Glycobiology Advance Access originally published online on April 20, 2007
Glycobiology 2007 17(10):1031-1044; doi:10.1093/glycob/cwm046
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REVIEW |
Structural views of glycoprotein-fate determination in cells
2 Graduate School of Pharmaceutical Sciences, Nagoya City University, 3-1 Tanabe-dori, Mizuho-ku, Nagoya 467-8603, Japan
3 Institute for Molecular Science, National Institutes of Natural Sciences, 5-1 Higashiyama Myodaiji, Okazaki 444-8787, Japan
4 GLYENCE Co., Ltd., 406 Nagoya Life Science Incubator, 2-22-8 Chikusa, Chikusa-ku, Nagoya 474-0858, Japan
5 The Glycoscience Institute, Ochanomizu University, 2-1-1 Ohtsuka, Bunkyo-ku, Tokyo 112-8610, Japan
1 To whom correspondence should be addressed; e-mail: kkato{at}phar.nagoya-cu.ac.jp
Received on March 19, 2007; revised on April 13, 2007; accepted on April 13, 2007
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Abstract |
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Top
Abstract
IntroductionProcessing of the N-glycans is coupled with the fates of glycoproteins in cells. A series of processing intermediates of high-mannose-type glycans are generated by specific glycosidases and thereby express biological signals recognized by intracellular lectins operating as molecular chaperones, cargo receptors, and ubiquitin ligases. Consequently, these lectins govern the intracellular processes of folding, transport, and degradation of the carrier polypeptides. To understand the underlying mechanisms of glycoprotein-fate determination, structural information on modes of molecular recognition by these lectins and enzymes is undoubtedly important. This article overviews our current knowledge of the structural basis for quality control of glycoproteins in cells.
Key words: glycoproteins / quality control / lectins / glycosidases / ERAD
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Introduction |
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N-glycans play a crucial role in keeping order in the ‘protein society’ in cells by controlling folding, transport, and degradation of their carrier polypeptide chains. The fates of glycoproteins are determined through interactions between partially trimmed intermediates of the high-mannose (Man)-type glycans displayed thereon with a variety of intracellular lectins (Helenius and Aebi 2001
, 2004; Schrag et al. 2003; Trombetta 2003; Kamiya and Kato 2006; Moremen and Molinari 2006; Ruddock and Molinari 2006) (Figure 1). In eukaryotes, polypeptides oriented toward the secretory pathway are co-translationally translocated into the endoplasmic reticulum (ER) through the Sec61 translocon complex. Subsequently, the oligosaccharyl transferase (OST), which is a hetero-oligomeric membrane protein in association with a translocon in the lumen of the ER, catalyzes the transfer of the triglucosyl high-Man-type oligosaccharides, i.e. Glc3Man9GlcNAc2, from dolichol pyrophosphate to the asparagine (Asn) residues in the Asn-X-Ser/Thr consensus sequences on the newly synthesized polypeptide (Chavan and Lennarz 2006; Kelleher and Gilmore 2006). This bulky N-glycan not only prevents polypeptides from reorienting within the translocon but also expresses various biological signals upon trimming by specific glucosidases (Glc'ases) and mannosidases (Man'ases), which gives rise to a series of high-Man-type oligosaccharides (Goder et al. 1999; Spiro 2004) (Figure 1). High-Man-type oligosaccharides have three branches designated as D1, D2, and D3 based on the notation for the terminal Man residues (Figure 2). The glucose (Glc) residue at the non-reducing terminal of the D1 branch is removed by Glc'ase I, and the second and third Glc residues are subsequently trimmed by Glc'ase II, giving rise to the M9 glycoform in the ER (Spiro 2004). Re-glucosylation at the D1 branch is catalyzed by uridine diphosphate (UDP)–Glc:glycoprotein glucosyltransferase (UGGT), reproducing a monoglucosylated glycoform such as GM9 (Parodi 2000). The ER chaperones calnexin (CNX) and calreticulin (CRT) assist protein folding by capturing the monoglucosylated glycans expressed on the nascent proteins (Helenius and Aebi 2004; Williams 2006). Hence, a cycle of Glc trimming and re-glucosylation is coupled with glycoprotein folding in the ER.
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Man trimming in the ER is carried out by ER
1,2-Man'ase I in the ER, which preferentially cleaves the Man1,2 glycosidic linkage at the D2 branch (Spiro 2004). It has been postulated that a glycoprotein is allowed to move onto the secretory pathway if it achieves correct folding during a certain period of Man trimming in the ER. The correctly folded glycoprotein is transported as "cargo" to the Golgi complex, where Man trimming proceeds further to give rise to a variety of complex-type oligosaccharides (Kornfeld and Kornfeld 1985). The vesicular transport between the ER and the Golgi complex is, at least in part, mediated by a group of lectin-like proteins, 53 kDa membrane protein of the ER–Golgi intermediate compartment (ERGIC-53) and vesicular integral protein of 36 kDa (VIP36), which serve as cargo receptors (Hauri et al. 2000). On the other hand, a glycoprotein that fails to be correctly folded during the Man trimming in the ER is retrogradely translocated to the cytosol through the protein-conducting channel (Tsai et al. 2002; Meusser et al. 2005). This process is also mediated by lectin-like molecules, i.e. ER degradation-enhancing -Man'ase-like protein (EDEM) and OS-9 (Hosokawa et al. 2001; Jakob et al. 2001; Nakatsukasa et al. 2001; Buschhorn et al. 2004).
