1 The Inositide Laboratory, The Babraham Institute, Babraham, Cambridge, CB2
4AT, UK
2 Bioinformatics, The Babraham Institute, Babraham, Cambridge, CB2 4AT, UK
* Author for correspondence (e-mail: chris.ellson{at}bbsrc.ac.uk )
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Summary |
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Key words: Phox, PI3-kinase, PtdIns(3)P, Trafficking, NADPH oxidase, SNX
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Introduction |
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First identified in two cytosolic components of the NADPH oxidase
(Ponting, 1996), PX domains
are found in >100 known and hypothetical eukaryotic proteins, which have
divergent functions and include the p40phox and
p47phox subunits of the NADPH oxidase, class II
phosphoinositide 3-kinases (PI3Ks), cytokine-independent survival kinase
(CISK), members of the phospholipase D (PLD) family, sorting nexins (SNX), bud
emergence (Bem) proteins and the t-SNARE Vam7p
(Fig. 1).
|
Recent simultaneous studies from several laboratories have now shown that
several PX domains act as specific phosphoinositide-binding modules
(Cheever et al., 2001;
Ellson et al., 2001a
;
Kanai et al., 2001
;
Song et al., 2001
;
Xu et al., 2001a
) that have
varying lipid-binding specificities (Table 1). The task of understanding their
structure and ultimately their context-specific function is now well
underway.
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PX domain structure |
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Very recently, Bravo et al. (Bravo et
al., 2001) reported a crystal structure of the PX domain of
p40phox bound to dibutanoyl-PtdIns(3)P (a soluble
form of PtdIns(3)P) at 1.7 Å resolution. This study is the most
detailed and accurate to date, allowing assignment of roles for individual
residues in interactions with the bound phosphoinositide. The crystal
structure confirmed that the overall topology of the PX domain is similar to
that reported for the p47phox and Vam7p PX domains: the
domain forms an overall wedge shape, one face forming the
phosphoinositide-binding pocket (Fig.
2A,B).
|
The interactions between all PX domains and their bound phosphoinositides most likely to be shared, regardless of specificity, involve the 1-phosphate and the inositol ring, because they are present in all phosphoinositide species. A hydrogen bond between a well conserved basic residue, Lys92*, and the 1-phosphate is the most important interaction with this group. Tyr59 forms the floor of the lipid-binding pocket in the PX domain, allowing the inositol ring of PtdIns(3)P to stack tightly against it (Fig. 2C). This carbohydrate-aromatic stacking is likely to be a common feature of binding, because all PX domains have either Tyr or Phe at the analogous position.
Lipid-binding specificity
Two of the most well conserved basic residues in the PX domain are at
positions 57 and 105 in p40phox. Arg105 forms hydrogen
bonds with the 4- and 5-hydroxyl groups of PtdIns(3)P; analogous
residues in other PX domains are probably well positioned to bind to phosphate
groups at these positions, perhaps allowing varied lipid-binding
specificities. Arg57, however, fulfils an entirely different role that was not
expected on the basis of previous work. Studies of the analogous residue in
other proteins had indicated that it might have a critical role in phosphate
ligation of the bound phosphoinositide. NMR spectra had revealed a large
chemical shift upon ligation of PtdIns(3)P in Vam7p
(Cheever et al., 2001). In
addition, a naturally occurring Arg
Gln mutation in
p47phox results in a non-functional NADPH oxidase
(Noack et al., 2001
), and
mutation of this residue in p47phox abrogates lipid
binding (Kanai et al., 2001
).
However, the crystal structure shows that this residue does not project into
the binding pocket but faces away from it
(Fig. 2C). This suggests that
Arg57 actually performs a vital structural role, forming hydrogen bonds within
the hydrophobic core to stabilise the unique fold of the PX domain
(Fig. 2C).
The residue that emerged as crucial for ligation of the 3-phosphate was
Arg58, which is sandwiched between the fundamentally important Arg57 and Tyr59
residues. Mutation of this residue completely abolishes PtdIns(3)P
binding in vitro and in vivo, despite the fact that structural integrity of
the domain remains intact (Bravo et al.,
2001).
