Secretory Pathways Laboratory, Cancer Research UK London Research Institute, 44 Lincoln's Inn Fields, London WC2A 3PX, UK
* Author for correspondence (e-mail: sharon.tooze{at}cancer.org.uk)
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Summary |
---|
Key words: AP-1, GGA protein, Golgi, Endosome, TGN
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Introduction |
---|
Although AP-2 has a well-established function in receptor-mediated
endocytosis (Kirchhausen,
2002; Slepnev and DeCamilli,
2000
; Takei and Haucke,
2001
), many views about AP-1 function have had to be modified in
recent years. It was long accepted that AP-1 functions in anterograde
trafficking from the TGN to endosomes; however, the picture emerging now is
that AP-1 functions in both anterograde and retrograde trafficking. Accessory
factors that might be specific for retrograde transport have been identified.
The recent discovery of GGA proteins monomeric, adaptor-related
proteins has extended our understanding of how clathrin-coated
vesicles form on the TGN. The domain organisation of adaptor complexes and
their structure-function relationships have been discussed in detail elsewhere
(Kirchhausen, 1999
), as have
AP-3 and AP-4 (Robinson and Bonifacino,
2001
). Here, we discuss the recent progress in our understanding
of AP-1 and GGA function and how they might interact.
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AP-1: subunit organisation and accessory factors |
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The large adaptins (, ß,
and
) have similar
domain organisations and consist of an N-terminal body/trunk domain, a
variable hinge region and a C-terminal ear/appendage domain, which fulfill
different functions (Fig. 1C).
AP-1 binds to clathrin mainly through its clathrin-box motif in the hinge
region of ß1-adaptin (Gallusser and
Kirchhausen, 1993
). ter Haar et al. have recently obtained a
crystal structure of the clathrin terminal domain (TD) complexed with a
peptide representing the clathrin box motif of ß3-adaptin, the
ß-subunit of AP-3 (ter Haar et al.,
2000
). The clathrin-box motif consensus sequence,
L(L/I)(D/E/N)(L/F)(D/E), binds to the WD40 motif of the clathrin TD
(Kirchhausen, 2000a
). More
recently, Doray and Kornfeld have shown that the hinge domain of
-adaptin, and to a lesser extent the ear domain of
-adaptin
(
-ear), can also bind to clathrin
(Doray and Kornfeld, 2001
).
The body domain of
-adaptin is responsible for correct membrane
targeting of the AP-1 complex: chimeric adaptor complexes consisting of AP-1
and AP-2 adaptor complexes in which the body and hinge from
-adaptin
are linked to the ear from
-adaptin (
-ear) still target to the
TGN (Robinson, 1993
).
The -ear is thought to recruit additional regulatory factors to the
site of vesicle formation (Fig.
1C). A two-hybrid screen has identified a novel factor that
interacts with the
-ear,
-synergin
(Page et al., 1999
). This
protein contains an Eps15-homology domain, and, by analogy with the well-known
protein network assembled on the
-ear, is thought to recruit additional
proteins. In GST-pulldown assays, the
-ear interacts with several
proteins, including rabaptin-5, although the function of rabaptin-5 in vesicle
biogenesis remains elusive (Hirst et al.,
2000
). Furthermore, Wasiak et al., using a proteomic approach,
have identified an additional ENTH-domain-containing protein, enthoprotin,
which is enriched in clathrin-coated vesicles and binds AP-1
(Wasiak et al., 2002
).
Kalthoff et al. identified the same protein, called Clint, by screening the
database for uncharacterized ENTH-containing proteins
(Kalthoff et al., 2002
). Nogi
et al. and Kent et al. recently determined the crystal structure of the
-ear (Fig. 1C),
revealing that this domain has an immunoglobulin-like ß-sandwich fold
similar to that of the
-ear and ß2-ear
(Nogi et al., 2002
;
Kent et al., 2002
). However,
the
-ear is about half the size of the ß-ear (and the
-ear)
and does not have a hydrophobic C-terminal platform domain (compare boxed ear
structures in Fig. 1B and C)
shown to be the binding site for accessory proteins in the AP-2 subunits
(Owen et al., 2000
;
Traub et al., 1999
). Rather,
the binding of accessory proteins to the
-ear is mediated by residues
found on the surface of the
-ear domain, although there are conflicting
views on exactly which residues are important
(Nogi et al., 2002
;
Kent et al., 2002
).
