Department of Molecular and Cell Biology, University of California, Berkeley, California 94720
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ABSTRACT |
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soluble N-ethylmaleimide-sensitive factor activating protein receptor
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LESSONS FROM NEURONAL SNARES |
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The structure of the core part of neuronal SNARE complex, consisting of the
SNARE domains assembled into an SDS-resistant complex (in the absence of
transmembrane or other domains), has been solved by both spin labeling
electron paramagnetic resonance and X-ray crystallography. In both cases, this
revealed a long (12 nm), twisted, parallel four-helix bundle composed of
SNARE domains oriented with their COOH termini toward the membrane
(30,
99,
119). SNAP-25 contributes two
helices to the bundle, and VAMP-2 and syntaxin 1A contribute one apiece. The
surface of the bundle has four prominent grooves and is highly polar, with
some very localized patches of charge
(30,
119); these features provide
putative binding sites for associated proteins. The coiled bundle is 16 layers
deep, and a layer near the middle, called the ionic central layer, contains
three glutamines and one arginine, the arginine being donated by VAMP-2 and
every other SNARE motif contributing one glutamine. The ionic central layer is
also commonly referred to as the "zero layer." The structure of
the core complex and the geometry of the ionic central layer are shown in
Fig. 1.
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THE SNARE HYPOTHESIS AND THE "MINIMAL FUSION MACHINERY" |
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A dramatic set of experiments conducted by Rothman and colleagues has sought to confirm the SNARE hypothesis and has resulted in a bold addendum to the hypothesis. Initially, the group reconstituted the neuronal SNAREs into liposomes. When liposomes containing VAMP-2 were mixed with liposomes containing syntaxin 1A and SNAP-25, they observed membrane fusion (131). This led to the conclusion that SNAREs are sufficient for membrane fusion, the "minimal machinery" for this process. This property of the system allowed the group to test the specificity posited in the SNARE hypothesis. Using proteins from Saccharomyces cerevisiae because of its completely sequenced genome, they created a combinatorial panel of liposomes containing v- and t-SNAREs known to be involved in three distinct membrane trafficking steps in the cell. With one exception, only the v- and t-SNARE combinations that function in vivo mediated membrane fusion in vitro (76). Furthermore, when liposomes containing the three sets of t-SNAREs were used against an expanded panel of all 11 v-SNAREs found in the yeast genome, only in vivo-identified complexes displayed fusion, again with one exception (76). They went on to show that complexes only form and lead to fusion when the v-SNARE resides on one membrane and the t-SNAREs reside on the other; the system does not tolerate topological switching within a functional complex (91). The group has since used the system to show that the SNARE complex forms in an orderly manner, "zippering" from NH2 terminus to COOH terminus, and that this zippering must be completed for membrane fusion to occur (78). Thus, in addition to the conclusion confirming the SNARE hypothesis, the group has asserted that SNAREs are also the minimal machinery for biological membrane fusion. These roles are illustrated in Fig. 2.
Numerous criticisms have confronted these experiments. First, many have pointed out that the speed with which the Rothman fusion reactions proceed is far too slow to be physiological. The group responded by repeating the experiments with a truncated version of syntaxin 1A that contains the SNARE domain but lacks a regulatory domain at its NH2 terminus (92). This approach did speed the in vitro fusion reaction from one round of fusion per hour to almost three rounds of fusion per hour (92). Though this is clearly an improvement, it is still nowhere near the speed with which the neuronal fusion reaction occurs in vivo. Second, the in vitro system does not use biological membranes. It is well established that synthetic membranes can be induced to fuse with each other under a number of conditions (12), some of which require no protein (45, 101, 128). The differences between biological and synthetic membranes manifest in both components of the membrane. First, consider the lipid composition of the membrane. Does the composition of the synthetic membrane reflect a genuine membrane? Do the supermolecular structures of a natural membrane form in the synthetic membrane (130)? What effects do they have on membrane merging? Second, the contribution of protein to the biophysical properties of the membrane should not be ignored. Many biological membranes are 50% or more protein by mass, obviously exerting a large effect on the properties of the membranes. Related to this is the concern that the membranes employed in the system simply need to be held in close apposition to undergo fusion. The Rothman group addressed this criticism by replacing the transmembrane domains of SNAREs with phospholipid anchors. These modified SNAREs formed complexes but were unable to mediate membrane fusion (77). Finally, the Rothman system was attacked by many who doubted whether the lipid-mixing assay of fusion employed by the group actually reflected genuine, complete membrane fusion. The group repeated the original experiments using a content-mixing assay and showed that the events that they reported reflected complete fusion of liposomes and mixing of aqueous contents (84).
