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An Evolutionary Perspective on Eukaryotic Membrane Trafficking

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The eukaryotic cell is defined by a complex set of sub-cellular compartments that include endomembrane systems making up the exocytic and endocytic trafficking pathways. Current evidence suggests that both the function and communication between these compartments are regulated by distinct families of proteins that direct membrane fission, targeting and fusion. These families include coat protein complexes (CPCs) involved in vesicle formation/fission, Rab GTPases involved in vesicle targeting, and soluble N-ethyl-maleimide-sensitive factor attachment protein receptors (SNAREs) involved in vesicle fusion. The origins of these gene families and their individual contributions to the evolutionary specialization of the membrane architectures of lower and higher eukaryotes are now better understood with the advent of powerful phylogenetic, structural and systems biology tools. Herein, we provide a perspective that suggests that while the core CPC and SNARE machineries have diversified modestly in the course of eukaryotic evolution, the Rab GTPase family expanded substantially to emerge as a key driving force in endomembrane specialization. The Rab GTPases appear to have provided the foundation for the intricate membrane architectures ranging from those requisite for the distinct amoebic life cycle stage of uni-cellular organisms such as the parasitic protozoa to the highly specialized tissue and cell type-specific endomembranes of multi-cellular eukaryotes. We propose that Rab-centric interaction networks orchestrate the divergent activities of fission and fusion through their capacity to control the sequential assembly of protein complexes that mediate endomembrane structure and communication.


The presence of sub-cellular compartments is a truly eukaryotic feature that provides spatially distributed chemical micro-environments required for the normal cell and tissue function. These compartments are distinguished by the varying lipid composition of the encapsulating bilayer as well as unique sets of integral and peripheral membrane proteins. In addition to the sub-cellular compartments such as mitochondria and chloroplasts, elaborate endomembrane systems also define the exocytic and endocytic vesicular trafficking pathways. These include the endoplasmic reticulum (ER) and the contiguous nuclear envelope (NE), the Golgi apparatus, as well as post-Golgi compartments such as lysosomes, secretory granules, and early/late endosomes. While the endosymbiotic origin of mitochondria and chloroplasts is generally accepted,1 hypotheses on the evolution of endomembranes from specialized invaginations of the plasma membrane largely remain controversial as they fail to account for specialized structures such as the nuclear pore complexes (NPCs).2-4

Endomembranes associated with sub-cellular trafficking are particularly dynamic structures that are in continuous communication afforded by the activity of highly-specialized protein complexes that harness and regulate the fundamental processes of membrane fission, tethering and fusion. For example, coat protein complexes (CPCs) mediate the biogenesis of cargo-bearing vesicles from the donor membranes while the Rab GTPases and soluble N-ethyl-maleimide-sensitive factor attachment protein receptors (SNAREs) mediate sub-cellular targeting and subsequent docking/fusion of these membrane-bound containers to the target membranes, respectively. In this respect, a hallmark of eukaryotic evolution has been the emergence of the Ras superfamily of GTPases that function as central regulators of membrane budding and trafficking, as well as cytoskeletal dynamics and the biogenesis of the nucleus.4,5

Notably, three out of at least seven major families comprising the Ras superfamily of small GTPases directly mediate specific aspects of endomembrane trafficking dynamics: the Sar1/ Sara and Arf GTPase families (at least 2 and 6 members in mammalian cells, respectively) regulate membrane recruitment and stability of CPCs, while the Rab GTPases (almost 70 members in mammalian cells) play essential roles in all stages of vesicular trafficking.5-8 Intriguingly, a recent phylogenetic analysis of the Ras superfamily led to the unprecedented hypothesis that the emergence of eukaryotic endomembranes might have predated that of phagocytosis, which is traditionally regarded as a prerequisite for the evolution of endomembrane systems, as well as that for the endosymbiotic organelles.1,4 For instance, the membrane tubulating activity of small GTPases from the Ras superfamily, such as that of Sar1,9,10 might have provided an alternative means for the first endomembrane biogenesis.4