Since Arg58 is so crucial for binding to the 3-phosphate, is it the residue
that confers selectivity upon the PX domain? Indeed, all PX domains possessing
a basic residue in this position that have been studied are specific for
3-phosphoinositides (Cheever et al.,
2001; Ellson et al.,
2001a
; Kanai et al.,
2001
; Song et al.,
2001
; Virbasius et al.,
2001
; Xu et al.,
2001a
; Xu et al.,
2001b
; Yu and Lemmon,
2001
). Conversely, the PX domains that exhibit alternative
phosphoinositide-binding specificity, that is, the mouse class II PI3K [which
binds to PtdIns(4,5)P2
(Song et al., 2001
)] and the
yeast Bem protein Bem1p [which binds to PtdIns(4)P
(Ago et al., 2001
)] both lack
the analogous basic residue (Fig.
1; Table 1). Such a theory, however, does not explain, for
example, why the p40phox PX domain does not bind to
PtdIns(3,4)P2, whereas the p47phox PX
domain does. One possibility may be that the binding pocket is too cramped to
allow access to the 4-phosphate. This means that Arg105, which would be well
placed to interact with the 4- and 5-phosphates of bound phosphoinositides,
instead forms hydrogen bonds with the hydroxyl groups in these positions of
PtdIns(3)P. In contrast, residues in this region of the
p47phox PX domain presumably do not present such stearic
hindrances, allowing p47phox to show a preference for
PtdIns(3,4)P2. Therefore, in addition to Arg58, the
specific sequences in the variable loop and around the residue analogous to
Arg105 of PX domains seem to be instrumental in determining lipid-binding
specificity. A combination of molecular modelling and sequence comparisons of
PX domains with known specificity may allow lipid-binding profiles to be
predicted for those PX domains without known ligands. However, only
comprehensive lipid-binding experiments will demonstrate actual
specificities.
The NMR studies of the PtdIns(3)P-bound Vam7p PX domain
(Cheever et al., 2001) also
defined a membrane-interaction loop that immediately follows the proline-rich
region and spans approximately eight hydrophobic and polar residues. This
feature of the PX domain might facilitate interactions with both the surface
and interior of the lipid bilayer (Fig.
2A,B). Interestingly, mutation of one residue in this region of
p40phox (Tyr94 to Ala) has little effect on binding to
soluble di-C4-PtdIns(3)P, demonstrating that a lipid bilayer is
necessary for detection of this interaction
(Bravo et al., 2001
).
PX domains as a ligand of SH3 domains
The existence of a conserved polyproline motif (PxxP) in many PX domains
suggested that it may act as a target for SH3 domains
(Fig. 2A,B). Numerous
PX-domain-containing proteins also contain SH3 domains and form multiple
contacts with other proteins. In fact, an NMR study of the isolated domains
revealed that the PX domain of p47phox binds to its own
C-terminal SH3 domain through this PxxP motif
(Hiroaki et al., 2001). It is
tempting to speculate that this is an inhibitory intramolecular association,
but studies on the full-length protein are required to test this idea. The
crystal structure shows that both proline residues in the PxxP motif of the
PtdIns(3)P-bound p40phox PX domain are internal and
therefore unavailable for interaction with an SH3 domain
(Bravo et al., 2001
). This
implies either that the PX domain of p40phox has no SH3
ligand or that a conformational change (perhaps linked to lipid dissociation)
allows the interaction to occur. Given that only one SH3-PX domain interaction
has been found, the issue of whether SH3 domain binding is a general feature
of PX domains is yet to be resolved.
A recent report also claims that the PX domains of
p40phox and p47phox can interact with
the ERM protein moesin, although the molecular mechanism for this interaction
remains to be defined (Wientjes et al.,
2001).