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DO SNARES MEDIATE SPECIFICITY IN VIVO? |
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SNAREs have been shown to be fairly promiscuous in their interactions. In fact, even SDS-resistant complexes readily form between noncognate SNAREs in vitro (31, 137). However, the Rothman group proposed that the apparent nonspecificity was due to the soluble SNARE fragments that were used in these studies; membrane association, they argued, would impose additional constraints on the proteins and lead to interactive specificity (76). Nevertheless, examples from cellular systems argue that SNAREs do not account for the specificity of membrane fusion. Certain SNAREs mediate more than one transport step and, in so doing, incorporate into more than one SNARE complex. The v-SNARE Vti1p forms a complex with the t-SNARE Vam3p in mediating two distinct biosynthetic pathways (36). It also pairs with two other syntaxin-like t-SNAREs: with Sed5p to mediate retrograde traffic to the cis-Golgi, and with Pep12p to mediate traffic from the Golgi to the prevacuolar compartment (73, 125). Vam3 and Pep12 deletions cause distinct trafficking defects that confirm their assignment to the specific steps described above. However, a Vam3 deletion can be rescued by Pep12 overexpression and vice versa (23), indicating that, in a pinch, either of these t-SNAREs can substitute for the other in vivo and the secretory pathway still functions normally. Moreover, besides its complex with Vti1p, Vam3p pairs with the v-SNARE Nyv1p to mediate homotypic fusion of the vacuole (83). A similar situation exists for Bet1p, a SNARE that can function in both ER-to-Golgi and intra-Golgi retrograde transport (123). In animals, the t-SNARE syntaxin 7 can interact with the v-SNAREs VAMP-7 and VAMP-8 (126). Furthermore, in Drosophila melanogaster, the neuronal VAMP-2 homolog can be functionally replaced in vivo by a v-SNARE that normally operates in an earlier stage of the secretory pathway and vice versa (10). Moreover, in Drosophila, syntaxin 1A is expressed throughout the axonal plasma membrane, yet synaptic vesicles only fuse with the plasma membrane at the synapse (110). These observations imply that SNAREs simply do not provide the level of specificity that is needed for cellular integrity. Additional mechanisms are clearly required.
Although SNARE complex formation does not critically determine the
specificity of intracellular membrane fusion events, some degree of subunit
composition specificity is encoded therein. The SNARE complex does not form if
its components are mutated so that more than one arginine is present in the
ionic central layer, though it does not matter which SNARE donates it. If the
ionic central layer glutamine in the syntaxin 1A homolog or either glutamine
in the SNAP-25 homolog is mutated to arginine, the SNARE complex will still
form normally as long as the VAMP-2 homolog arginine is mutated to glutamine
(58,
89). The ionic central layer
can therefore help prevent formation of complexes without the appropriate
subunit composition by preventing multiple v-SNAREs from incorporating into
complex. This subunit composition specificity may not be absolutely conserved,
however, because functional SNARE complexes can sometimes still form if the
ionic central layer arginine is not present at all
(58,
89). One must therefore
conclude that the ability of the ionic central layer to mediate even subunit
composition specificity is not complete. In fact, the primary purpose of the
central layer may be to assist in complex disassembly by NSF and -SNAP
(108).
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ARE SNARES THE MINIMAL FUSION MACHINERY? |
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The idea that SNAREs might be the minimal fusion machinery was proposed with knowledge of another well-studied fusion system, that of viral fusion proteins. A number of enveloped viruses, including influenza and human immunodeficiency virus (HIV), use these proteins to invade host cells through a membrane fusion process. The proteins responsible for this event, which include influenza hemagglutinin and HIV gp41, are single integral membrane proteins that undergo a pH-dependent conformational change, often a proteolytic processing step, and invade the host membrane by inserting into it a short sequence known as the fusion peptide (50). There are remarkable structural similarities between the fusogenic state of viral fusion proteins and the core SNARE complex, suggesting a related function (13, 50, 51). It has been proposed that one of the functions of viral fusion proteins is to bring the fusing membranes close together, a role that these proteins could very well share with SNAREs. Many other aspects of the structure and biology of viral fusion proteins, including the nature of the fusion peptide (120, 121), are active and productive areas of research and beyond the scope of this review. However, they do provide a strong rationale for the minimal fusion machinery idea, as was appreciated in the proposal of this idea (131).
