffic between organelles, with 66 Rabs encoded in the human genome. Rabs direct the organelle-specific recruitment of vesicle tethering factors, motor proteins, and regulators of membrane traffic. Each organelle or vesicle class is typically associated with one or more Rab, with the Rabs present in a particular cell reflecting that cell's complement of organelles and trafficking routes. Through iterative use of hidden Markov models and tree building, we classified Rabs across the eukaryotic kingdom to provide the most comprehensive view of Rab evolution obtained to date. A strikingly large repertoire of at least 20 Rabs appears to have been present in the last eukaryotic common ancestor (LECA), consistent with the 'complexity early' view of eukaryotic evolution. We were able to place these Rabs into six supergroups, giving a deep view into eukaryotic prehistory. Tracing the fate of the LECA Rabs revealed extensive losses with many extant eukaryotes having fewer Rabs, and none having the full complement. We found that other Rabs have expanded and diversified, including a large expansion at the dawn of metazoans, which could be followed to provide an account of the evolutionary history of all human Rabs. Some Rab changes could be correlated with differences in cellular organization, and the relative lack of variation in other families of membrane-traffic proteins suggests that it is the changes in Rabs that primarily underlies the variation in organelles between species and cell types.
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