Department of Neurology and Neurosurgery, Montreal Neurological Institute, McGill University, Montreal, QC H3A 2B4, Canada
Author for correspondence (e-mail: peter.mcpherson{at}mcgill.ca)
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Summary |
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Key words: ENTH domain, ANTH domain, Phosphoinositides, Clathrin-coated vesicle, trans-Golgi network
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Introduction |
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Identification of the ENTH domain |
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Members of the epsin family of endocytic regulatory proteins are important binding partners for the -ear (Chen et al., 1998
; Yamabhai et al., 1998
; Nakashima et al., 1999
; Rosenthal et al., 1999
; Spradling et al., 2001
) (Fig. 1). The best characterized member of this family, epsin 1, is unusual in that the C-terminal two-thirds of the molecule contains essentially no secondary structure (Kalthoff et al., 2002a
). Within this extended, unstructured domain are multiple short peptide motifs that mediate interactions with endocytic proteins (Fig. 1). Included are eight copies of the DPW tripeptide that mediates binding to the
-ear (Owen et al., 1999
; Traub et al., 1999
) and two distinct clathrin-binding motifs, which mediate interactions with the clathrin heavy chain (Hussain et al., 1999
; Rosenthal et al., 1999
; Drake and Traub, 2001
). Epsin 1 also contains three NPF motifs, which bind to the EH (Eps15 homology) domains of the endocytic proteins Eps15 and intersectin (Chen et al., 1998
; Hussain et al., 1999
). Epsin 1 is localized to CCPs, and disruption of its interactions with other endocytic proteins blocks clathrin-mediated endocytosis (Chen et al., 1998
).
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Sequence alignments revealed an 150 residue region at the epsin 1 N-terminus that is highly conserved in organisms as diverse as yeast, plant, frogs and humans (Rosenthal et al., 1999
; Kay et al., 1999
). This sequence, first noted in a plant protein (Jones and Hooley, 1997
), was called the ENTH domain (Rosenthal et al., 1999
; Kay et al., 1999
). X-ray crystallography has shown that the ENTH domain from epsin 1 has a compact globular structure in which eight
-helices are connected by loops of varying length (Hyman et al., 2000
; De Camilli et al., 2002
). Structurally, the ENTH domain is similar to the VHS (Vps27p, hepatocyte growth-regulated tyrosine kinase substrate, Hrs; signal-transducing adaptor molecule, STAM) domain (Hyman et al., 2000
), which is found at the N-terminus of proteins that participate in membrane trafficking (Lohi et al., 2002
).
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ENTH and ANTH domains bind inositol phospholipids |
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An important breakthrough in understanding the function of E/ANTH domains came with the observation that they bind inositol phospholipids and exhibit a preference for phosphatidylinositol 4,5-bisphosphate [PtdIns(4,5)P2] (Ford et al., 2001; Itoh et al., 2001
). Nuclear magnetic resonance and X-ray crystallography revealed that PtdIns(4,5)P2 binds to the epsin 1 ENTH domain through basic residues in
-helix 1, the
1-2 loop,
-helix 3 and
-helix 4. By contrast, in the case of the ANTH domain of AP180, PtdIns(4,5)P2 binding is mediated by lysine residues in
-helix 1 and
-helix 2 and the loop between them. In fact, the sequence around this region (K/G)A(T/I)x6(P/L/V)KxK(H/Y) is conserved in all ANTH domains and might represent an ANTH-defining consensus sequence (Ford et al., 2002
). The corresponding region in ENTH domains is not involved in PtdIns(4,5)P2 binding and is not conserved between ENTH and ANTH domains (Ford et al., 2002
). Intriguingly, on binding of PtdIns(4,5)P2, the region at the N-terminus of the ENTH domain, which is unstructured when not bound to ligand, forms an
-helix referred to as
0 (Ford et al., 2002
). Basic residues on the inner face of
0 stabilize PtdIns(4,5)P2 binding and their mutation abrogates lipid interactions.
0 is not present or generated in the ANTH domain (Ford et al., 2001
; Itoh et al., 2001
; Ford et al., 2002
). These differences contribute to the classification of ENTH and ANTH domains as distinct modules, despite their overall structural similarities.