The glycoproteins pulled out to the cytosol are ubiquitinated by ubiquitin (Ub) ligases, deglycosylated by peptide:N-glycanase (PNGase) and, finally, subjected to proteasomal degradation (Suzuki and Lennarz 2003). Some Ub ligases and PNGase also possess lectin-like domains. Hence, the processing of the high-Man-type glycans catalyzed by the Glc'ases and Man'ases is tightly coupled with their interactions with intracellular lectins operating as the molecular chaperones, cargo receptors, and Ub ligases and thereby can govern the fates of the carrier proteins in cells (Table I). This review presents an overview of structural information of sugar recognition by lectins and enzymes that contribute to the determination of the fates of glycoproteins in cells, predominantly focusing on the processes in mammalian cells.
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Deglucosylation of the D1 branch |
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Figure 2 shows the three-dimensional structural model of G3M9, the common precursor of the N-glycans. As exemplified by this structure, the three branches of the high-Man-type oligosaccharides extend in different orientations with significant degrees of freedom in internal motion (Homans et al. 1987
; Woods et al. 1998). Consequently, each branch plays a distinct role in expression of biological signals, which evolve due to interplay among the branches on the glycan-processing pathway. For example, the non-reducing terminal Glc residues not only mask the biological code carried by the D1 branch but also prevent the other branches from interacting with lectins and enzymes because of steric hindrance. Hence, the N-glycan processing is initiated by the removal of the outermost Glc, which is catalyzed by Glc'ase I (Grinna and Robbins 1980). This "unsealing" enzyme is a type II membrane glycoprotein with a luminal catalytic domain belonging to glycoside hydrolase family 63. Both OST and Glc'ase I act on a site located approximately 72 amino acid residues from the ribosomal P site on a newly synthesized polypeptide (Deprez et al. 2005). This suggests that the active sites of these enzymes are in close spatial proximity to each other and therefore the removal of the outermost Glc occurs immediately after attachment of a glycan molecule to the polypeptide chain.
Subsequently, the middle Glc is removed by Glc'ase II, giving rise to the monoglucosylated glycan GM9, which is capable of interacting with the ER chaperones CNX and CRT (vide infra). Glc'ase II is a soluble heterodimer that is composed of a catalytic subunit belonging to glycoside hydrolase family 31 and a ß subunit containing an EF hand, Man-6-phosphate receptor homology (MRH) domains, and a C-terminal His-Asp-Glu-Leu sequence (Arendt and Ostergaard 2000). This enzyme is also responsible for the cleavage of the Glc1-3Man linkage, giving rise to the M9 glycoform that can no longer interact with CNX or CRT. Hence, Glc'ase II plays a crucial role in regulating both entry to and exit from the CNX–CRT cycle of the substrate glycoproteins. Efficiencies of deglucosylation catalyzed by Glc'ase II critically depend on the number of Man residues present in the 6'-pentamannosyl branch (composed of Man-4', Man-A, Man-B, Man-D2, and Man-D3) (Grinna and Robbins 1980; Totani et al. 2006). It is conceivable that some interaction of this branch with the MRH domain of the ß subunit contributes to the up-regulation of the deglucosylation activity. Concerning this issue, Deprez et al. (2005) have proposed a model where trimming of the middle Glc of one glycan requires a trans interaction between the MRH domain of Glc'ase II and the 6'-pentamannosyl branch of a second glycan on the nascent polypeptide chain (and therefore depends on the number and location of glycans present in the substrate protein), while the trimming of the innermost Glc is activated through the Man of the same glycan ("cis" interaction). This model explains how Glc'ase II deals with the two cleavage sites, i.e. Glc1-3Glc and Glc1-3Man, which are in opposite orientation and have different accessibility in one glycan (Figure 2), using two different modes of interactions. On the other hand, using synthetic high-Man-type glycans, Totani et al. (2006) have argued that Glc'ase II can trim liberated oligosaccharides efficiently. They have also reported that Glc'ase II recognizes the D3 branch whereas the trimming of the D2 branch has little impact on the activity of Glc'ase II. This may be attributed to the conformations of the high-Man-type oligosaccharides, where the D3 branch is closer to the D1 branch, while the D2 branch is rather in spatial proximity to the chitobiose core (Figure 2).