Despite their respectively crucial roles in membrane trafficking, the molecular basis for the integrated function of the CPC, Rab, and SNARE machineries has so far been elusive. Traditionally, phylogenetic analyses of proteins in a gene family are used to identify potential functional relationships to other family members, such as in the case of Rabs and SNAREs.8,11-13 Computational approaches that apply hierarchical clustering algorithms to systematic tissue mRNA expression profiling can be used to complement this phylogenetic annotation by providing further insights into the physiological activity of closely related and distant family members, and to different gene families in different cell types.6,14 Indeed, recent results from our laboratory using one such systems biology approach now suggest that Rab-regulated activity hubs may constitute an integrated coding system, the membrome network, that orchestrates the dynamics of the specialized membrane architecture of differentiated cells.6 In this chapter we will focus on the Rab-centric integration of the eukaryotic membrane trafficking machineries from an evolutionary perspective, and also briefly discuss the origins of the nuclear and exocytic/endocytic endomembrane systems.

Coat Protein Complexes: Cellular Machineries Driving Vesicle Formation/Fission

Biogenesis of transport containers that shuttle cargo between endomembranes and/or to and from the plasma membrane is mediated by CPCs. These include the coat protein complex II (COPII) that mediates ER-to-Golgi vesicular trafficking, coat protein complex I (COPI) that mediates intra-Golgi and Golgi-to-ER trafficking,15 and the clathrin-based CPCs that are involved in endocytosis and trafficking between the Golgi, lysosomes and endosomes.16 The core CPC machineries are highly conserved throughout eukaryotic evolution: Saccharomyces cerevisiae (6 members, 31 subunits), Caenorhabditis elegans (6 members, 29 subunits), Drosophila melanogaster (6 members, 29 subunits), and Homo sapiens (7 members, 53 subunits).8 In other words, higher eukaryotes use the same basic modular system (i.e., core CPCs) where specificity demanded by the specialized membrane trafficking events and increased cargo complexity is achieved through the differential use and specialization of subunits (i.e., CPC components) that diversified significantly from yeast to human.

Initial evidence towards the shared origins of highly-specialized CPCs emerged from phylogenetic studies that demonstrated an evolutionary link between the components of the COPI and Adaptor Protein complexes 1, 2 and 3 (AP-1, AP-2 and AP-3),17 as well as from structural18 and biochemical19 comparisons of COPI and AP-2 or AP1/AP-3 subunits (Fig. 1A and B). In the case of COPI and AP-1/AP-3, a shared structural principle was already evident from the observation that the small Arf1 GTPase is involved in the membrane recruitment of both type of CPCs.17,19 Moreover, a recent study using computational and biochemical methods predicted that most components of COPI, COPII and clathrin-based CPCs may share the same basic set of structural domains, namely α-propeller and α-solenoid folds that comprise of repeating WD-40 containing α-sheets, and α-helices, respectively (Fig. 1A-C).20 While these structural folds are common protein domains, the distinctive domain arrangement of an N-terminal α-propeller followed by an α-solenoid observed in most CPC components is absent in bacteria and archaebacteria.20

Figure 1. Schematic depiction of typical clathrin-based (A), COPI (B), and COPII (C) coat protein complexes (CPCs) emphasizing their structural and functional homologies emerging from biochemical, biophysical, and in silico prediction studies.

Figure 1

Schematic depiction of typical clathrin-based (A), COPI (B), and COPII (C) coat protein complexes (CPCs) emphasizing their structural and functional homologies emerging from biochemical, biophysical, and in silico prediction studies.,,,