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Regulation of proteins by the PX domain binding to phosphoinositides |
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PtdIns(3)P in endosome and vacuole targeting
The majority of PX domains studied so far show binding selectivity for
PtdIns(3)P, and the importance of this lipid in vesicle trafficking
in yeast and mammalian cells is well described (reviewed in
Stenmark and Aasland, 1999).
The only yeast PI3K is Vps34p, which exclusively generates
PtdIns(3)P. Mutation of the vps34 gene results in aberrant
sorting of proteins to the vacuole, defective endosomal processing and
abnormal vacuole morphology (Herman and
Emr, 1990
). Levels of PtdIns(3)P in yeast appear to be
constant, presumably maintained by an equilibrium of synthesis and
degradation. By extrapolation, the human homologue of the yeast PI3K, hVps34,
is thought to be responsible for maintaining the constitutively high levels of
PtdIns(3)P found in mammalian cells
(Siddhanta et al., 1998
).
Previously, the only known targets for PtdIns(3)P were proteins
containing FYVE domains. FYVE domains are present in many proteins involved in
vesicle trafficking, including EEA-1 and Hrs
(Burd and Emr, 1998
;
Gaullier et al., 1998
).
PtdIns(3)P binding is required for the correct localisation and hence
function of several of these proteins
(Gaullier et al., 2000
). Two
examples of PX-domain-containing proteins thought to be involved in this type
of trafficking pathway have been described: the yeast t-SNARE Vam7pp
(Cheever et al., 2001
) and the
human sorting nexins SNX3 (Xu et al.,
2001a
) and RGS-PX1 (Zheng et
al., 2001
).
Vam7pp is a yeast t-SNARE localised to the vacuole, comprising an
N-terminal PX domain and a C-terminal coiled-coil region. It has a role in the
docking and subsequent fusion processes of vesicles with the vacuole, acting
as a SNAP-25 homologue. Vam7p-null (Vam7p) mutant cells
accumulate aberrant membranous compartments
(Sato et al., 1998
). A mutant
protein lacking the PX domain (Vam7p
PX) is cytosolic, demonstrating
that the PtdIns(3)P-specific PX domain of Vam7p is required for
appropriate vacuolar localisation (Cheever
et al., 2001
). Studies using the Vam7p
mutant
cells show that high levels of exogenous Vam7p
PX can complement the
Vam7p
phenotype, demonstrating that the PX domain is not
essential for Vam7pp function. Taken together, these data suggest that the
role of the PX domain is to concentrate Vam7pp on the vacuole, where it
interacts with other components that regulate docking and fusion
(Fig. 3A).
|
Mammalian sorting nexins are a family of related proteins implicated in the
endocytic pathway that also contain PX domains
(Teasdale et al., 2001).
Several also bind to cell-surface receptors, but their exact function remains
undefined (Haft et al., 1998
).
Xu et al. have studied SNX3 (Xu et al.,
2001a
), an interesting protein in that it is little more than a PX
domain (130 residues of 162 make up the PX domain). Selective binding of the
SNX3 PX domain to PtdIns(3)P primarily localises this protein to
early endosomes. Overexpression leads to swelling of the endosomal compartment
reminiscent of that seen after overexpression of PtdIns(3)P-binding
FYVE domain constructs (Gillooly et al.,
2000
). These SNX3-induced expanded membranous structures contain
markers of sorting, recycling and late endosomes, perhaps indicating mixing of
these compartments. In addition, overexpression of SNX3 leads to internalised
EGF being retained in the swollen structures rather than being targeted to the
lysosome for degradation. Microinjection of anti-SNX3 antibodies inhibited
transport of internalised transferrin receptors from early to recycling
endosomes, implicating SNX3 in the regulation of this trafficking event.
Exactly how SNX3 performs its function is unclear, but, if it acts within a
multiprotein complex, the only evident protein-protein-interaction module is
the polyproline region in the PX domain. In this view, the PX domain of SNX3
could then act as a regulator of a secondary protein, which raises the
possibility that PX domains of this protein family differ by binding to
distinct protein partners or phosphoinositide species.