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Function of E/ANTH domains |
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Both epsin 1 and AP180 stimulate the assembly of soluble clathrin triskelia into clathrin cages, the assembly activity being located outside the E/ANTH domain (Ahle and Ungewickell, 1986; Morgan et al., 2000
; Kalthoff et al., 2002a
). Thus, an attractive model is that E/ANTH proteins are anchored to the membrane by PtdIns(4,5)P2, leaving their extended C-terminal regions available to recruit coat components and catalyze clathrin assembly (Kalthoff et al., 2002a
). Indeed, in vitro, both epsin 1 and AP180 recruit clathrin to PtdIns(4,5)P2 monolayers and stimulate its polymerization into lattices (Ford et al., 2002
). However, clathrin patches formed by epsin 1 are invaginated, whereas AP180-induced lattices are flat (Ford et al., 2002
). These data suggest that clathrin assembly may not be sufficient to stimulate membrane invagination and that epsin 1 harbors an activity contributing to membrane curvature that is not found in AP180. One caveat to this interpretation comes from recent studies indicating that Eps15 can bind to AP180 and potently stimulate its clathrin assembly activity (Morgan et al., 2003
). Thus, in the absence of Eps15, the studies of Ford et al. may have failed to reveal the full contribution of AP180 to the formation of invaginated CCPs (Ford et al., 2002
).
An important distinction between ENTH and ANTH domains is the generation within the ENTH domain of 0 on binding to PtdIns(4,5)P2.
0 has a series of hydrophobic residues on its outer surface, which has led McMahon and colleagues to speculate that insertion of
0 into the cytosolic leaflet of the bilayer could mechanically facilitate membrane curvature by pushing the lipid head groups apart (Ford et al., 2002
) (Fig. 2). To test this hypothesis, Cho and colleagues monitored changes in surface pressure of phospholipid monolayers as a measure of membrane insertion (Stahelin et al., 2003
). The presence of PtdIns(4,5)P2 in the monolayers induced the membrane insertion of the epsin 1 ENTH domain, leading to membrane deformation, and this depended on the presence of the hydrophobic residues on the surface of
0 (Stahelin et al., 2003
). No membrane insertion was seen with the ANTH domain of AP180. Thus, the ENTH domain can perform mechanical work on membranes, suggesting two possible models for the formation of membrane curvature. Insertion of the ENTH domain could function synergistically with clathrin assembly to drive membrane invagination. Alternatively, ENTH domains might be sufficient for membrane curvature, with assembled clathrin stabilizing the deformed membrane. The function of the ANTH domain is less clear. The clathrin lattices assembled on PtdIns(4,5)P2 monolayers in the presence of AP180 are more uniform in size than those assembled by epsin 1 alone, suggesting that ANTH domains may contribute to the regulation of lattice size (Ford et al., 2002
). Interestingly, in Drosophila AP180-knockout animals, abnormally large and pleiomorphic synaptic vesicles arise during reformation from CCVs (Zhang et al., 1998
). Thus, E/ANTH domains have fundamental functions in the formation of CCPs and CCVs.
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E/ANTH domain proteins and PtdIns(4,5)P2 cycling |
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Although E/ANTH proteins are sufficient to bridge coat components to PtdIns(4,5)P2-containing membranes in vitro (Ford et al., 2002), the situation appears to be more complex in vivo. Interestingly, Fisher and colleagues determined that the D. melanogaster epsin homologue, liquid facets, can be divided into two pieces, an ENTH domain and an ENTH-less protein, and each part retains partial endocytic function (Overstreet et al., 2003
). These observations support the view that the ENTH domain and the remainder of the protein can function separately and that both parts of the protein contribute to epsin targeting and function. Also, Wendland and colleagues recently showed that, in the case of yeast epsin, Ent1p, the ENTH domain interacts with phospholipids, whereas ubiquitin-interaction motifs (UIMs) in the C-terminal region (Fig. 1) bind to ubiquitylated proteins at the membrane (Aguilar et al., 2003
). These events in turn promote interactions between NPF motifs in Ent1p and EH-domain-bearing proteins (Aguilar et al., 2003
). Moreover, as epsin binds to AP-2 and both proteins interact with PtdIns(4,5)P2, they are likely to bind to membranes in a cooperative manner (Cremona and De Camilli, 2001
). Thus, epsins are recruited to biological membranes by multiple independent interactions instead of being targeted to the membrane by the ENTH domain alone. These results suggest that E/ANTH proteins are unlikely to simply bridge coat components to membranes but instead contribute to the formation of networks of protein-protein and protein-lipid interactions that lead to the stable recruitment of clathrin coats (Fig. 2).