Based on the prediction that an essential step in the evolution of endomembranes must have been the emergence of coated vesicle budding, Cavalier-Smith1 also previously hypothesized that COPI, COPII and clathrin-based CPCs are likely to have a common ancestral origin. Cavalier-Smith1 further suggested the following sequence of events for the coated vesicle evolution: (1) an ancestral COPII evolved first to drive budding from primitive, rough-ER like endomembranes, (2) fusion of some of the COPII-driven vesicles with each other generated a smooth endomembrane compartment, a proto-Golgi/lysosome intermediate between the ER and the plasma membrane, (3) clathrin-based CPCs evolved allowing the separation of lysosomes from the Golgi, with a secondary role in endocytosis, and finally (4) COPI evolved, creating the trans-Golgi network as an intermediate compartment between Golgi cisternae and lysosomes. This hypothesis remains intriguing as it is consistent with the recent biochemical and computational data (Fig. 1A-C),20 and the earlier observations of closer phylogenetic, biochemical and structural links between the components of the clathrin-based and COPI CPCs (Fig. 1A-B).17-19 Further support for this hypothesis is available from earlier phylogenetic analysis that suggested a more ancestral character for the COPII-mediating Sar1 GTPase among the members of the Ras superfamily.4 This is also consistent with the fact that Sar1 has the unique capability to complement the sporulation defects of a Myxococcus xanthus strain deficient in MgIA, a member of the prokaryotic GTPase family that is the closest relative of the eukaryotic Ras superfamily.21 Finally, the argument that endocytosis might have emerged only as a secondary clathrin-based CPC function is suggested by the fact that the endocytic event mediated by clathrin/AP-2 is truly unique among CPCs in not requiring a small GTPase (e.g., Sar1 or Arf ) for its membrane recruitment, but instead relies on direct interaction with a phospholipid, namely PtdIns(4,5)P2.16 This may reflect a more specialized process that is likely to have evolved along with a unique class of lipid effectors mediating cell surface signaling events.

A clearer picture is now emerging regarding the molecular basis for the overall membrane dynamics of coated vesicle formation and the precise role played by the individual CPC components. For example, the minimal COPII machinery that mediates ER cargo export comprises of the activated Sar1 GTPase (GTP-bound) and the Sec23/Sec24 (Sec23/24) and Sec13/Sec31 (Sec13/31) hetero-oligomers (Fig. 1C).15,16,22 Here, Sec23 acts as a Sar1-specific GTPase activating protein (GAP) and Sec24 functions as a cargo adaptor specific for the ER exit signals, while Sec13/31 largely plays a structural role. The Sar1 GTPase may promote the initial membrane morphogenesis through its tubulating activity,9,10 in addition to its well-established role in nucleating the COPII assembly.22 This initial membrane curvature is then likely to be ‘captured’ by the electrostatic interactions between the concave surface of Sec23/24, which is enriched in basic residues and predicted to make an extensive contact with the underlying lipid bilayer,9,23 and presumably further propagated by the polymerizing properties of the Sec13/31 hetero-oligomers.16 During the biogenesis of clathrin coated vesicles (CCVs), the molding of the target membranes into regions of high curvature is also thought to be primarily promoted by the accessory proteins rather than the roughly spherical structure of the clathrin cage itself.16,24 In general, cognate adaptors provide CPCs with a direct link to biosynthetic cargo destined for export and also coordinate cargo selection with vesicle and tubule formation.16,25

Intriguingly, the α-propeller and α-solenoid folds described above, as well as their unique N- to C-terminal domain arrangement predicted to constitute some of the CPC components (Fig. 1A-C), may also be shared with some of the NPC components.2,20 This suggests unprecedented evolutionary links between the components of the NPCs and CPCs. The likelihood of these evolutionary links is strengthened by the observations that: (1) the ER and the nuclear envelope form a contiguous membrane where the latter is absorbed into the former during mitosis, and then subsequently reassembled from the former by membrane tubulation,26 (2) the Sec13 subunit of the COPII coat complex and its larger isoform Sec13 like/Seh1, which has no hitherto known function in COPII vesicle biogenesis, play well-established structural roles in NPCs,27,28 (3) assembly of nuclear membranes and NPCs is regulated by another member of the Ras superfamily, the Ran GTPase family,5 and (4) unlike the conventional transmembrane channels, NPCs do not span the lipid bilayer but instead form aqueous channels that stabilize the sharp convex curvature formed by the contiguous inner and outer NE membranes, reminiscent of the basic CPC function during membrane vesiculation.29 At the molecular level, one of the most fundamental events during the evolutionary leap from prokaryotes to eukaryotes must have involved a radical change in membrane topologies associated with the emergence of CPC-mediated budding and NPCs.1 Based on recent computational and biochemical data, Devos et al20 proposed that early eukaryotes might have had a ‘protocoatomer’ module that induced curvature of endomembranes, and which subsequently gave rise to variants with the specialized functions of CPCs and NPCs. In a sense, the primordial NPC could then be envisaged as a ‘defective’ vesicle budding complex enveloping and curving membranes linked to the chromatin.20,30