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Folding of glycoproteins assisted by ER chaperones |
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In the ER, the re-glucosylation reaction is catalyzed by UGGT, which is a soluble, lumenal glycoprotein composed of the larger N-terminal and smaller C-terminal domains connected by a flexible linker (Guerin and Parodi 2003
). This enzyme operates as a folding sensor in the ER, because it preferentially glucosylates partially unfolded glycoproteins, but has little catalytic activity for native or completely unfolded glycoproteins (Ritter and Helenius 2000; Trombetta and Helenius 2000; Caramelo et al. 2003). The C-terminal domain, which is classified into glycosyltransferase family 24, senses local hydrophobicity surrounding the glycosylation site through interaction with the innermost N-acetylglucosaminyltransferase (GlcNAc) residue exposed to the solvent and thereupon catalyzes glucosylation, whereas the N-terminal domain is assumed to play a role in the recognition of the exposed hydrophobic patches of the substrate remote from the glycosylation site (Taylor et al. 2004). Trimming of the D2 and D3 branches of the substrate negatively influences the reactions by UGGT (Totani et al. 2005). No three-dimensional structure has yet been reported for this enzyme.
Upon removal of the middle Glc of the D1 branch by Glc'ase II or reglucosylation of non-glucosylated glycans by UGGT, the resultant monoglucosylated oligosaccharides become capable of interacting with CRT and CNX (Helenius and Aebi 2004). Glycoproteins that lack a Glc residue at the D1 branch cannot interact with these chaperones, but can be re-glucosylated by UGGT for rechallenging, if they are not in a native form yet (Ritter and Helenius 2000; Trombetta and Helenius 2000; Caramelo et al. 2003;). Thus, folding of glycoproteins can be achieved through repetition of this CRT–CNX cycle.
CRT and CNX are soluble lumenal and transmembrane proteins, respectively, but share homologous luminal regions that comprise a globular lectin domain adopting a legume lectin-like ß-sandwich fold and a protruding proline-rich domain designated as the P-domain (Schrag et al. 2001) (Figure 3). As compared with CNX, CRT has a shorter P-domain and possesses a C-terminal acidic domain containing a Lys-ASp-Glu-Leu (KDEL) sequence instead of the transmembrane region. A three-dimensional model of the lectin domain of CRT provides the structural basis of the specificity of CRT for the monoglucosylated D1 branch by showing that this branch is entirely accommodated within a concave ß-sheet forming hydrogen bonds of the hydroxyl group at C-2 of the Glc residue with Asp317 and Tyr109 of CRT (Kapoor et al. 2003). We have examined the sugar-binding properties of CRT by frontal affinity chromatography (FAC) using a pyridylaminated sugar library. The results summarized in Table II demonstrate that removal of the Glc residue from the D1 branch results in complete loss of ability to interact with CRT and, furthermore, trimming of the Man residues in the D2 or D3 branches causes significant reductions in affinities for CRT (D. Kamiya et al., unpublished data). These data are consistent with the previous report by Ito et al. (2005), indicating that all three branches of GM9 positively contribute to CRT binding.
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The P-domains of CRT and CNX are highly flexible in solution and capable of interacting with ERp57/ER-60, a thioldisulfide oxidoreductase (Frickel et al. 2002
; Pollock et al. 2004). This enzyme is a member of the protein disulfide isomerase (PDI) family, and accelerates folding of glycoproteins by catalyzing the formation, reduction, and rearrangement of disulfide bridges of the substrates (Zapun et al. 1998; Molinari and Helenius 1999; Urade et al. 2004). ERp57 comprises four thioredoxin-like domains, a, b, b', and a' with a C-terminal basic extension (Figure 3). The homologous a and a' domains contain a cysteine pair in the active site, whereas the b and b' domains form a platform for the interaction with the tip of the P-domains of CRT and CNX (Kozlov et al. 2006). It is plausible that CNX and CRT assist the folding of the glycoprotein by capturing its monoglucosylated oligosaccharide moiety and thereby orienting its polypeptide portion to the active sites of ERp57 recruited on the P-domain (Williams 2006). It is still controversial whether CRT and CNX interact not only with the carbohydrate moieties but also with the polypeptide portions of the substrate to suppress its aggregation. Thus, the underlying mechanisms for sequestration of the non-native glycoprotein by these chaperones remain incompletely understood. |
Irreversible Man trimming: Man timer |
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Man trimming is carried out in the ER by ER
1,2-Man'ase I, which belongs to glycosyl hydrolase family 47 (Weng and Spiro 1993) and removes the terminal Man of the D2 branch giving rise to M8B. The crystal structure of yeast ER 1,2-Man'ase I, which interacts with an N-glycan of an adjacent molecule, demonstrates that Man-A is located toward the bottom of the catalytic cavity by a key interactions of an Arg residue (Arg273 in yeast) with three Man and one GlcNAc residues at the branch points of the glycans (Vallee et al. 2000) (Figure 4). A modeling study predicted that the D2 branch can exclusively fit in the binding site of yeast and human ER 1,2-Man'ase I enzymes (Lobsanov et al. 2002). Upon mutation of the Arg273 to leucine, yeast ER 1,2-Man'ase I becomes capable of trimming Man9GlcNAc to Man5GlcNAc (Romero et al. 2000). The enzyme action of ER 1,2-Man'ase I has been reported to be hampered by monoglucosylation in the D1 branch of the substrate (Weng and Spiro 1993). Since trimming of the D2 and D3 branches impairs reactivities of the resultant glycoproteins with CRT, CNX, and UGGT, it is conceivable that ER 1,2-Man'ase I facilitates the release of glycoproteins from the CRT–CNX cycle (Spiro 2004; Totani et al. 2005, 2006). The irreversible cleavages of the D2 and D3 branches serve as "Man timer", which virtually start upon deglucosidation at the D1 branch and ticks during the probation period for glycoprotein folding, or otherwise degradation. Indeed, overexpression of ER 1,2-Man'ase I results in acceleration of the ER-associated degradation (ERAD), which involves retrograde transfer of proteins from the ER into the cytosol and subsequent degradation mediated by the Ub–proteasome systems and thereby prevents the accumulation of misfolded glycoproteins in cells (Tokunaga et al. 2000; Hosokawa et al. 2003).