Complex formation is closely followed temporally by exocytic fusion in permeabilized PC-12 cells (18), and the authors of this study assert that a tight temporal correlation makes a fusion mechanism in which SNAREs directly mediate membrane fusion the most likely. This is somewhat unconvincing because of the time resolution in the study, which is much slower than the exocytic events that were being measured. More significantly, the invocation of the temporal and/or spatial correlation of SNARE complex formation with fusion as evidence that SNAREs are the minimal fusion machinery in vivo underscores the difficulties in proving this hypothesis. Studies correlating complex formation with fusion in vivo show that the SNARE complex is important for fusion, not that it is the minimal fusion machinery because many other components are also present. This was a part of the rationale for undertaking the in vitro experiments of the Rothman group (131), and these experiments remain the most compelling evidence that SNAREs fulfill the role of minimum fusion machines. One must remain cognizant of the aforementioned difficulties in extending these results to in vivo systems, however.
Empirical difficulties with the proposal that SNAREs are minimal fusion machines arise in the permeabilized PC-12 cell study cited above, in which SNARE complexes with markedly lower stability than wild type supported exocytosis at or above wild-type levels (18). Other studies also indicate that SNAREs are not the cell's minimal fusion machinery. In both isolated sea urchin cortical granules (20) and yeast vacuoles (124), SNARE complexes form as a part of the fusion process but can then be disassembled before completion of the process without affecting the kinetics or frequency of fusion. In fact, at least two requisite fusion steps occur downstream of SNARE complex formation in the yeast vacuole: one is dependent on protein phosphatase 1 activity (94), and one is sensitive to Ca2+/calmodulin (96). The fusion events facilitated by VAMP-2 continue to occur in VAMP-2 knockout mice, though with lower frequency (109). Moreover, the thermodynamic and kinetic properties of SNAREs may not be suitable for driving fusion as it is observed in vivo. In vitro, SNARE complex formation is a two-step process with a half-time (t1/2) of 1 min for the first step and a t1/2 of 1 h for the second step (32). Without the help of other proteins, complex formation simply cannot support the millisecond fusion observed at the synapse or even the slower events observed in secretory cells. Furthermore, the unusual stability of the SNARE complex is difficult to reconcile with the fast reversibility of kiss-and-run-type fusion events, in which the vesicular contents are released into the outer environment and the vesicle is reformed on an extremely fast (subsecond) time scale (1, 25, 117).
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ALTERNATE ROLES FOR SNARES IN FUSION |
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The idea that SNAREs may serve a signaling role is supported by the fact that the surface of the SNARE complex contains many distinctive subsurfaces (e.g., grooves, charged patches) that are putative binding sites for other proteins (4, 119). Given this hypothesis, however, it would not then be necessary for the complex to be embedded in both fusing membranes to function. As long as the complex were targeted to the correct site and formed at the appropriate time, it would be able to support membrane fusion. There are hints of this in the literature. First, though fusion steps are inhibited in yeast whose t-SNARE Pep12 is deleted, the phenotype can be rescued by expressing a truncated version of Pep12 whose transmembrane domain has been deleted (41). In permeabilized PC-12 cells, a mutation in SNAP-25 that eliminates a feature at the surface of the SNARE complex (i.e., the signaling part) is deficient in its ability to support exocytosis, despite the wild type stability of the complex (18). Certainly, the signaling hypothesis presents an exciting possibility.
If the SNARE complex is to organize the fusion machinery, then there have to be other components of the machinery. Proteins must be identified that interact with SNAREs and/or the SNARE complex. At the current time, a number of proteins have been shown to interact with these proteins and play a role in membrane fusion. One group of such proteins is the SM proteins. SM proteins are a family of soluble proteins with the ability to bind to t-SNAREs (38). They are known to regulate membrane fusion in a variety of systems, including the neural synapse and the yeast secretory pathway (7, 88). SM proteins were originally thought to bind to syntaxin and make it unavailable for complex formation (26), though it has become clear that, at least in some cases, they can bind the entire SNARE complex (15). Moreover, this binding can have effects quite distinct from negative regulation of complexation. In yeast, the SM protein Sly1p binds the t-SNARE Sed5p and readily allows SNARE complexes to form, while apparently controlling the specificity of SNARE associations (93). Sly1p can also bind preformed SNARE complexes in vitro (93). This is not always the case for SM proteins, because binding nSec1, a neuronal SM protein, precludes incorporation of syntaxin 1A into SNARE complexes (138). Furthermore, various SM proteins can bind to different domains of the SNAREs with which they associate (26, 60, 61). These data indicate that the mechanism of SM and SNAREs in vivo may not be entirely universal. Gallwitz and Jahn (38) have hypothesized that SM proteins also interact with non-SNARE proteins in the process of membrane fusion and that these interactions are just as important as SM protein-SNARE interactions. In the end, it is currently difficult to say whether SM proteins are generally regulators of SNARE function, components of the fusion machinery (see below), or both.