The µ-subunit mediates cargo recognition and recruitment
(Fig. 1A). It binds to
tyrosine-related sorting motifs in the cytoplasmic tails of transmembrane
proteins (Ohno et al., 1995;
Owen and Evans, 1998
). It is
still a matter of debate which adaptor subunit binds to dileucine sorting
motifs: two-hybrid studies and phage display identified the µ1 subunit as
the interacting subunit of the AP-1 complex
(Rodionov and Bakke, 1998
;
Storch and Braulke, 2001
), but
crosslinking studies identified the ß1-body as the region that interacts
with dileucine-motif containing-peptides
(Rapoport et al., 1998
). Note
that these studies are usually complicated by the fact that most cargo
proteins bind to several adaptor complexes and accordingly contain several
adaptor-interaction motifs; thus it is difficult to study these interactions
with native, full-length proteins.
Knockout mice lacking the 1-adaptin or the µ1a-adaptin genes die
early in embryonic development (Meyer et
al., 2000
; Zizioli et al.,
1999
), although µ1a knockouts survive for longer, presumably
because the µ1b subunit can substitute for µ1a in early development. The
µ1a-knockout animals die at day 13.5 of embryonic development and show
evidence of haemorrhage into the ventricles and the spinal canal.
Interestingly, no AP-1 subunits are found in
1 knockouts at all.
Because the mRNA levels of the other subunits are not reduced, the remaining
subunits must be unstable and degraded rapidly. By contrast, embryonic
fibroblasts from µ1a-knockout animals contain trimeric complexes consisting
of ß1-adaptin,
-adaptin and
-adaptin. However, these
complexes appear to be nonfunctional since no membrane-associated
-adaptin could be observed.
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What is the exact function of the AP-1 complex? |
---|
The first doubts that AP-1 indeed functions in anterograde transport
appeared when Meyer et al. investigated the trafficking of MPRs in the
µ1a-knockout mice (Meyer et al.,
2000). If AP-1 mediates anterograde transport from the TGN to
endosomes, one would expect that in AP-1 knockouts the MPRs would get stuck in
the TGN. This is not the case, however: the MPRs exit the Golgi, get
transported to the plasma membrane and are re-endocytosed from there,
accumulating in an early endosomal compartment that contains the early
endosome marker EEA1. This indicated that AP-1 might mediate not anterograde,
but retrograde, transport between endosomes and TGN. The observation that
Shiga toxin
co-localises with AP-1 on early/recycling endosomes during a 20°C block of
retrograde transport and that toxin transport is inhibited by BFA supports
this idea (Mallard et al.,
1998
). Recently this model gained further support when Bonafacino
and co-workers suggested that the recently discovered GGA proteins mediate
anterograde transport of MPRs and other transmembrane proteins that have
acidic dileucine motifs (Puertollano et
al., 2001a
). However, it is not easy to reconcile the idea that
AP-1 acts only in retrograde transport with its steady-state distribution
concentrated at the TGN, and indeed AP-1 is involved in anterograde transport
(see below).
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GGAs |
---|
![]() |
GGA function in S. cerevisiae |
---|
The effect of GGA mutants on CPY sorting and -factor processing
resembles the phenotype of yeast expressing a temperature-sensitive mutant of
clathrin under non-permissive temperature
(Deloche et al., 2001
) and
thus was the first indication that GGAs might interact with clathrin. Indeed,
GST pulldown and co-immunoprecipitation experiments have shown that clathrin
and GGAs proteins interact and that a triple knockout of clathrin and the GGA
proteins is either synthetically lethal or aggravates the phenotype, depending
on the yeast background that is used
(Costaguta et al., 2001
;
Hirst et al., 2001
). Taken
together, these results suggest that clathrin and GGAs act together in
anterograde transport from the TGN to the vacuole.