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Retro-translocation from the ER to the cytosol |
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EDEM has been identified as a stress-inducible ER membrane protein that possesses a lumen domain homologous to ER
1,2-Man'ase I and accelerates ERAD of glycoproteins (Hosokawa et al. 2001). EDEM and its Saccharomyces cerevisiae ortholog Htm1p/Mnl1p are postulated to act as lectins that recognize the M8B glycoform and thereby sort misfolded glycoprotein for ERAD (Jakob et al. 2001; Nakatsukasa et al. 2001), because no glycosidase activity was originally reported for these proteins notwithstanding the fact that the catalytic residues employed by ER 1,2-Man'ase I are all conserved. No direct evidence, however, has yet been provided about interaction between N-glycans and EDEM. Also, no crystal structure has been available for EDEM, although its homology model has been described based on the crystal structure of ER 1,2-Man'ase I (Moremen and Molinari 2006; Ruddock and Molinari 2006). Success in the expression of EDEM as a recombinant protein would provide a breakthrough in structural studies of this protein. It has been reported that EDEM and CNX interact with each other through their transmembrane regions and thereby facilitate a transfer of misfolded glycoprotein from the CNX–CRT cycle to the ERAD pathway (Molinari et al. 2003; Oda et al. 2003).
Recently, two distinct EDEM homologs (EDEM 2 and EDEM 3) were identified as soluble ER glycoproteins that accelerate glycoprotein ERAD (Hirao et al. 2006; Mast et al. 2005; Olivari et al. 2005). Hirao et al. (2006) have demonstrated that overexpression of EDEM 3 greatly stimulates Man trimming, giving rise to M6 and M7 glycoforms. On the other hand, Olivari et al. (2006) have reported that overexpression of EDEM1 (originally described as EDEM) can accelerate the removal of a terminal Man from the D1 branch. These data suggest that the EDEM family proteins potentially have a role in Man trimming at the D1 branch, and thereby irreversibly release the terminally non-native glycoproteins from the CRT–CNX cycle for their ERAD. Intriguingly, Frenkel et al. (2003) have reported that ERAD of glycoprotein involves Man trimming that give rise to Man6-5GlcNAc2 structures, which lack the Man residue as the Glc acceptor site at the D1 branch.
For ERAD, misfolded or unassembled glycoproteins have to cross the ER membrane through a protein-conducting channel (Osborne et al. 2005). While the Sec61 translocon was originally proposed to be used for retro-translocation, four-transmembrane proteins, Derlin-1, -2, and -3, and its yeast homolog Der1p, have recently been suggested to be components of the channel responsible for ERAD (Lilley and Ploegh 2004; Ye et al. 2004). These proteins have been reported to form a multiprotein complex (Lilley and Ploegh 2005; Ye et al. 2005; Carvalho et al. 2006; Denic et al. 2006) that is composed of transmembrane E3 Ub ligases Hrd1 and gp78/AMFR (Hrd1p in yeast) and a cytosolic AAA ATPase consisting of p97/VCP (Cdc48p in yeast) and its cofactors Ufd1 and Npl4 (Ufd1p and Npl4p, respectively, in yeast) (Figure 5). In yeast, Hrd1p forms a complex with Hrd3p, a type I transmembrane protein equipped with a sizable luminal domain (Gardner et al. 2001).
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Yos9p, a newly identified soluble lectin with an MRH domain, associates with the luminal domain of Hrd3p as well as Kar2p, the yeast ortholog of immunoglobulin-binding protein (BiP) (Carvalho et al. 2006
; Denic et al. 2006; Gauss et al. 2006). This lectin has been shown to interact with glycoproteins carrying the Man8GlcNAc2 or Man5GlcNAc2 glycoform (Szathmary et al. 2005). The lectin activity of Yos9p is required for ERAD, but neither for the maturation nor for the transport of secretory cargo glycoproteins (Bhamidipati et al. 2005; Kim et al. 2005). It is possible that Yos9p specifically recruits terminally misfolded glycoproteins that bear extensively trimmed oligosaccharides to the ERAD machinery in collaboration with Kar2p. Detailed structures and sugar-binding properties of Yos9p and its mammalian orthologs OS-9 and XTP3B remain to be addressed. The retrograde dislocation of misfolded glycoproteins may require extensive trimming of the carbohydrate moieties and reduction of disulfide bridges to avoid steric hindrance that can preclude the transfer through the channel. Further investigation of these is awaited with great interest. |
Ubiquitination and degradation in the cytosol |
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The p97 ATPase complex is responsible for extraction of the ERAD substrate into the cytosol, which depends on p97-catalyzed ATP hydrolysis and ubiquitination of the substrate, catalyzed by transmembrane E3 Ub ligases Hrd1 and gp78 (Bays et al. 2001
; Fang et al. 2001). In the ERAD process, Ub attached onto the substrate seems to serve not only as a "degradation tag" recognized by the proteasome but also as a ratchet preventing the polypeptide segments from moving back through the protein-conducting channel into the ER lumen and even contributing to the substrate "pulling" mechanism through interaction with the p97 ATPase complex (Jarosch et al. 2002; Rabinovich et al. 2002). The mechanisms underlying the retrograde transport are more complicated, because the ERAD process is proposed to consist of several different pathways, including a direct connection between Sec61 and the proteasome (Kalies et al. 2005). It has been reported that Derlin-2 and -3, but not Derlin-1, are associated with EDEM and p97 (Oda et al. 2006). In addition, evidence is emerging that novel proteins contribute to these processes (Nagasawa et al. 2007).