SNARE Proteins: Cellular Machineries Driving Membrane Docking/Fusion

The SNARE family consists of a cognate group of integral and peripheral membrane proteins that function in the final stages of vesicular transport. This step involves tethering/ docking and subsequent fusion of the transport container with the target membrane.13,31 The core structural feature of all SNAREs is an evolutionarily conserved SNARE motif of about 60 residues.32 Based on their highly conserved structural features that contribute to the reversible assembly of quaternary docking-fusion complexes, SNAREs are classified into Q- and R-SNARE sub-families.32 Here, each Q- and R-SNARE family member is believed to contribute differentially to docking and fusion by providing specific information that correctly directs the close juxtaposition of two membrane bilayers at specific steps of the exocytic and endocytic pathways. Finally, bilayer docking/fusion mediated by the SNARE complexes is highly regulated by a variety of pathway-specific effectors that either promote (matchmakers) or prevent (matchbreakers) SNARE assembly pathways.33

With the completion of major eukaryotic genome projects, it is now clearly evident that only a modest increase (˜1.5-fold) has taken place in the number of SNARE family members with the expanding developmental complexity from yeast to human: S. cerevisiae (21 members), C. elegans (23 members), D. melanogaster (20 members), and H. sapiens (36 members).8,13 At a first glance, this rather modest increase in SNARE diversification may suggest that multi-cellular organisms do not necessarily have an inherently more complex sub-cellular trafficking system, and that a core set of SNAREs is largely sufficient for requisite membrane fusion events.8 This is reminiscent of the limited diversification observed for the core CPC machineries from yeast to human as discussed in the previous section. However, it is clearly evident that higher eukaryotes do indeed have more complex sub-cellular trafficking systems. To accommodate the needs of multi-cellular specialization, higher eukaryotes might have used the tissue-specific differential expression of an increased number of SNAREs and other additional regulatory membrane trafficking components.6,8

Rab GTPases: Key Regulators of Membrane Trafficking

Rab GTPases comprise the largest family of the Ras superfamily of small GTPases and function as molecular switches that regulate the dynamic assembly and disassembly of multi-protein scaffolds involved in vesicular traffic.5,6,34,35 Most Rabs are post-translationally modified with geranylgeranyl hydrocarbon chains that enable their partitioning into membranes. 36 Moreover, the membrane association of Rabs is under the control of the Rab-GDI recycling system.37 Fundamentally, Rab proteins can be viewed as simple molecular switches (‘on’ and ‘off ’ being their GTP- and GDP-bound states, respectively) that are associated with membranes in their activated state. However, Rabs have weak intrinsic guanine nucleotide exchange and hydrolysis activities, therefore their interactions with downstream effectors are regulated by guanine nucleotide exchange factors (GEFs) and GTPase activating proteins (GAPs) that promote the cyclical assembly and disassembly of Rab-mediated protein complexes.38,39 Effector complexes formed in response to Rab activation perform diverse functions that include coupling of endomembranes to motors, and hence to the cytoskeleton, as well as long-range vesicle docking/tethering interactions that are likely to regulate the membrane fusion activity mediated by the SNARE machinery.6,34,35

The number of Rab family members closely correlates evolutionarily with increasing endomembrane complexity: Schizosaccharomyces pombe (7 members), S. cerevisiae (11 members), C. elegans (29 members), D. melanogaster (29 members), Arabidopsis thaliana (57 members), and H. sapiens (63 members).8,11,12 This nearly 6-fold expansion in the number of Rab family members from yeast to human reflects the larger number of specialized trafficking pathways in the differentiated cell types forming organ systems of higher eukaryotes.6 In protozoal parasites such as Entamoeba histolytica and Trichomonas vaginalis, the Rab diversity may be as large as or even higher than that observed in higher eukaryotes,40,41 which could be due to expanding membrane trafficking needs associated with their amoebic life cycle phase as in the case of Dictyostelium discoidium that may have up to 54 Rabs.41

