MRC Laboratory of Molecular Biology, Hills Road, Cambridge CB2 2QH, UK
* Author for correspondence (e-mail sean{at}mrc-lmb.cam.ac.uk )
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Summary |
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Key words: Vesicle tethering, Membrane traffic, Exocyst, Sec34/35 complex, COG complex, GARP complex, TRAPP
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Introduction |
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Several aspects of this model have recently been questioned. In particular,
it is unclear whether further factors provide specificity, help in SNARE
assembly or even assist in the fusion event itself. The rate of trans complex
formation is too slow in vitro to account for the rate of membrane fusion
observed in vivo, which suggests that accelerating factors are involved
(Fasshauer et al., 2002).
There is also evidence that in some cases fusion events are regulated
downstream of SNARE complex assembly, although the generality of this is
unclear (Muller et al., 2002
).
Most debate, however, has focused on whether interactions between v- and
t-SNAREs can account for the specificity of membrane transport events
(Pelham, 2001
). Biochemical
and genetic studies have identified several proteins that appear to play a
role in membrane transport steps after vesicle formation. These factors could
contribute to the fidelity of vesicle fusion and function in a process that
has become known as tethering (Fig.
1). This is the formation of physical links, often over
considerable distances, between two membranes that are due to fuse, before
trans SNARE complex formation (for reviews, see
Guo et al., 2000
;
Lowe, 2000
;
Waters and Hughson, 2000
).
Tethering might represent the earliest stage at which specificity is conferred
on a fusion reaction. Both yeast and mammalian systems have been used in the
discovery of tethering factors, and, although our understanding of the process
is still limited, the emerging picture is of a series of perhaps inter-related
steps that determine the specificity of membrane fusion.
What is the evidence that SNAREs do not provide all the specificity in
vivo? The ubiquitous distribution of SNAREs on some membranes is not
sufficient to account for the fusion of vesicles to localised regions of those
membranes. For example, the yeast plasma membrane SNAREs Sso1p and Sso2p are
distributed over the entire plasma membrane, and yet vesicles fuse with only
certain parts of the membrane during periods of polarised growth
(Brennwald et al., 1994).
Cleavage of squid synaptic SNAREs with toxins prevents SNARE complex formation
but results in the association of more, not fewer, vesicles with the membrane
(Hunt et al., 1994
).
Similarly, the percentage of tethered neuronal vesicles is significantly
higher in flies lacking syntaxin or synaptobrevin than in wild-type flies
(Broadie et al., 1995
). These
results are consistent with SNAREs being involved in membrane fusion but
dispensable for a prior tethering event that initially attaches the vesicle to
its target without causing it to fuse. Vesicle tethering has been observed in
an in vitro reconstituted system, which demonstrated that ER-derived vesicles
attach to the Golgi apparatus, losing their ability to diffuse freely, in a
reaction that is independent of functional SNARE proteins
(Cao et al., 1998
). A growing
number of factors proposed to be involved in tethering have been identified.
In many cases, the mode of action, interactions and indeed identities of these
factors remain obscure. Although it is still far from clear how tethering
occurs at a molecular level, connections between the variety of seemingly
disparate tethering factors are beginning to become apparent and may prove
useful in elucidating their roles.
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Protein complexes and coiled-coil proteins as potential tethering factors |
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Although the coiled-coil proteins are known in many cases to bind to a
target membrane and/or vesicle, their receptors on the membranes are generally
not known. One exception is p115, which tethers COPI vesicles to the Golgi.
Its receptors are two other coiled-coil proteins: giantin on the vesicles and
GM130 on the Golgi (Sonnichsen et al.,
1998). However, the simultaneous binding of p115 to both these
molecules has been called into question by the finding that they share, and
compete for, a common binding site on p115
(Linstedt et al., 2000
).
Nevertheless, the in vivo significance of the interaction between p115 and
GM130 is demonstrated by the accumulation of transport vesicles and reduction
of secretory transport when this interaction is inhibited
(Seemann et al., 2000
).
Giantin is membrane anchored, and GM130 interacts with Golgi membranes through
another protein, GRASP65 (Barr et al.,
1998
). Even in the case of p115, stripped of its complications,
the idea that a long, coiled-coil tether links the vesicle and the target has
yet to be confirmed. p115 and Uso1p may not even be typical of other large,
coiled-coil proteins, since they are unique in having a large globular domain
at one end.