Key to the idea of a PtdIns(4,5)P2-mediated switch in CCV formation is a mechanism to terminate the signal. Dephosphorylation of PtdIns(4,5)P2 by lipid phosphatases could weaken the association of E/ANTH proteins and other coat components with membranes (Fig. 2). This would destabilize the clathrin coat and contribute to uncoating along with Hsc70 and auxilin (Lemmon, 2001). Synaptojanin, an endocytic PtdIns(4,5)P2 phosphatase (McPherson et al., 1996
), is a probable candidate to trigger this switch because synaptojanin knockouts have increased endogenous levels of PtdIns(4,5)P2 and a corresponding increase in the numbers of coated CCVs (Cremona et al., 1999
). Another way of modulating PtdIns(4,5)P2 levels at the plasma membrane involves the regulation of ARF6 activity by regulatory proteins such as guanine nucleotide exchange factors (GEFs) and GTPase-activating proteins (GAPs). In fact, cycles of activation-inactivation of ARF6 are crucial for trafficking through the plasma-membrane-endosome recycling pathway (Jackson and Casanova, 2000
; Donaldson, 2003
). Activation of ARF6-specific GAPs could decrease ARF6-GTP levels, decreasing PtdIns(4,5)P2 production (Donaldson, 2003
). Thus, cycles of association of E/ANTH-bearing proteins with membranes coupled to cycles of PtdIns(4,5)P2 synthesis and dephosphorylation may be a key factor in regulating CCV formation.
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Additional roles for E/ANTH proteins in endocytosis |
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Protein binding by E/ANTH domains |
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Recently, we and others have determined that E/ANTH domains isolated from various species are binding partners for tubulin and microtubules (De Camilli et al., 2002; Hussain et al., 2003
). A wealth of information has revealed complex links between the endocytic machinery and the actin cytoskeleton (for reviews, see Qualmann et al., 2000
; McPherson, 2002
), although a role for microtubules in endocytosis is less clear. Interestingly, Simon and colleagues have recently used total internal reflection fluorescence microscopy to show the lateral motion of dsRed-tagged clathrin parallel to the plasma membrane (Rappoport et al., 2003
). The dsRed-clathrin spots clearly run on microtubule tracks, depolymerization of microtubules decreases their motility and overexpression of the microtubule-associated protein tau decreases spot run length (Rappoport et al., 2003
). Whether these spots represent CCPs or pinched-off CCVs that have failed to uncoat is unclear. Regardless, these data show a clear link between endocytic membranes and microtubules. E/ANTH-bearing proteins could thus link clathrin-coated membranes to microtubules. Microtubule-mediated retrograde transport of epsin 1 from the cell surface to the nucleus could also explain the observation that epsin 1 is present at both cellular localizations. Thus, E/ANTH domains are reminiscent of other modules, such as PH domains, which bind to both inositol phospholipids and proteins (Lemmon et al., 2002
). For example, the PH domain of the ß-adrenergic receptor kinase binds to both PtdIns(4,5)P2 and the G protein ß
subunit, and, in fact, simultaneous interaction with both ligands is necessary for the recruitment of the kinase to membranes (Pitcher et al., 1995
). Together, these studies suggest multiple roles for E/ANTH domains as lipid- and protein-binding modules.