Compared to the 6-fold increase in the number of Rab GTPases from yeast to human, as indicated previously, only a marginal and at most modest increase has taken place in the number of core CPC modules and SNARE family members, respectively. This raises the possibility that Rabs may function as tethering/targeting/fusion activity hub organizers that provide the primary diversification element for membrane trafficking pathways by altering the combinatorial potential for protein interactions through coupling their GTPase activity with effector interacting (switch) domains (Fig. 2).6,38,42 While SNAREs direct late events leading to membrane docking/fusion, Rabs mediate vesicle targeting through the recruitment of membrane oriented tethering components that forge links with fusion factors to coordinate cargo transport with membrane flow. Moreover, the ability of Rab GTPases to couple transport containers to motor proteins can be conceptually viewed as a ‘tethering’ function that establishes the distribution of organelles within the cytoskeletal network. Such Rab-based hubs will rely heavily on the unique tissue distribution of Rab GEFs and GAPs as well as general modulators such as GDIs that facilitate Rab GTPase recycling.6

Figure 2. A) The three-dimensional structure of the rat Rab3A GTPase (PDB ID: 3RAB).

Figure 2

A) The three-dimensional structure of the rat Rab3A GTPase (PDB ID: 3RAB). The conserved RabF motifs are highlighted in red. B) Primary amino acid sequence alignment of 50 human Rab GTPases [see Gurkan et al for a complete list of GenBank® accession (more...)

The above observations suggest that during the course of eukaryotic evolution and the accompanying increase in the developmental complexity (i.e., presence of an amoeboid life cycle phase, tissue differentiation and organogenesis), the Rab GTPases are likely to have emerged as the main regulatory system orchestrating the requisite membrane trafficking pathways. Given the assumption that the dramatic diversification of the Rab GTPases in higher eukaryotes reflects the membrane specialization, we have found that mRNA expression profiling provides a useful and unbiased bioinformatics approach to understanding Rab-centric organization of the membrane architecture of cells and tissues.6,14 These Rabs-centric coding systems are likely to regulate specific membrane interactions and cargo flow between the sub-cellular compartments. We define this general system of Rab-regulated hubs of protein interactions in higher eukaryotes as the ‘membrome’ for a given cell type or transport activity.6 In this view, Rab and SNARE machineries, which are possibly linked through the activity of tethers, constitute the minimal core components of the membrome and their activity is regulated by cohub components that include Rab/SNARE regulators and effectors, which directly or indirectly interact with the components of CPCs to define cargo trafficking pathways. In a given cell type (or specialized life cycle stage), the membrome varies substantially to reflect the unique expression profiles of its components, thereby dictating unique membrane architectures and their consequential functionalities.

How do Rab-based hubs function at the molecular level? Rab function is based on the simple chemical reaction of hydrolysis of a phospho-diester bond in the guanosinetriphosphate (GTP) molecule, which results in conformational changes in the GTPase effector/switch regions. Analysis of the primary protein sequences within the Rab family of proteins reveals strongly conserved motifs, namely RabF motifs, which contain the effector-interacting switch I and II regions (Fig. 2A and B).11,12 In addition to the high degree of sequence conservation within the switch I and II regions, structural data demonstrate remarkable preservation of the three-dimensional fold.43 However, despite this sequence and structural homology between the individual Rabs, a clearly divergent course of molecular evolution has taken place within the Rab family. Interestingly, phylogenetic analyses allow the arrangement of all Rabs into eight functional sub-groups, such as group V – endosomal, group III – secretory, etc.12 It is now evident that the specificity of the interactions between the Rab GTPases and their corresponding effector proteins has been finely tuned during evolution through the introduction of subtle changes in the amino acid composition that map onto the surface of Rab effector regions. Interestingly, these changes have been limited to those preserving the chemical properties of the individual amino acid residues. For example, variations in the RabF1 motif of human Rabs are largely limited to a substitution of Isoleucine with a Valine, which are both alipathic amino acid residues, and/or an Aspartate with a Glutamate, which are both charged residues (Fig. 2B).