RGS-PX1 (also called SNX14) is another mammalian sorting nexin that is
localised to endosomes through a PtdIns(3)P-specific PX domain
(Zheng et al., 2001). In
contrast to SNX3, RGS-PX1 has a defined catalytic activity. It is a
GTPase-activating protein (GAP) that specifically binds to
G
s and accelerates the catalytic rate of GTP hydrolysis.
Overexpression of RGS-PX1 significantly attenuates the effects of
G
s-mediated signalling, such as increases in cAMP levels,
through its GAP activity. Additionally, overexpression also causes a delay in
EGF receptor degradation following ligand-dependent internalisation, as well
as influencing EGF-dependent MAP kinase activation. RGS-PX1 may therefore act
as a bridge between G protein signalling and regulation of vesicular
traffic.
Two independent groups have also described PX-domain-dependent endosomal
localisation of a serum- and glucocorticoid-regulated kinase (SGK) family
member (Virbasius et al.,
2001; Xu et al.,
2001b
). Cytokine-independent survival kinase (CISK) is a Ser/Thr
kinase that can protect cells from apoptosis following serum withdrawal. It
shares significant homology with protein kinase B (PKB) in its kinase domain
and is also thought to share at least a subset of the same substrates, such as
Bad and the forkhead transcription factor FKHRL1 (which is inhibited by
phosphorylation) (Liu et al.,
2000
). Work on PKB has shown that it has a PH domain specific for
PtdIns(3,4)P2 and PtdIns(3,4,5)P3
N-terminal to the kinase domain. Production of
PtdIns(3,4)P2 and PtdIns(3,4,5)P3 at
the plasma membrane recruits PKB, colocalising it with its upstream activating
kinase PDK1 (which also contains a
PtdIns(3,4,5)P3-specific PH domain)
(Alessi et al., 1997
;
Stephens et al., 1998
).
Binding of lipids to PKB is thought to induce a conformational change in the
protein that relieves an inhibitory constraint, allowing activating
phosphorylation by PDK1 (Stokoe et al.,
1997
).
CISK has an N-terminal PX domain, rather than the PH domain of PKB, and is
activated through stimulation of cell surface receptors coupled to IGF-1 and
EGF. Non-lipid-binding mutants prevent both endosomal localisation of the
protein and downstream inhibition of FKHRL1. Interestingly, deletion of the PX
domain enhanced inhibition of FKHRL1 activity, suggesting that the unliganded
PX domain autoinhibits CISK in a manner analogous to that predicted for the PH
domain of PKB (Xu et al.,
2001b). These analogies may extend further in that the key
activating phosphorylation sites in PKB (Thr308 in the kinase domain and
Ser473 in the C-terminal tail) also appear to be conserved in CISK, which
suggests that PDK1 or a PDK-like kinase is responsible for the
phosphoinositide-dependent phosphorylation and activation of CISK
(Fig. 3B). The lipid-binding
properties of the CISK PX domain are somewhat disputed: Xu et al. report
specificity for PtdIns(3,4,5)P3 and
PtdIns(3,5)P2, whereas Virbasius et al. demonstrate
exclusive binding to PtdIns(3)P. The reason for this discrepancy is
not clear because both groups use essentially the same `protein-lipid overlay'
binding assay, although Virbasius et al. also present convincing liposome
binding data. Certainly, PtdIns(3)P binding more easily explains the
endosomal localisation of CISK; however, PtdIns(3,4,5)P3
binding would more easily explain how CISK couples to agonist-stimulated
events originating at the plasma membrane. Whatever the precise lipid-binding
specificity of CISK, there seem to be very strong parallels, both in the way
CISK and PKB are regulated by phosphoinositides and in the roles these two
kinases play in the regulation of cell survival.