The only adaptor complex that interacts with clathrin in yeast is AP-1.
Disruption of any of the AP-1 subunits, which results in an absence of
heterotetrameric complexes, gives no phenotype with respect to CPY sorting and
-factor processing; however, simultaneous knockout of AP-1 and GGA
exacerbates the phenotype of GGA knockouts, enhancing the effect on
-factor processing more than the effect on CPY transport
(Costaguta et al., 2001
;
Hirst et al., 2001
). This
result suggests that AP-1 and GGA proteins cooperate in anterograde transport
from the TGN to the vacuole.
Several possible models could explain how AP-1 and GGA proteins might
interact in yeast. One possibility is that they act in parallel
clathrin-dependent pathways. In this case, two populations of clathrin-coated
vesicles would bud from the TGN, one population that contains AP-1, and
prefers Kex2p as cargo, and one that contains GGA proteins and prefers Vps10p
as cargo, although it remains to be determined how Vps10p is recruited into
clathrin-coated vesicles, since the cytoplasmic domain of Vps10p is
dispensable for clathrin-dependent transport
(Deloche et al., 2001). Such
vesicles could have different destinations: AP-1-coated vesicles would be
targeted to early endosomes, whereas GGA containing vesicles would travel to
late endosomes (Black and Pelham,
2000
). The model that they form distinct vesicles is consistent
with the notion that GGA proteins and AP-1 show only limited co-localisation
in mammalian cells (Dell'Angelica et al.,
2000
; Hirst et al.,
2000
). Another possibility is that GGA proteins and AP-1 are
present in the same coated vesicles but recruit different types of cargo. This
would be consistent with the finding that AP-1 and GGA proteins
co-immunoprecipitate in yeast (Costaguta
et al., 2001
).
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GGA function in mammalian cells |
---|
Although the structures of the VHS domain of TOM1 (target of myb1) and Hrs
have been determined (Mao et al.,
2000; Misra et al.,
2000
), the function of this domain remained unknown for some time.
Recently, it was shown that the VHS domain of the GGA proteins binds directly
to the acidic dileucine motifs of CI-MPR and the cation-dependent (CD)-MPR
(Puertollano et al., 2001a
;
Zhu et al., 2001
),
sortilin¶
(Nielsen et al., 2001
) and
LRP3 (Takatsu et al., 2001
).
The determination of the crystal structure of the complex demonstrated that,
like the VHS domains of TOM1 and Hrs, that of the GGA proteins forms a
right-handed superhelix consisting of eight
helices
(Fig. 1D). The acidic dileucine
motif binds to GGA in an extended conformation by electrostatic and
hydrophobic interaction with helix 6 and helix 8
(Misra et al., 2002
;
Shiba et al., 2002
). However,
it remains to be determined whether other VHS domains bind at all to acidic
dileucine motifs.
The mammalian GGA proteins are essential for the anterograde transport of
MPRs from the TGN to the endosome, which is consistent with the observed
interaction between the GGA VHS domain and the dileucine motif of MPRs.
Remarkably, proteins that have similar dileucine sorting motifs, such as
tyrosinase, LAMP-2 and the transferrin-receptor [for the full list of analysed
proteins, see Puertollano et al.