Concurrently, the Rab GTPases are promiscuous in their interactions with effectors. For example, Rab27a can interact with both melanophilin (Slac2-a) or MyRIP (Slac2-c), which are effectors that couple it to the molecular motors MyosinVa and Myosin VIIa, respectively.44 MyosinVa is responsible for the localization of melanosomes in melanocytes,45 while the same function in retinal pigment epithelial cells is performed by MyoVIIa.46 Clearly, this is an evolutionary adaptation in response to the different motility needs of the same organelle in different cell types reflecting myosin specialization. Given that multiple specialized Rabs are present across a variety of different tissues,6 it is very likely that this adaptation is a general feature within the Rab family. Thus, evolution has allowed the regulation of related trafficking steps using variations in the effector domain function coupled to the availability of different ensemble of effectors in each tissue.

In addition to the above levels of specificity, it is also possible that within the same cell type, Rabs may bind different effectors as a function of the spatial sub-cellular distribution of these partners. For example, the same Rab GTPase may be responsible for the tethering of an organelle to a motor and also for its interaction with the target membrane-bound tethering molecules as part of a sequential pathway of effector interactions (Fig. 3). If the function of Rab GTPases is to allow tethering of vesicle membranes to molecular motors (or other molecules), then a wide variety of biological activities arises from the combinatorial interactions of a given Rab with a wide array of downstream effectors and their respective binding partners. Such an array of interactions will depend on: (1) availability of each specific effector within the given tissue based on its expression levels and local protein concentration, and (2) the binding constant for this interaction. In other words, the biological activity of a Rab GTPase can be defined as the following function (f ):

Figure 3. Schematic representation of the known Rab GTPase functions.

Figure 3

Schematic representation of the known Rab GTPase functions. Rabs operate as molecular switches in at least two different scenarios: tethering membrane transport vesicles to molecular motors (top) or effector molecules (bottom) that mediate the assembly (more...)

Biological activity = (Kd1,[e1],Kd2,[e2]...Kdn,[en])

where Kdn is an affinity constant of a given Rab to an effector en, and [en] is the local concentration of the given effector. The nature of this relationship remains to be tested as more accurate measurements become available and more effectors are identified.

The seemingly simple cycle of GTP-/GDP-bound (‘on’/‘off ’) state of Rabs that constitutes the basis for Rab activity as molecular switches, has also been augmented during evolution by multiple layers of regulation. In addition to the Rab-GDI recycling system that mediates the membrane recruitment of the Rab GTPases,37 the specific activity of a given Rab is governed by the unique tissue/sub-cellular distribution of its requisite GEFs and GAPs that facilitate different Rab/effector exchange reactions. Thus, Nature has managed to respond kinetically to the various intracellular trafficking needs of complex multi-cellular organisms by utilizing these multiple regulatory mechanisms to generate a large variety of activities.6


The evolutionary leap from single to multi-cellular organisms did not require a substantial increase in the number of the core CPC and SNARE machineries that mediate the fundamental events of vesicle fission and fusion, respectively. Rather, they have a limited evolutionary course where the core CPC machineries (i.e., the cage-forming modules) and SNARE complexes (i.e., the membrane fusion modules) appear to have specialized with expanding cargo complexity through the diversification of the adaptor, regulatory factors and accessory proteins instead. In contrast, the drastic diversification of the Rab GTPases that regulate the protein interaction hubs, such as that orchestrating the tethering and fusion processes, suggests that Rabs are the principal evolutionarily element facilitating the expansion and specialization of membrane trafficking pathways. It now appears that specialization and functional divergence of membrane function has arisen through the ability of Rab GTPases to interact with a vast array of effectors in a combinatorial fashion. This is further fine-tuned by tissue-specific expression and the action of Rabs GTPases and their respective regulators. A formidable challenge in the field of cell biology will be the elucidation of the molecular mechanisms by which Rab-regulated tethering-fusion activity hubs integrate with that of coated vesicle formation/fission to shape the unique architectures of eukaryotic cells.


This work is supported by grants from the National Institutes of Health (GM33301 and GM42336) to WEB. CG and AVK are Cystic Fibrosis Foundation Postdoctoral Research Fellowship recipients. This is TSRI Manuscript No.: 17795-CB.


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