Apart from their involvement in the Golgi and in endosomal fusion
(Nielsen et al., 2000), long,
coiled-coil proteins are not associated with other transport steps. We
therefore focus here on the second class of tethering factor, multisubunit
complexes, since there has been recent and rapid progress in their
characterisation. The overall molecular function of the complexes is still
unknown, but biochemical studies have revealed their subunit compositions and
interactions with other membrane-trafficking components. The complexes can
thus now be grouped and distinguished on the basis of sequence similarity. The
resulting classification suggests that the functions of some complexes differ
and that tethering is a complex process that encompasses several steps both
upstream and downstream of a stable, physical attachment of a vesicle to a
target membrane.
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Multisubunit tethering complexes |
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A family of quatrefoil tethering complexes |
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The exocyst
Probably the best-characterised tethering complex is the exocyst. Most of
its eight subunits were originally identified as products of genes whose
mutation causes yeast to accumulate vesicles destined for plasma membrane
(Guo et al., 1999a;
TerBush et al., 1996
). The
complex is localised to sites of polarised exocytosis in yeast, to which one
of the subunits, Sec3p, is localised independently of the cytoskeleton and the
secretory pathway (Finger et al.,
1998
). This contrasts with the localisation of the other
components to such sites, which requires both actin and a functional secretory
pathway. Sec3p might thus act as a landmark for polarised secretion
independently of the rest of the exocyst. One of the other components, Sec15p,
binds to Sec4p, the Rab GTPase present on secretory vesicles
(Guo et al., 1999b
). Moreover,
it appears to bind preferentially to the activated, GTP-bound form of Sec4p.
Sec10p and Sec15p co-immunoprecipitate from the soluble fraction of cytosol,
which indicates that they form a subcomplex. These findings lead to a model in
which activated Sec4p on a Golgi-derived vesicle binds to the Sec10p-Sec15p
subcomplex, which results in its assembly with Sec3p and the remainder of the
exocyst on the plasma membrane and thereby tethers the vesicle
(Guo et al., 1999b
).
The localisation of Sec3p appears to be mediated by its interaction with
the GTP-bound form of two Rho family GTPases, namely Rho1p
(Guo et al., 2001) and Cdc42p
(Zhang et al., 2001
), which
also have a role in the polarisation of actin. Vesicles travel along actin
filaments en route to the sites of polarised secretion
(Karpova et al., 2000
;
Pruyne and Bretscher, 2000
);
the Rho GTPases might therefore coordinate the cytoskeletal tracks along which
vesicles travel with the machinery that tethers them to their target. The
synthetic lethality of the combination of sec3 and mutations in
profilin, which regulates actin polymerisation and depolymerisation,
illustrates the importance of the actin cytoskeleton in this process
(Finger and Novick, 1997
;
Haarer et al., 1996
).
The mammalian counterpart of the exocyst consists of homologues of the
eight yeast proteins and is also localised to sites of polarised growth
(Brymora et al., 2001;
Hsu et al., 1996
;
Kee et al., 1997
). In some
non-polarised cell types, the exocyst is associated both with the trans Golgi
network (TGN) and with the plasma membrane, and antibody inhibition of each
pool affects cargo exit from the TGN and delivery to the plasma membrane,
respectively (Yeaman et al.,
2001
). In polarised epithelial cells, antibodies inhibit
basolateral but not apical traffic, and overexpression of human Sec10 results
in increased synthesis and delivery of secretory and basolateral, but not
apical, plasma membrane proteins
(Grindstaff et al., 1998
;
Lipschutz et al., 2000
). The
mammalian exocyst has been reported to interact with microtubules
(Vega and Hsu, 2001
) and
septins (Hsu et al., 1998
),
although the localisation of Sec3p in yeast is not dependent on, or coincident
with, the septins (Finger et al.,
1998
). The mammalian exocyst also interacts with Ca2+
signalling proteins (Shin et al.,
2000
) and, as in yeast, it is probably regulated by small GTPases.
Sec5 is an effector of the GTPase RalA, and inhibition of Ral function leads
to a decrease in the formation or stability of a mammalian exocyst subcomplex
containing Sec6 and Sec10 (Brymora et al.,
2001
; Moskalenko et al.,
2002
; Sugihara et al.,
2002
).
The COG complex
The COG complex has been proposed to act as a tether at the Golgi
apparatus, although it is unclear which vesicles are its substrates.