Synaptotagmins are proteins with Ca2+- and phospholipid-binding C2 domains that reside in plasma membranes and vesicles. Their requirement for fast synaptic transmission has led to the proposal that they are the Ca2+ sensors in this process (17). Syntaxin 1A and SNAP-25 isolated from bovine brain bind endogenous synaptotagmin I (104). Moreover, binding of synaptotagmins I and IX to SNAP-25 is required during Ca2+-dependent exocytosis in PC-12 cells (27, 139). A study has suggested that synaptotagmins bind Ca2+ and transduce a signal to associated t-SNAREs, which then interact with v-SNAREs (67). Synaptotagmins also associate with v-SNAREs, a phenomenon that may regulate posttranslational O-glycosylation of synaptotagmin (37). The necessity of the SNARE-synaptotagmin interaction for membrane fusion, however, has not been unequivocally established. For instance, there is evidence in PC-12 cells that the process of membrane fusion critically depends on the ability of synaptotagmins to bind phospholipids and not SNARE complexes (111). This is consistent with the hypothesis that SNAREs are involved in regulating the fusion machine, rather than being its minimal component.
A variety of other fusion components also interact with SNAREs in ways indicating that the fusion machine may be built on the SNARE complex. Complexins are proteins that rapidly and tightly bind to the SNARE complex (48, 90) and are also required for fusion in the neural synapse, though their exact function is unclear (105). It has been suggested that complexins regulate closure of the SNARE-based fusion pore and could be critical for kiss-and-run exocytosis (6, 103). Calmodulin kinase II (CaMKII) interacts with syntaxin at the neural synapse exclusive of the SM protein munc18 (86). This interaction increases the ability of syntaxin to bind both synaptotagmin and SNAP-25, suggesting that the CAMKII/syntaxin 1A complex may regulate or coordinate a step in core complex formation. In the yeast vacuole system, a t-SNARE was found to interact with proteolipid subunits (V0) of the v-ATPase (95), and a v-SNARE was found to indirectly associate with V0 through a complex of vacuolar transport chaperone (Vtc) proteins (80). Though these results do not establish that V0 binds the entire SNARE complex, they do indicate that the function of this putative component of the fusion machinery is affected by its binding (or not) to SNAREs. In PC-12 cells, binding of calmodulin and phospholipids to VAMP is required for exocytosis, though not for formation of the SNARE complex (100). [This is not the only indication that binding of the fusion machinery to phospholipids is important for fusion. In the yeast vacuole, the SNAP-25 analog Vam7p cycles off of the membrane and is re-recruited to the fusion machinery via binding to phosphatidylinositol 3-phosphate (11).] A number of other proteins are known or implicated to regulate exocytosis, interact with one or more individual SNAREs, and could be regulated by interactions with either individual SNAREs or SNARE complexes. Among these proteins are the recently described syntaphilin (66), the VSM1 gene product (75), and the Chediak-Higashi protein (122). Ion channels, a class of proteins of high interest to physiology, are also known to associate with certain SNARE proteins. N- and Q-type Ca2+ channels were first observed to behave this way (9), though epithelial Na+ channels (ENaC) (19) and cystic fibrosis transmembrane conductance regulator (CFTR) (22) also participate in interactions with SNAREs. The role that this phenomenon plays in the fusion process (if any) is unclear, though it is clear that SNARE binding to ion channels can alter the open probability (16) and/or affect the slow inactivation process of the channel (24). Table 1 lists several proteins that have been shown to interact directly with SNAREs.