(Puertollano et al., 2001a)],
do not bind to GGA proteins. Furthermore, the GGA VHS domain can not be
substituted by VHS domains from other proteins, such as STAM1, Hrs, TOM and
TOML1. This indicates a high degree of selectivity for the interaction of VHS
domains with particular dileucine motifs. Site-directed mutagenesis of the
MPRs revealed that the acidic cluster N-terminal of the dileucine-motif is
essential for GGA binding. Furthermore, Misra et al. demonstrated that the
dileucine motif must be located at the C-terminus of the protein and that
there must be a spacing of two residues between the two leucine residues and
the C-terminus for optimal binding (Misra
et al., 2002
). Thus, it came as a surprise when Dennes et al.
demonstrated that the cytoplasmic tail of Vps10p binds to mammalian GGA
proteins, because the dileucine motif is localised to the middle portion of
the cytoplasmic tail (Dennes et al.,
2002
). While Dennes et al. did not use mutagenesis of the
dileucine motif to demonstrate that the internal dileucine motif is required,
they were able to show a chimeric protein consisting of the lumenal and
transmembrane domains of CI-MPR and the cytoplasmic tail of Vps10p is sorted
like wild-type CI-MPR and, in MPR-deficient cells, can rescue missorting of
soluble lysosomal hydrolases with the same efficiency as wild-type CI-MPR.
When the N-terminal portion of a GGA protein that has the VHS and GAT
domains, but lacks the clathrin-binding hinge domain and the GAE domain is
expressed in mammalian cells, both MPRs accumulate in the TGN and clathrin is
no longer detected on TGN membranes
(Puertollano et al., 2001a).
AP-1 localisation is unaltered if the expression of the GGA N-terminus is kept
at moderate levels. These data suggest that GGA proteins mediate
clathrin-dependent anterograde transport of MPRs from the TGN to endosomes, a
function long attributed to AP-1. Time-lapse microscopy showing vesicles
containing fluorescently labelled CD-MPR and GGA1 budding from the TGN
provides further support for this hypothesis
(Puertollano et al., 2001a
).
Given the work of Meyer et al. on MPR trafficking in AP-1-deficient mice
(Meyer et al., 2000
),
clathrin-coated vesicles containing AP-1 might thus mediate retrograde
trafficking from endosomes to the TGN, whereas clathrin-coated vesicles
containing GGA proteins could mediate anterograde trafficking.
So far, however, in mammalian cells there is no evidence that GGA proteins
are a stable component of clathrin-coated vesicles; instead they redistribute
very quickly to the cytoplasm under conditions where AP-1 stays on the
membrane (Hirst et al., 2001).
This could be a preparation artefact, but it could also indicate that GGA
proteins are not necessarily packaged into vesicles but rather help recruit
coat components and cargo into a budding vesicle. New exciting data support
this hypothesis, extending the data that demonstrate cooperation between AP-1
and GGA proteins in yeast (Costaguta et
al., 2001
), Doray et al. show that the GGA hinge region binds to
the
-ear of AP-1. This indicates that AP-1 and GGA proteins might
interact and cooperate in the same sorting step
(Doray et al., 2002b
). In
immunoelectron microscopic studies using cells stably transfected with GGA2,
the authors demonstrate co-localisation of GGA2 and AP-1 on coated buds of the
TGN. Moreover, mutant MPR that does not bind GGA proteins fails to enter
AP-1-coated vesicles. Waguri et al. provide further support for AP-1-mediated
transport of CI-MPR from the TGN in their recent study of fluorescently
labeled CI-MPR and AP-1 in living cells. Their images show AP-1 and CI-MPR in
tubules forming and detaching from the TGN and moving out towards the
periphery of the cells (Waguri et al.,
2003
).
Additional circumstantial evidence suggests that GGA proteins regulate coat
assembly rather than form a stoichiometric component of clathrin-coated
vesicles. The GGA GAT domain is necessary and sufficient to target GGA
proteins to the TGN. This domain binds ARFs and inhibits GAP-mediated GTPase
activity of ARF, presumably because GGA proteins and GAPs compete for binding
to the switch 2 domain in ARF (Puertollano
et al., 2001b). GGA proteins might therefore provide a
proof-reading mechanism by controlling the kinetics of ARF-mediated GTP
hydrolysis, allowing activated ARF to be transiently stabilised on the
membranes and thus recruit AP-1 and clathrin. In the absence of coat proteins,
ARF would hydrolyse GTP quickly and recirculate into the cytoplasm. Indeed,
when the GGA GAT domain is expressed at high levels, AP-1 redistributes to the
cytosol, presumably because the GGA hinge (the AP-1 binding domain) is missing
(Puertollano et al., 2001b
).