Yoshida et al. (2002) have identified sugar-recognizing Skp1–Cullin1–F-box (SCF) protein complexes as novel members of the ERAD-linked Ub ligases (Yoshida et al. 2002). The SCF complex is a multisubunit E3 Ub ligase that regulates degradation of a broad range of cellular proteins (Petroski and Deshaies 2005). The F-box protein consists of an F-box domain that binds to Skp1, and various C-terminal substrate recognition domains (Winston et al. 1999), while the really interesting new gene-finger protein Rbx1 recruits E2 Ub-conjugating enzymes upon covalent attachment of Ub-like (Ubl) modifier Nedd8 to the cullin-1 subunit (Sakata et al. 2007). In the sugar-recognizing SCF complexes, the lectin activities are carried by the F-box proteins that belong to one group consisting of at least five homologous members (Ilyin et al. 2002). Among them, Fbs1–Fbx2–NFB42–Fbg1 and Fbs2–Fbx6b–Fbg2, which are neural specifically and ubiquitously expressed, respectively, have been demonstrated to bind to glycoproteins expressing high-Man-type oligosaccharides (Yoshida et al. 2003). X-ray crystallographic and nuclear magnetic resonance (NMR) data indicate that the sugar-binding domain of Fbs1 is composed of a 10-stranded ß-sandwich with two -helices, and binds the Man3GlcNAc2 portion of oligosaccharides through the loops connecting the ß-strands (Figure 6) (Mizushima et al. 2004, 2007). Moreover, the NMR analyses revealed that the innermost GlcNAc and glycosylated Asn residues are involved in the interaction with Fbs1 when glycopeptides are used as ligands (Kato et al. 2005). In native glycoproteins, however, the sugar–polypeptide junction is shielded by the amino acid residues surrounding the glycosylation site, in general, and therefore is unlikely to make contacts with Fbs1. Both Fbs1 and Fbs2 interact more efficiently with denatured glycoproteins than with native glycoproteins (Yoshida et al. 2005). It is plausible that the sugar–protein junction is exposed to solvent in the misfolded glycoprotein and therefore recognized by these Ub ligases. Isothermal titration calorimetric analyses indicated that the core pentasaccharide of N-glycans exhibits substantially stronger binding than high-Man-type glycans M9 and M8B, probably because outer Man residues cause steric repulsion (Hagihara et al. 2005). This might reflect that the ERAD substrates exhibit smaller oligosaccharides in the cytosol. Recently, Yoshida et al. (2007) have reported that in vivo, the majority of Fbs1 is present as Fbs1–Skp1 heterodimers or Fbs1 monomers, but not as a subunit of the SCF complex, suggesting that Fbs1 operates as a chaperone by suppressing aggregation of glycoproteins in neuronal cells, independent of Ub ligase activity (Yoshida et al. 2007). Functional interplay between the sugar-recognizing SCF complexes and the other ERAD-linked Ub ligases such as Hrd1 and gp78 remains to be clarified.
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The carbohydrate moieties are bulky and therefore postulated to preclude proteasomal degradation of ubiquitinated substrate, because the active sites for proteolysis are within a narrow channel of the proteasome (Hirsch et al. 2003
). PNGase is a cytosolic enzyme that cleaves the ß-aspartyl-glucosamine bond and contributes to the ERAD system, because it can remove the carbohydrate moieties from the misfolded glycoproteins and thereby facilitates proteasomal degradation of the resultant polypeptides (Hirsch et al. 2003; Kim et al. 2006). The catalytic domain of PNGase belongs to the transglutaminase-like superfamily (Makarova et al. 1999) and possesses a catalytic Cys-His-Asp triad required for enzyme activity (Katiyar et al. 2002; Suzuki et al. 2002). On the basis of the crystallographic data of yeast PNGase in association with sucrose molecules and a tripeptide caspase inhibitor, carbobenzyloxy-Val-Ala-Asp--fluoromethylketone (Z-VAD-fmk), a substrate-binding mode of this enzyme has been proposed where the active site is in a deep cleft, which is sufficiently wide to accommodate unfolded polypeptide but not open for native glycoprotein (Lee et al. 2005). This model explains why yeast PNGase specifically catalyzes deglycosylation of denatured glycoproteins (Hirsch et al. 2004; Joshi et al. 2005). Recently, it was demonstrated that haloacetamide derivatives of N,N'-diacetylchitobiose can be irreversible inhibitors of PNGase by covalent attachment to the catalytic cysteine in a highly specific manner (Suzuki et al. 2006).