Wuestehube et al. identified sec34 and sec35 mutants in a
screen designed to identify yeast genes involved specifically in early stages
of the secretory pathway (Wuestehube et
al., 1996). Two groups subsequently showed that Sec34p (now Cog3p;
Table 1) and Sec35p (Cog2p)
associate as part of a large complex (Kim
et al., 1999
; VanRheenen et
al., 1999
). Identification of the other six components of the
complex (Whyte and Munro,
2001
) showed that the eight components fall into two phenotypic
groups. The data are best explained by a model in which two distinct classes
of vesicle are tethered by the complex to the early Golgi: vesicles recycling
within the Golgi, and vesicles recycling to the Golgi from later, endosomal
compartments (Fig. 2). Defects
in the former process could lead indirectly to a failure in ER-to-Golgi
transport, as observed for sec34 and sec35 mutants in vivo
(Wuestehube et al., 1996
) and
in vitro (VanRheenen et al.,
1998
).
A function for the COG complex in recycling of Golgi components is
supported by the identification of COG3 (as GRD20) as a gene
required for the proper localisation of a TGN protein
(Spelbrink and Nothwehr,
1999). Two reports reiterating the identification of a subset of
the subunits did not resolve the issue of anterograde versus retrograde
transport (Kim et al., 2001b
;
Ram et al., 2002
), but a third
shows interactions of the COG complex that support a recycling role
(Suvorova et al., 2002
). These
interactions are with SNAREs involved in intra-Golgi recycling and with the
COPI vesicle coat, which is involved in retrograde transport, but not with a
component of the ER-to-Golgi COPII coat. Mutants show Golgi-associated
glycosylation and sorting defects at temperatures permissive for the in vitro
ER-to-Golgi tethering assay (Suvorova et
al., 2002
), and indeed a mutant of one of the subunits, Cog1p,
shows no defect when tested in the in vitro assay for ER-to-Golgi transport at
restrictive temperature (Ram et al.,
2002
). The ER-to-Golgi tethering defect may therefore be an
indirect effect, but a recent report shows a defect in a different in vitro
assay that measures tethering of ER-derived vesicles, whether homotypic or to
another membrane (Morsomme and Riezman,
2002
). The same report suggests that, in addition to a tethering
function, the complex could have a separate and unexpected involvement in a
sorting event that occurs in vitro to create two classes of ER-derived vesicle
(Morsomme and Riezman, 2002
).
The exact role of the complex remains contentious, but, by analogy with other
tethering complexes, the COG complex is expected to interact with a Rab. The
most likely interaction would be as an effector of an early Golgi Rab such as
Ypt1p (Short and Barr, 2002
),
and this is supported by an in vitro interaction of the complex with Ypt1p
that occurs preferentially in the presence of GTP
(Suvorova et al., 2002
).
Identification of the eight yeast components of the complex revealed
homology to several, characterised and uncharacterised, mammalian proteins
(Whyte and Munro, 2001). In
particular, it led to the prediction that the mammalian Sec34p-containing
complex (Suvorova et al.,
2001
) is the same as the GTC
(Walter et al., 1998
), which
was purified from bovine brain cytosol on the basis of its stimulatory
activity in an intra-Golgi-transport assay. The GTC in turn was already
suspected to be the same as the ldlCp complex, a Golgi-associated complex
thought to contain ldlBp and ldlCp, two proteins that complement mutant
cultured cell lines that have a range of Golgi defects
(Chatterton et al., 1999
;
Podos et al., 1994
).
Identification of the eight components of the mammalian COG complex has shown
these predictions to be correct (Loh and
Hong, 2002
; Ungar et al.,
2002
). Interestingly, some of the components appear to be in a
subcomplex, which may represent one lobe of the two-lobed structure seen by
electron microscopy of the whole complex
(Ungar et al., 2002
). This
division is consistent with the phenotypic division of the yeast proteins into
two halves, but the existence of a subcomplex in yeast has not been
investigated.
Perhaps the most interesting finding to come from analysis of the
components of the COG complex is that some show extensive, albeit distant,
sequence similarity to components of the exocyst and the GARP complex, and
many of the subunits of all three complexes appear to have at their N-termini
a common domain (Whyte and Munro,
2001). An alignment of these domains is shown in
Fig. 4A. The domain is
predicted to form two short stretches of potential coiled coil or amphipathic
helix (not to be confused with the sequences in the long, coiled-coiled
tethering proteins such as Uso1p). For at least some of these components, the
sequence similarity is likely to reflect more than simply a shared structure,
because similarity searches find other components before any other coiled-coil
proteins (Whyte and Munro,
2001
). The presence of the common domain is not discernible in all
of the components by sequence similarity searches. It remains to be seen
whether this is because of its absence in some cases or because of an
inability to detect a structural similarity at the sequence level owing to
sequence divergence. The latter is at least suggested by the presence of
regions of predicted short coiled-coil near the N-termini of all components of
the human COG complex and exocyst (Fig.