Although these data are consistent with the model that GGA proteins help
recruit AP-1, an alternative explanation for this phenomenon is that the high
GGA protein levels lock all ARF proteins onto the membrane. This would make it
impossible for AP-1 to be recruited through simple competition for ARF-binding
sites, although this is unlikely since AP-1 binds to the switch 1 domain
(Austin et al., 2000
). Such a
model is, however, consistent with the fact that AP-1 is redistributed only at
very high GGA expression levels. It should be possible to distinguish between
these two models by the following experiments. If GGA proteins and AP-1
compete for ARF-binding sites, then simultaneous overexpression of ARF should
compensate for the GGA effect, and AP-1 should be recruited to the membrane.
If GGA proteins help recruit AP-1, then overexpression of full-length GGA
proteins should enhance recruitment of AP-1 to membranes.
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Is retrograde transport AP-1 dependent? |
---|
The protein TIP47 binds specifically to both CI-MPRs and CD-MPRs and is
essential for their retrograde trafficking
(Diaz and Pfeffer, 1998).
TIP47 is a Rab9 effector, and Rab9 recruits TIP47 to endosomal membranes,
where it then interacts with MPRs (Carroll
et al., 2001
). Both MPRs have cytoplasmic palmitoylation sites,
which might affect TIP47 binding. So far, clathrin and AP-1 appear not to
participate in this transport step.
Phosphorylation of transmembrane proteins also determines their direction
of transport (Breuer et al.,
1997; Jones et al.,
1995
; Méresse and
Hoflack, 1993
; Pitcher et al.,
1999
). Proteins such as
furin** contain
phosphorylation sites that are not part of a dileucine motif and thus act
independently as sorting motifs. At steady state, furin is localised to the
TGN, from where it recycles to and from endosomes
(Jones et al., 1995
).
Phosphorylation of furin enhances recruitment of AP-1 to membranes, and
mutation of the phosphorylation sites results in missorting of the protein
(Dittié et al., 1997
).
PACS-1, a ubiquitous cytosolic protein identified in a two-hybrid screen for
proteins that bind to the phosphorylated cytoplasmic tail of furin (Wan,
1998), facilitates retrograde transport from endosomes to the TGN in a
phosphorylation-dependent manner. It can also bind to CI-MPR and importantly
AP-1. Thus, a trimeric complex consisting of a cargo protein bound to AP-1
forms and is stabilised by PACS-1 (Crump
et al., 2001
). Further evidence for its involvement in retrograde
transport comes from antisense experiments demonstrating that furin
accumulates in endosomes in the absence of PACS-1. AP-1 thus probably mediates
retrograde trafficking in cooperation with PACS-1. In such a model,
phosphorylation of furin and CI-MPR would occur on endosomes and recruit
PACS-1 and AP-1.
PACS-1-dependent and TIP47-dependent retrograde transport mechanisms need not to be mutually exclusive for two reasons. First, TIP47 seems to recognise specifically MPRs; thus other transmembrane proteins may be recognised by other proteins that regulate retrograde transport. Second, retrograde transport from different endosomal compartments may be regulated by different proteins: TIP47-mediated transport originates from late endosomal compartments, whereas PACS-1-mediated transport may start on early endosomes.
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How does phosphorylation influence transport between trans-Golgi network and endosomes? |
---|
Kato et al. have recently shown a direct increase in affinity of CI-MPR for
GGA proteins when CI-MPR is phosphorylated: binding of the phosphorylated MPR
was increased 3 fold compared with the non-phosphorylated protein
(Kato et al., 2002
). The
determination of the crystal structure of the complex confirmed that the
increase is caused by electrostatic interaction of phosphoserine at position
2485 upstream of the dileucine motif of CI-MPR with Lys86 and Arg88 of GGA3.