Whereas yeast PNGase has only a catalytic domain, mammalian PNGase possesses additional domains flanking it. The N-terminal PUB [peptide:N-glycanase/Ub-associated (UBA) or Ubiquitin regulatory X-containing proteins] domain consists of a bundle of five -helices that pack onto a short three-stranded anti-parallel sheet (Allen et al. 2006). This domain is engaged in interactions with Derlin-1 and p97, and thereby contributes to recruitment of PNGase to the ERAD machinery (Figure 5) (Katiyar et al. 2005; Li et al. 2006). It has previously been reported that enzymatic activity of mouse PNGase is inhibited by 3, 6-mannotriose (Suzuki et al. 1994, 1995). The recently reported crystal structure has illustrated that the C-terminal domain of mouse PNGase assumes a ß-sandwich architecture resembling the sugar-binding domain of Fbs1 and accommodates the Man1-6(Man1-3)Man1-6 moiety of N-glycans in a saddle-shaped depression at one end distal to the N- and C-termini of this domain (Figure 7) (Zhou et al. 2006). On the basis of the crystal structure, it has been proposed that the C-terminal domain captures the mannosyl branches of high-Man-type glycans of substrates, leaving their sugar–polypeptide junction oriented toward the active site, and thereby enhances the catalytic activity.
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The ERAD machinery is likely to form an efficient assembly line for protein ubiquitination, deglycosylation, and proteasomal degradation (Hampton 2002
). The two-hybrid library screening identified several mouse PNGase-interacting proteins that are involved in the Ub/proteasome-mediated protein degradation system (Park et al. 2001). PNGase closely associates with proteasome either by directly binding to 19S proteasome subunit or through its interaction with HR23A/HR23B, the mammalian homologs of Rad23 in yeast (Suzuki et al. 2001). Both HR23 and Rad23 are Ub receptors that contain N-terminal Ubl domains, which interact with the proteasome, and two UBA domains, which interact with Ub (Bertolaet et al. 2001; Lambertson et al. 2003). These proteins are also involved in the nucleotide excision repair pathway and form a tight complex with xeroderma pigmentosum complementation group C (XPC) or its yeast ortholog Rad4 through their highly conserved region flanked by two UBA domains (Sugasawa et al. 1996; Ng et al. 2003). The XPC-binding domains (XBDs) of Rad23 and HHR23 are also responsible for interaction with the catalytic domain of PNGase. The crystal structures of the catalytic domain complexed with XBD were determined for mouse and yeast PNGases (Figure 7) (Lee et al. 2005; Zhao et al. 2006). Interestingly, the modes of the PNGase–XBD interactions were different between these two complexes, suggesting a co-evolution of the ERAD and the DNA repair pathways. The oligosaccharides liberated by PNGase are further catabolized in the cytosol by endo-ß-N-acetylglucosaminidase (Suzuki and Funakoshi 2006) and by Man2C1 (Costanzi et al. 2006; Suzuki et al. 2006), an -Man'ase also known as ER 1,2-Man'ase II or neutral/cytosol Man'ase (Daniel et al. 1994; Weng and Spiro 1996), which preferentially releases the terminal Man of the D3 branch (Weng and Spiro 1993; Costanzi et al. 2006). This enzyme was previously postulated to contribute to Man trimming in the ER but has now been suggested to function mainly in the cytosolic catabolism of oligosaccharides (Suzuki et al. 2006). |
Vesicular transport mediated by cargo receptors |
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Correctly folded glycoproteins are translocated as cargos from the ER via the ERGIC (ER–Golgi intermediate compartment) to the Golgi complex through loading onto the transport vesicles. Emp46p and Emp47p in yeast and p58/ERGIC-53, VIP36, and VIP36-like (VIPL) in mammals have been identified as putative transmembrane cargo receptors having carbohydrate recognition domains (CRDs) that belong to the leguminous lectin family (Fiedler and Simons 1994
; Sato and Nakano 2002; Neve et al. 2003; Nufer et al. 2003). ERGIC-53 and its yeast orthologs Emp46p and Emp47p consist of the CRD, coiled-coil domain, transmembrane region, and cytosolic region that contains both ER exit and ER retrieval motifs, and cycle between the ER and the Golgi complex riding on the vesicles that are coated with coat protein complexes I and II (Schroder et al. 1995; Hauri et al. 2000; Sato and Nakano 2002). The crystal structures of the CRDs of Emp46p, Emp47p, and ERGIC-53 exhibit ß-sandwich folds homologous to the leguminous lectins (Figure 8) (Velloso et al. 2002, 2003; Satoh et al. 2006). VIP36 and VIPL also possess the homologous CRDs, but have a stalk region instead of the coiled-coil domain. VIP36 is highly localized in the cis-Golgi network, but modified with complex-type oligosaccharides (Fullekrug et al. 1999), suggesting that this lectin recycles between the Golgi complex and the ER, whereas VIPL remains in the ER (Neve et al. 2003; Nufer et al. 2003).