4B). Similar predictions are seen for the yeast COG complex,
exocyst and GARP complex (TerBush et al.,
1996
) (data not shown). The significance of this putative domain
is not yet known; it may be involved in assembly of the complex or have some
other function. Nevertheless, its existence reveals a similarity between some
of the tethering complexes and suggests that they have similar modes of
action.
|
The GARP complex
Retrograde traffic from endosomes to the Golgi has not been as extensively
characterised as other transport steps, but the GARP complex localises to the
TGN and is required for this process
(Conboy and Cyert, 2000;
Conibear and Stevens, 2000
).
The GARP complex consists of four proteins (Vps51p, Vps52p, Vps53p and Vps54p)
(Conibear and Stevens, 2001
;
Gavin et al., 2002
) (E.
Conibear, personal communication), some of which show extensive sequence
similarity to other quatrefoil complex components
(Whyte and Munro, 2001
).
Whether it functions as a tethering complex has yet to be established, but
strong evidence for this comes from the finding that it is an effector of the
Rab Ypt6p and interacts with the SNARE Tlglp
(Siniossoglou and Pelham,
2001
). That its components share the domain found in the exocyst
and COG complex additionally suggests a tethering function, but confirmation
of such a role awaits development of an in vitro assay for this transport
step. Genes encoding mammalian homologues of Vps52p, Vps53p and Vps54p are
discernible in the databases but have not been characterised.
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Non-quatrefoil tethering complexes |
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The TRAPP complexes
The TRAPP (transport protein particle)
complex was originally described as a large protein complex functioning in the
later stages of ER-to-Golgi traffic in yeast
(Sacher et al., 2000;
Sacher et al., 1998
). After
its initial identification, it transpired that TRAPP represents two distinct
complexes. TRAPP I is
300 kDa in size and contains seven subunits,
whereas TRAPP II is
1000 kDa and contains an additional three subunits
(Fig. 3)
(Sacher et al., 2001
).
Subunits of these complexes share some sequence similarity, the six smallest
subunits falling into two families of three (Bet3p, Trs33p and Trs31p; and
Bet5p, Trs20p and Trs23p) (Sacher et al.,
2000
). TRAPP I and TRAPP II both cofractionate with an early Golgi
marker but not late-Golgi markers and are also present in a cytosolic pool.
The Golgi association is stable, in that Bet3p does not relocate to the ER
when anterograde ER-to-Golgi traffic is blocked, unlike components that cycle
between the ER and Golgi, and the complex remains assembled under these
conditions (Barrowman et al.,
2000
). The Golgi receptor for TRAPP is not known.
TRAPP I, but not TRAPP II, is required for an in vitro ER-to-Golgi
transport assay (Sacher et al.,
2001). TRAPP I binds to COPII vesicles formed in vitro from
permeabilised yeast cells. This binding appears to be independent of other
factors, since it occurs even when the COPII vesicles are formed from purified
coat components in the absence of cytosol and Golgi. Moreover, if Bet3p is
depleted from both vesicles and Golgi, no tethering occurs, which indicates
that other factors are not sufficient to tether vesicles in the absence of
TRAPP I (Barrowman et al.,
2000
). TRAPP II, in contrast, might be required for a later
transport step. A temperature-sensitive mutant of a TRAPP II-specific subunit
accumulates Golgi forms of invertase and CPY, as well as aberrant Golgi
structures. Its subunits also show synthetic interactions with mutants of
ARF1 and components of COPI but not COPII
(Sacher et al., 2001
).
Immobilised TRAPP I and TRAPP II both act as exchange factors for the early
Golgi Rab Ypt1p (Sacher et al.,
2001), and there is conflicting evidence about whether either acts
as an exchange factor for the late Golgi Rabs Ypt31p and Ypt32p
(Jones et al., 2000
;
Wang et al., 2000
). It is also
not clear whether or how the Ypt1p exchange activity is regulated, and why
Uso1p (a long coiled-coil protein and Ypt1p effector) is required in vitro to
tether COPII vesicles to the Golgi (Cao et
al., 1998
) when TRAPP I alone can bind to COPII vesicles. Perhaps
the combined interactions are required for proper tethering; binding of TRAPP
I to vesicles could stimulate its GEF activity, resulting in recruitment of
Uso1p by Ypt1p and additional binding of the vesicle by Uso1p.