The kinase that performs these phosphorylation reactions is casein kinase 2
(CK2), a heterotetrameric protein (Pinna,
2002
), that co-purifies with adaptor complexes
(Doray et al., 2002b
;
Méresse et al., 1990
).
GGA1 and GGA3 have very recently been identified as CK2 substrates
(Doray et al., 2002a
). The GGA
hinge region contains an acidic dileucine motif very similar to that in
CI-MPR. When the GGA hinge becomes phosphorylated, the neighboring VHS domain
binds to this motif, and the molecule undergoes intramolecular autoinhibition
such that it cannot bind MPRs.
These two opposing effects of CK2 on GGA1/3-MPR interaction during coat recruitment seem paradoxical at first, and at the moment we can only speculate on how CK2 regulates the interaction between GGA1/3 and MPRs in vivo. One possibility is that one, or several, as-yet-unknown phosphatases act as a "timer" to ensure cargo recruitment into budding vesicles. In this scenario, non-phosphorylated GGA proteins would initially bind to phosphorylated MPRs, thus facilitating clathrin recruitment and allowing the vesicle to bud off the donor membrane. The activation of a phosphatase that dephosphorylates MPRs and the continued action of CK2 would then produce phosphorylated GGA proteins and non-phosphorylated MPRs, triggering the dissociation of the complex and possibly uncoating of the vesicle.
If GGA proteins cooperate with AP-1 during coat recruitment, however, then
the phosphorylation of GGA proteins would explain why they are not part of
clathrin-coated vesicles. The model shown in
Fig. 2, which extends the model
proposed by Kornfeld and co-workers (Zhu
et al., 2001), is consistent with the hypothesis that GGA proteins
help to recruit cargo into AP-1-containing clathrin-coated vesicles
(Fig. 2). First, activated ARF
recruits GGA proteins to TGN membranes. GGA inhibits the ARF GAP; thus ARF
stays on the membrane for longer and increases the probability of recruiting
AP-1 to this site. Meanwhile, GGA proteins recruit cargo proteins and
clathrin. Together with AP-1, CK2 or a CK2-like enzyme is then recruited. CK2
phosphorylates the cargo protein as well as GGA proteins, subsequently causing
the GGA proteins to dissociate and the cargo protein to bind AP-1. Budding
then proceeds. As before, the action of one or more phosphatases is
indispensable in this scenario.
|
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Conclusions |
---|
Our understanding of GGA function has grown tremendously over the past two years. Although at first AP-1 and GGA proteins appeared to function at different transport steps in mammalian cells, it seems more likely now that in fact they cooperate. GGA proteins might even regulate anterograde, AP-1-mediated transport. Genetic manipulation of GGA proteins in multicellular organisms and the development of in vitro recruitment and budding assays for GGA proteins and AP-1 should clarify how they interact during clathrin coat recruitment.
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Acknowledgments |
---|
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Footnotes |
---|
Shiga toxin is a bacterial toxin from Shigella dysenteriae. Cell
biologists use the B-subunit of the toxin as a tool to follow retrograde
transport from the plasma membrane, where it becomes endocytosed and
transported through endosomes and the Golgi apparatus to the ER.
Hrs (hepatocyte growth factor-regulated tyrosine kinase substrate) is a
substrate for activated tyrosine kinase receptors that is involved in
endosomal membrane trafficking.
¶ Sortilin is considered the mammalian orthologue of Vps10p. However, the
cytoplasmic tails do not share homology and the function of sortilin remains
unknown to date.
** Furin, the mammalian Kex2p orthologue, is a transmembrane endoprotease that
catalyses the maturation of some secretory proteins, bacterial toxins and
viral envelope proteins.
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