PtdIns(3)P as a target on phagosomes
Two reports have recently demonstrated a new cellular site of
PtdIns(3)P generation (Vieira et
al., 2001; Ellson et al.,
2001b
). These studies focused on professional phagocytic cells
that engulf pathogenic material and cell debris and breakdown the contents of
the ingested phagosome by the co-ordinated delivery of vesicle-bound digestive
enzymes and reactive oxygen species (reviewed in
Berón et al., 1995
;
Desjardins et al., 1994
;
Desjardins et al., 1997
;
Babior, 1999
). Both groups
observed that PtdIns(3)P is rapidly and transiently generated on
phagosomal membranes following closure of the phagosome. The kinetics of this
rise and fall in PtdIns(3)P levels strongly suggest a role for this
lipid in temporal localisation of proteins involved in maturation of the
phagosome as a prerequisite for entry into the lysosomal pathway. Using
inhibitory antibodies, Vieira et al. also demonstrated that hVps34 activity is
required for this rise in PtdIns(3)P to occur and that the
PtdIns(3)P is necessary for efficient maturation of the
phagosome.
These are the first reports to show rapid upregulation of PtdIns(3)P synthesis is response to extracellular stimuli, which contrasts with the maintenance of steady-state levels of PtdIns(3)P in endosomes. What are the targets of PtdIns(3)P in this pathway? Clearly, PX-domain-containing proteins involved in vesicle trafficking, such as members of the sorting nexin (SNX) family, are obvious candidates. FYVE-domain-containing proteins (such as EEA1) could also interact with this PtdIns(3)P, allowing docking and fusion of digestive-enzyme-containing vesicles.
In addition to these reports, previous studies have shown that the entire
process of phagocytosis correlates with spatially and temporally regulated
synthesis of three other phosphoinositide species:
PtdIns(3,4,5)P3, PtdIns(3,4)P2 and
PtdIns(4,5)P2 (Botelho
et al., 2000; Marshall et al.,
2001
). This again provides potential localisation signals for
lipid-binding-domain-containing proteins, including those that have PX
domains.
In conjunction with content delivery from intracellular vesicle
populations, production of microbicidal reactive oxygen species into the
phagosomal vacuole is also essential for efficient killing of ingested
material. The enzyme complex responsible for the generation of these
superoxide anions is the NADPH oxidase. It contains a membrane-bound
cytochrome and four cytosolic components Rac,
p67phox, p47phox and
p40phox (reviewed in
Babior, 1999). Many regulatory
inputs are known to impinge on the assembly and activity of the oxidase, and
now lipid regulation through PX-domain-containing proteins must be integrated.
p40phox and p47phox contain PX domains
showing specificity for PtdIns(3)P and
PtdIns(3,4)P2, respectively (although the
p47phox PX domain is much less selective, exhibiting
significant binding to several other phosphoinositides)
(Ellson et al., 2001a
,
Kanai et al., 2001
). The
cytosolic phox proteins are generally thought to exist in a basal complex,
translocating to the membrane-bound cytochrome upon activation by stimulation.
The phagovacuole-localised rise in PtdIns(3)P levels is clearly a
potential target for the translocation of PtdIns(3)P-binding
p40phox. This translocation may help recruit other members
of the cytosolic complex, facilitating interaction with the cytochrome and,
ultimately, activation of the oxidase. Similarly,
PtdIns(3,4)P2, which was shown to accumulate in the
phagocytic cup (Marshall et al.,
2001
), could target the cytosolic complex by interacting with the
p47phox PX domain. This potential mode of activation
illustrates the importance of establishing the credentials of the
p47phox PX-SH3 domain interaction, that is, what is the
relationship between phosphoinositide binding and SH3 domain binding?
Phosphorylation of p47phox is thought to disrupt
intramolecular associations (perhaps including the PX-SH3 domain interaction)
to expose previously masked domains, subsequently allowing direct interaction
of p47phox with the cytochrome
(p40phox has not been shown to bind to the cytochrome)
(Ago et al., 1999
). This
suggests that the PX domains in this pathway act as both spatiotemporal and
allosteric regulators. Note, however, that, to date, there is no direct
evidence for these PX-domain-mediated mechanisms in oxidase activation.
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Conclusion |
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Acknowledgments |
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Footnotes |
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References |
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