At least seven of the TRAPP subunits are well conserved in mammals and are
present in a large complex (Gavin et al.,
2002; Sacher et al.,
2000
). The mammalian complex(es) has not been extensively
characterised but has been shown to localise to the Golgi
(Gecz et al., 2000
;
Sacher et al., 2000
).
Mutations in the homologue of yeast Trs20p are responsible for the human
disease spondyloepiphyseal dysplasia tarda (SEDL)
(Gecz et al., 2000
). The
non-lethality of this X-linked skeletal disorder might be caused by the
presence of an additional, autosomal, version of the SEDL gene that
appears to be a processed pseudogene but is nonetheless expressed.
The Class C Vps complex
The Class C Vps complex was identified through characterisation of the many
yeast mutants that show defects in the sorting of proteins to the vacuole.
Such vacuolar protein sorting (vps) mutants have been classified on
the basis of their phenotypes, and Class C mutants are those that lack
coherent vacuoles altogether (Raymond et
al., 1992). All four of the mutants in this class (Pep3p, Pep5p,
Vps16p and Vps33p) are part of a very large (38S) complex that appears to
function at two distinct transport steps
(Rieder and Emr, 1997
). It was
first identified as being involved in fusion to the vacuole of both transport
vesicles and other vacuoles. At the vacuolar surface, the Class C Vps complex
has another two components: Vam2p (Vps41p) and Vam6p (Vps39p). The latter is a
GEF for the Rab Ypt7p (Wurmser et al.,
2000
). The complex is also an effector of Ypt7p
(Seals et al., 2000
) and also
binds to the unpaired vacuolar SNARE Vam3p. This binding is probably through
Vps33p, which is a member of the Sec1 (or Munc18) family of SNARE-binding
proteins (Jahn, 2000
;
Sato et al., 2000
). This has
led to a model in which the Class C complex recruits Vps39p to both the
vacuole and incoming vesicles. Vps39p activates Ypt7p, which in turn acts on
the complex to promote a tethering interaction. Inhibition of Vam3p is then
relieved, which allows trans SNARE complex formation and fusion to
proceed.
The components of the complex do not show any clear homology to other known
Rab GEFs or to other tethering complexes. However, several of the components
have a domain related to the repeating structure of clathrin
(Conibear and Stevens, 1998)
and also contain RING-H2 domains, which are zinc-binding motifs that mediate a
number of protein-protein interactions. In yeast and Drosophila,
mutations in the RING-H2 domain abrogate function
(Rieder and Emr, 1997
;
Sevrioukov et al., 1999
). In
many other proteins, RING domains serve to recruit ubiquitin-ligases
(Borden and Freemont, 1996
;
Joazeiro and Weissman, 2000
),
and given the recent revelation of ubiquitin as a key sorting determinant in
the endocytic/vacuolar pathway, they might have a similar function here
(Hicke, 2001
). Human
homologues of Class C Vps subunits have recently been characterised and found
to be in a complex localized on late endosomes/lysosomes
(Caplan et al., 2001
;
Kim et al., 2001a
;
McVey Ward et al., 2001
).
The same complex also appears to function in Golgi-to-endosome transport.
This is indicated by genetic and physical interactions between Class C mutants
and genes encoding proteins known to promote tethering and fusion at the
endosome (Peterson et al.,
1999; Tall et al.,
1999
). Furthermore, Class C mutants show allele-specific defects
in either Golgi-to-endosome or endosome-to-vacuole transport
(Peterson and Emr, 2001
).
Parallels with the vacuolar function of the Class C complex have yet to be
addressed. However, the Class C Vps complex is not the only factor that has
been proposed to contribute to tethering in the endosomal system. In mammalian
cells the long coiled-coil protein EEA1 appears to act as a tether during
homotypic fusion of early endosomes
(Christoforidis et al., 1999
).