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The FAC analysis revealed that the CRD domain of VIP36 preferentially binds the D1 branch of high-Man-type oligosaccharides, but exhibits obviously different sugar-binding properties from those of CRT and CNX (Table II): glucosylation and Man trimming of the D1 branch significantly impairs VIP36 binding, whereas trimming of the D2 and D3 branches nominally affected the interaction with this lectin (Kamiya et al. 2005
). These data indicate that VIP36 exhibits optimal binding affinities for the glycoproteins that leave the CNX–CRT cycle in the ER and yet does not undergo trimming of the D1 mannosyl branch in the cis-Golgi. Sugar binding of VIP36 is Ca2+-dependent and exhibited a bell-shaped pH dependence with an optimal pH value of approximately 6.5, which corresponds to the typical pH value in the cis-Golgi. On inspection of the specificity and optimal pH value of the sugar binding of VIP36 and its subcellular localization, together with the organellar pH, it has been suggested that VIP36 binds glycoproteins that retain the intact D1 mannosyl branch in the cis-Golgi network and recycles to the ER, where, because of higher pH, it releases its cargos. Imperfectly folded or partially assembled glycoproteins that somehow escape from the ER might be captured by VIP36 and retrogradely transported from post-ER compartments to the ER. This process is mediated, at least partially, by proteins having the C-terminal KDEL sequence, such as BiP and the KDEL receptor (Yamamoto et al. 2001). A cross-linking experiment has shown that VIP36 interacts with BiP in HEK293 cells (Nawa et al. 2004). It has been proposed that VIP36 contributes to the retrieval quality control mechanism, by protecting the D1 branch of the cargo, which is crucial for the CNX–CRT cycle in the ER afterward, against the attack by Golgi 1,2-Man'ase I (Kamiya et al. 2005). Although sugar binding of ERGIC-53 is also Ca2+ dependent, this lectin efficiently binds immobilized Man at pH 7.4, but not at slightly lower pH (Appenzeller-Herzog et al. 2004). It has been reported that ERGIC-53 catches the glycoprotein cargo in the ER and releases them before reaching the cis-Golgi (Appenzeller et al. 1999).
The CRD of ERGIC-53 possesses two Ca2+-binding sites and exhibits Ca2+-dependent conformational alteration in a putative sugar-binding pocket on the concave ß-sheet, which provides structural basis for the Ca2+-dependent sugar binding of ERGIC-53 (Figure 8) (Velloso et al. 2002, 2003). The mutagenesis data suggested that ionization of His-178, which is located in the -helix participating in the Ca2+ coordination, leads to the loss of Ca2+ in the sugar-binding pocket and, therefore, results in the reduction in lectin activity under lower pH conditions (Appenzeller-Herzog et al. 2004). Unlike ERGIC-53 and VIP36, the CRD of Emp46p contains no Ca2+ ion but instead binds K+ at the edge of the ß-sheet, whereas that of Emp47p binds no metal ions (Satoh et al. 2006). These crystal structures suggest that transport of glycoproteins in yeast is regulated by some Ca2+-independent mechanisms.
Lysosomal glycoproteins, cathepsin C, and cathepsin Z are the most extensively characterized cargos of ERGIC-53 (Vollenweider et al. 1998; Appenzeller et al. 1999; Nyfeler et al. 2005). On the basis of the mutational data, Appenzeller-Herzog et al. (2005) have demonstrated that efficient transport of procathepsin Z depends on the ERGIC-53-binding motif composed of a high-Man-type glycan at a specific position and a ß-hairpin in close proximity. A similar oligosaccharide–ß-hairpin loop structure is present in cathepsin C, suggesting the general structural properties of the ER-exit signal recognized by ERGIC-53. Since such a conformation-dependent motif is only present in fully folded glycoprotein as cargo, ERGIC-53 may contribute to quality control in the ER as a folding sensor that operates in a complementary manner to the CRT–CNX cycle.
Mutations in ERGIC-53 can cause combined factor V and VIII deficiency in human (Nichols et al. 1998). Recently, the multiple coagulation factor deficiency 2 gene (MCFD2) was identified as a second locus responsible for this deficiency (ZhaNg et al. 2003). This gene encodes a soluble 16 kDa protein that possesses two EF-hand domains and interacts with ERGIC-53 in a Ca2+-dependent manner. This interaction has been thought to be necessary for the recruitment of blood coagulation factors V and VIII, whereas MCFD2 is dispensable for the binding of cathepsin Z and cathepsin C (Nyfeler et al. 2006). It is possible that MCFD2 interacts with the factors V and VIII in a glycan-independent fashion. Structural data on the interplay among ERGIC-53, MCFD2, and their cargos are highly desirable.