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Enthoprotin (Clint/epsinR): an ENTH-domain-containing protein at the TGN |
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Further evidence of such a role for E/ANTH proteins has come with the identification in yeast of Ent3p and Ent5p, and ENTH- and ANTH-bearing proteins, respectively (Fig. 1), which Payne and colleagues recently identified though two-hybrid screens using Gga2p and the -adaptin subunit of yeast AP-1 (Duncan et al., 2003
). Ent3p and Ent5p localize to the TGN and early endosomes. Interestingly, individual deletions of ENT3 or ENT5 do not lead to defects in clathrin-mediated protein transport, but double mutants display delayed maturation of carboxypeptidase S (normally processed to a mature form in the vacuole) and of the
-factor mating pheromone (which depends on clathrin-mediated traffic between Golgi and endosomes) (Duncan et al., 2003
). These data strongly support a role for Ent3p and Ent5p in TGN-endosomal traffic. Moreover, they show that E/ANTH protein function on intracellular membranes is conserved throughout eukaryotic evolution.
Interestingly, ENTH domains appear to form two large clusters phylogenetically (Fig. 4). One branch contains mammalian epsins and epsin homologues in Drosophila melanogaster and Caenorhabditis elegans (liquid facets) (Cadavid et al., 2000). This branch also contains the budding yeast Saccharomyces cerevisiae epsin orthologues Ent1p and Ent2p (Wendland et al., 1999
) (Fig. 4). The second branch contains enthoprotin, its D. melanogaster orthologue, a C. elegans protein originally denoted as an epsin, and the S. cerevisiae protein Ent3p (Fig. 4). The fission yeast Schizosaccharomyces pombe has two genes that encode for ENTH-bearing proteins. One (NP_588237), which has an ENTH domain that clusters with epsins, contains a clathrin-binding domain and multiple copies of the NPF tripeptide, like epsin, Ent1p and Ent2p (Fig. 1). The second (NP_587759) clusters in the enthoprotin branch (Fig. 4) and contains a clathrin-binding domain and a putative
-ear/GAE domain-binding motif, similar to enthoprotin (Fig. 1). Thus, there appears to be two ENTH domain families: the epsin family, which interacts through NPF motifs with EH domains and functions at the cell surface; and the enthoprotin family, which contains sequences for binding to GGAs and
-adaptin and functions on internal membranes. Importantly, these families have been maintained in such divergent species as budding yeast, fission yeast and humans. Ent4p, which has not been well characterized, does not fit obviously into either family (Fig. 4).
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Enthoprotin function |
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Fig. 3 shows a model of enthoprotin interactions at the TGN. In this model, binding of the ENTH domain to phospholipids couples with additional membrane-targeting activities in the C-terminal region, including binding to GGA2 and AP-1, to recruit the protein to the TGN. There, through interactions with AP-1, GGA2 and clathrin, enthoprotin contributes to a network of interactions that lead to the formation of CCPs. Enthoprotin has been shown to stimulate clathrin assembly in vitro at acidic pH (Wasiak et al., 2002), although assembly does not occur at physiological pH (Mills et al., 2003
). This situation is similar to that seen for AP180 (Morgan et al., 2003
). However, AP180 does assemble clathrin at physiological pH following binding to Eps15 (Morgan et al., 2003
). In an analogous manner, enthoprotin could stimulate clathrin assembly following its binding to one of its TGN partners (Fig. 3). In this way, enthoprotin could stimulate the formation of CCPs on the TGN in proximity to GGAs and AP-1, which bind to the cytoplasmic domains of TGN sorting receptors, allowing for the concentration of the receptors in nascent CCPs. Indeed, overexpression of full-length enthoprotin in COS cells leads to abnormal secretion of the lysosomal hydrolase pro-cathepsin D, which is normally transported in CCVs from the TGN to the late endosome and lysosome (Mills et al., 2003
). Surprisingly, however, depletion of enthoprotin by RNAi in COS and HeLa cells does not alter the trafficking of cathepsin D (Hirst et al., 2003
), which suggests that enthoprotin is not absolutely required for this trafficking pathway. Enthoprotin may therefore function in AP-1 and GGA-dependent pathways that do not involve transport of lysosomal hydrolases. More experiments will be needed to determine how enthoprotin contributes to TGN-endosomal trafficking. Interestingly, disruption of the gene encoding enthoprotin is pupal lethal in D. melanogaster (P. A. Leventis, S.W., P.S.M. and G. L. Boulianne, unpublished). Analysis of trafficking defects in mutant larvae should resolve this issue and provide new insights on enthoprotin function.
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Concluding remarks |
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Acknowledgments |
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Footnotes |
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