There is no clear homologue of EEA1 in yeast, although it was initially
proposed that Vac1p (Pep7p) might be related, and both are effectors for Rab5
GTPase (Vps21p in yeast) (Peterson et al.,
1999
; Tall et al.,
1999
). However a second Rab5-effector, Rabenosyn-5, appears to be
more related to Vac1p, although the latter has a RING domain that is absent
from the mammalian protein (Nielsen et
al., 2000
). The function of Vac1p and Rabenosyn-5 is unknown, but
yeast lacking Vac1p show defects in delivery of proteins from the Golgi to the
endosome (Weisman and Wickner,
1992
). Vac1p interacts genetically and physically with components
of the Class C Vps complex, and so it is possible that Vac1p and Rabenosyn-5
are involved in recruiting the Class C Vps complex to endosomal membranes
(Peterson and Emr, 2001
;
Srivastava et al., 2000
;
Webb et al., 1997
). However
both Vac1p and Rabenosyn-5 also bind to the Sec1-related protein Vps45p
(Burd et al., 1997
;
Nielsen et al., 2000
). Thus it
is also possible that there are further proteins stably associated with Vac1p
or Rabenosyn-5, which form another entirely distinct tethering complex that
acts on endosomal membranes.
Dsl1p complex
So far, there is no clearly described mechanism to tether Golgi-derived
vesicles to the ER in this vital recycling pathway. If there is such a
mechanism, it may well involve Dsl1p, a peripheral membrane protein of the ER
that is required for retrograde traffic and binds to another peripheral
membrane protein, Tip20p (Andag et al.,
2001; Reilly et al.,
2001
). Tip20p is part of a complex that contains the SNARE-like
membrane protein Sec20p, and together they bind to the ER SNARE Ufe1p
(Lewis et al., 1997
;
Sweet and Pelham, 1993
). It
therefore seems likely that a complex consisting of at least
Dsl1p-Tip20p-Sec20p exists and that it interacts with the SNARE Ufe1p. Mutants
of TIP20 are synthetically lethal in combination with those of
several subunits of the Golgi-to-ER (COPI) vesicle coat
(Frigerio, 1998
), and Dsl1p
interacts with a COPI subunit in two-hybrid assays
(Reilly et al., 2001
).
Clarification of the function of the Dsl1p complex awaits further
investigation of its biochemical role and protein-protein interactions, but
interestingly Dsl1p has a short stretch of predicted coiled coil near its
N-terminus, in common with components of quatrefoil tethering complexes.
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Mechanistic ideas |
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Interactions with SNAREs
Some t-SNAREs possess, in addition to the core SNARE domain, an N-terminal
domain that can bind to the core domain and thereby prevent its participation
in a trans SNARE complex. An attractive idea is that tethering complexes might
relieve this autoinhibition by promoting an open conformation of the
N-terminal domain relative to the core domain; recent evidence supports the
idea that tethering complexes bind to such N-terminal domains although not
necessarily that the complexes thereby relieve autoinhibition.
Deletion of the N-terminal domain of Vam3p results in a significant
reduction in homotypic vacuolar fusion in yeast and a significant reduction in
the formation of trans SNARE complexes
(Laage and Ungermann, 2001).
The Class C Vps complex also binds much less efficiently to the truncated
Vam3p, which suggests that the reduction in fusion is caused by an inability
of the Class C Vps complex to promote trans SNARE complex formation. The GARP
complex provides another example of the binding of a putative tethering
complex to an N-terminal SNARE domain, that of Tlg1p
(Siniossoglou and Pelham,
2001
).
The N-terminal domain of the yeast plasma membrane t-SNARE Sso1p is
essential. However, a constitutively open mutant of Sso1p is viable
(Munson and Hughson, 2002).
Thus the requirement for growth is not that the N-terminal domain be able to
bind to the core domain, although the constitutively open mutant does indeed
form complexes with other SNAREs more readily. This implies that the
N-terminal domain has an activating function as well as an inhibitory role.
The activating function could be provided by the binding of the exocyst or
another tethering factor, although there is currently no direct evidence for
this.
A variation on this idea is that tethering factors relieve the inhibition
of SNAREs by Sec1 family proteins (for details, see
Waters and Hughson, 2000),
which in some cases hold the SNARE N-terminal domain in a closed conformation.
In neuronal exocytosis, for instance, nSec1 binds to the monomeric form of the
SNARE syntaxin1A, preventing it from interacting with its t-SNARE partners
(Misura et al., 2000
;
Yang et al., 2000
). This sort
of mechanism may be employed by the Class C Vps complex, one subunit of which
is a Sec1 homologue. As ever, the real situation may be more complicated,
since some Sec1 proteins might themselves have an activating role in SNARE
assembly (Carr and Novick,
2000
; Jahn,
2000
).
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Conclusion |
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Acknowledgments |
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References |
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