Glycoproteins correctly folded and transported to thecis-Golgi undergo further Man trimming by Golgi 1,2-Man'ases. There exist three mammalian Golgi 1,2-Man'ases, i.e. IA, IB, and IC, each of which is capable of catalyzing the cleavage of the Man1-2 linkages at all three mannosyl branches with slight preferences (Lal et al. 1998; Tremblay et al. 1998; Tremblay and Herscovics 2000). The crystal structure of mouse Golgi 1,2-Man'ase IA expressed by Pichia pastoris reveals that the D3 branch of a Man6GlcNAc2 oligosaccharide linked to one molecule is surrounded by a number of water molecules in the active site pocket of an adjacent molecule in the crystal (Figure 4) (Tempel et al. 2004). Such indirect interaction may contribute to accommodation of the Man1-2Man branches non-selectively. Glycoproteins are further subjected to the N-glycan processing catalyzed by GlcNAc TI, by Golgi Man'ase II, and subsequently by a variety of glycosyl transferases to express complex-type N-glycans. In the Golgi, endo--D-Man'ase provides a Glc'ase-independent pathway for the N-glycan processing (Moore and Spiro 1990; Hiraizumi et al. 1994). The roles of these enzymes in quality control of glycoproteins have yet to be elucidated.
|
Concluding remarks |
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The modes of sugar recognition by the intracellular lectins seem to be distinct from those involved in extracellular events, notwithstanding the fact that they frequently share similar folds of CRD domains. On cellular surfaces and extracellular matrices, in general, sugar–protein interactions are greatly enhanced through multivalent binding of lectins with the carbohydrate chains that are branched and clustered. Although some intracellular lectins such as ERGIC-53 exist as oligomers, it is unclear to what extent the multivalent binding contributes to the sugar–lectin interactions that govern the fates of glycoproteins in cells. It is not likely that branching of the high-Man-type oligosaccharides simply contributes to multivalent interactions. Rather, the individual branches cooperate as well as interfere with one another to exhibit specific three-dimensional structures of high-Man-type oligosaccharides recognized by lectins and enzymes and to open a previously shielded biological code upon Glc or Man trimming with the appropriate timing. As a typical example, the Glc residues linked to the D1 branch act not only as a tag recognized by the chaperones but also as a blocker against
1,2-Man'ases. Furthermore, sugar-binding affinities of the intracellular lectins can be finely tuned by sensing environmental factors, e.g. pH, metal ion concentrations, and local protein concentrations, which provides mechanisms for catching- and -releasing glycoproteins under appropriate conditions. In addition, many of the intracellular lectins are thought to interact with the polypeptide portions of the target glycoprotein in a direct fashion, as shown in the case of Fbs1, or indirectly through cooperating molecules. Such sugar–protein dual binding modes might be adopted to gain affinities and specificities for the targets and to check their folding states. To gain deeper insights into the mechanisms of the quality control of glycoprotein, more detailed information is obviously needed for the elucidation of three-dimensional structures and dynamics at the atomic level of the individual intermediates of the high-Man-type glycans on the processing pathway in both free and lectin-bound forms, taking into account of rigidity and flexibility of glycan structures and contributions of the polypeptide portions of glycoproteins. |
Conflict of interest statement |
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None declared.
|
Acknowledgements |
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We are grateful to Dr Robert J. Woods, University of Georgia, for his kind cooperation in calculation and presentation of the structure models of G3M9. Financial support from the CREST (Core Research for Evolution Science and Technology) project from the Japan Science and Technology Agency and by Grants-in-Aid from the Ministry of Education, Culture, Sports, Science, and Technology of Japan are acknowledged. Y.K. is a recipient of Japan Society for the Promotion of Science Research Fellowships for Young Scientists.
|
Abbreviations |
|---|
Asn, asparagine; BiP, immunoglobulin binding protein; CNX, calnexin; CRD, carbohydrate recognition domain; CRT, calreticulin; EDEM, ER degradation-enhancing
-mannosidase-like protein; ER, endoplasmic reticulum; ERAD, endoplasmic reticulum-associated degradation; ERGIC-53, 53 kDa membrane protein of the ER–Golgi intermediate compartment; FAC, frontal affinity chromatography; Glc, Glucose; Glc'ase, glucosidase; GlcNAc, N-acetylglucosaminyltransferase; KDEL, Lys-ASp-Glu-Leu; Man, mannose; Man'ase, mannosidase; MCFD2, multi coagulation factor deficiency 2; MRH, Man-6-phosphate receptor homology; NMR, nuclear magnetic resonance; OST, oligosaccharyl transferase; PDB, Protein Database; PDI, protein disulfide isomerase; PNGase, peptide:N-glycanase; PUB, peptide:N-glycanase/UBA or UBX-containing proteins; SCF complex, Skp1–Cullin1–F-box protein complex; Ub, ubiquitin; UBA, ubiquitin-associated.; Ubl, ubiquitin-like; UDP, uridine diphosphate; UGGT, uridine diphosphate–Glc:glycoprotein glucosyltransferase; VIP36, vesicular integral protein of 36 kDa; VIPL, VIP36-like; XBD, XPC-binding domain; XPC, xeroderma pigmentosum complementation group C; Z-VAD-fmk, carbobenzyloxy-Val-Ala-Asp--fluoromethylketone. |
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