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In several cases, knowledge of the fusion machinery has expanded beyond elucidation of single proteins that interact with SNAREs and/or SNARE complexes. In the yeast vacuolar sorting pathway, the t-SNARE Pep12p interacts with the SM protein Vps45p, which interacts with an adaptor (Vac1p) that associates with the rab-like GTPase Vps21p in its GTP-bound form (97). Similarly, in the yeast Golgi, the t-SNARE Tlg1p and GTP-bound Ypt6p (another rab GTPase) interact indirectly through binding different subunits of a proteinaceous complex that mediates membrane association before trans-SNARE complex formation, the VFT (Vps fifty-three) docking complex (112). These results are provocative because they link two protein families required for trafficking, SNAREs and rabs, more precisely and convincingly than previous studies (70, 74). The indirect and transient nature of these connections also highlights the technical challenges involved in identifying all components of the fusion machinery. A summary of the roles that SNAREs may play in some or all complex fusion machines can be found in Table 2.
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The identification of SNARE-interacting proteins does not in itself prove the SNARE signaling hypothesis. These proteins could also reflect an elaborate cellular scheme by which to regulate formation of the minimal fusion machinery. However, in addition to the data summarized in the previous section, the SNARE signaling hypothesis is recommended by its resolution of some issues in the fusion area. For example, it can reconcile the permissiveness of SNARE-SNARE interactions with the specificity of the fusion events in which they participate, implied by their distinct subcellular localizations. Rather than being a lock-and-key determinant of specificity, SNAREs may fit specific fusion reactions by the surfaces they create upon complexation, thereby directing the assembly of specific fusion machines, though the cohorts of fusion machine participants may overlap. The SNARE signaling hypothesis can thus explain why SNAREs are required for so many mechanistically and kinetically distinct fusion steps in a more satisfying way than the minimal fusion machinery idea can. Also, it is much easier to reconcile the fact that SNARE complexes with submaximal stabilities can support exocytosis very well, while some complexes with high stability cannot at all (18, 43) within the framework of the signaling idea. It is important to remember, however, that not everything known about SNAREs may be equally applicable to different systems. Two of the best-studied fusion systems, the neural synapse and the yeast vacuole, have many similarities in terms of the types of proteins involved yet have apparently very distinct mechanisms of fusion. Table 3 provides a brief comparison of these two events, highlighting some of what is known about SNARE-interacting proteins and the potential role of SNAREs in each system.
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IS THE SNARE COMPLEX NECESSARY FOR FUSION? |
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Another alternative SNARE complex is the so-called t-SNARE complex. The t-SNARE complex is a binary association of, for example, syntaxin 1A and SNAP-25. The structure of the neuronal t-SNARE complex has been determined, revealing a four-helix parallel bundle consisting of two copies of syntaxin 1A and one copy of SNAP-25 (135). It is generally thought that the t-SNARE complex represents a starting point for formation of the classic ternary SNARE complex, though a recent observation questions this view. In permeabilized chromaffin cells, stimulation of exocytosis led to increased formation of a variety of t-SNARE complexes, having different sizes and, presumably, states of oligomerization and quaternary structure (67). Interestingly, inhibition of secretion by botulinum neurotoxin A, which cleaves SNAP-25, did not inhibit the formation of t-SNARE complexes in response to Ca2+, though it did alter the composition of t-SNARE complexes and increase the number of ternary SNARE complexes drastically (67). These results suggest that there may be a role for the t-SNARE complex(es) in membrane fusion besides, or in addition to, a precursor to formation of the classic SNARE complex.
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SNARES BEYOND THE SNARE DOMAIN |
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Conclusion
In summary, SNAREs have captured the imagination of virtually everyone in the field of membrane fusion. They possess features that recommend them as specificity determinants as well as possibly the minimal fusion machinery. From the Rothman SNARE experiments, both of these roles are forwarded, though a growing body of evidence suggests that the actual physiological process of membrane fusion is much more complicated. Proteins that interact with SNAREs, many of which may facilitate complex formation, are still being discovered today (54). Understanding the functions of these proteins may give us the insight we need to finally appreciate the contribution of SNAREs to cell function. We may also discover that another assumption that is widely held, explicitly and implicitly, that the function of SNAREs is perfectly analogous in every organism and transport step is not actually true, despite the dramatic similarities in structure and biochemistry between divergent SNARE complexes. In any case, the groundwork for an exciting and contentious continuing debate has been laid, and SNAREs will likely continue to make cell biology headlines for the foreseeable future.
Address for reprint requests and other correspondence: J. G. Forte, Dept. of
Molecular and Cell Biology, Univ. of California, Berkeley, CA 94720 (E-mail:
jforte{at}uclink.berkeley.edu).
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