Departments of Biological Chemistry and Medicine, Harvard Medical School, and the Joslin Diabetes Center, One Joslin Place, Boston, MA 02215, USA
Accepted on January 30, 2002;
Abstract
Formation of the sugaramino acid linkage is a crucial event in the biosynthesis of the carbohydrate units of glycoproteins. It sets into motion a complex series of posttranslational enzymatic steps that lead to the formation of a host of protein-bound oligosaccharides with diverse biological functions. These reactions occur throughout the entire phylogenetic spectrum, ranging from archaea and eubacteria to eukaryotes. It is the aim of this review to describe the glycopeptide linkages that have been found to date and specify their presence on well-characterized glycoproteins. A survey is also made of the enzymes involved in the formation of the various glycopeptide bonds as well as the site of their intracellular action and their affinity for particular peptide domains is evaluated. This examination indicates that 13 different monosaccharides and 8 amino acids are involved in glycoprotein linkages leading to a total of at least 41 bonds, if the anomeric configurations, the phosphoglycosyl linkages, as well as the GPI (glycophosphatidylinositol) phosphoethanolamine bridge are also considered. These bonds represent the products of N- and O-glycosylation, C-mannosylation, phosphoglycation, and glypiation. Currently at least 16 enzymes involved in their formation have been identified and in many cases cloned. Their intracellular site of action varies and includes the endoplasmic reticulum, Golgi apparatus, cytosol, and nucleus. With the exception of the Asn-linked carbohydrate and the GPI anchor, which are transferred to the polypeptide en bloc, the sugaramino acid linkages are formed by the enzymatic transfer of an activated monosaccharide directly to the protein. This review also deals briefly with glycosidases, which are involved in physiologically important cleavages of glycopeptide bonds in higher organisms, and with a number of human disease states in which defects in enzymatic transfer of saccharides to protein have been implicated.
Key words: consensus sequence of glycoproteins/diseases of protein glycosylation/glycosyltransferases/N-glycosylation/O-glycosylation
Introduction
It has been appreciated for some time that the attachment of sugar residues is the most complicated co- or posttranslational modification that a protein can undergo (Spiro, 1973). Indeed, the modification of proteins through enzymatic glycosylation is an event that reaches beyond the genome and is controlled by factors that differ greatly among cell types and species. Many elaborate glycosylation routes have been identified in a host of organisms that lead to the mature carbohydrate units on glycoproteins that are secreted by cells or become components of its membranes, cytoplasm, or nucleus. The defining event in the biogenesis of peptide-linked oligosaccharides is clearly the formation of the sugaramino acid bond; this in most instances determines the nature of the carbohydrate units that will subsequently be formed by the cellular enzymatic machinery, which in turn influences the proteins biological activity.
Since the description of the GlcNAc-ß-Asn linkage in ovalbumin by Neuberger and colleagues (Johansen et al., 1961), glycopeptide linkages have been described involving almost every functional group occurring on peptide chains and most of the commonly occurring monosaccharide residues, so that a multitude of diverse sugaramino acid combinations have been described. With the recognition that eubacteria and archaea (Lechner and Wieland, 1989
; Messner, 1997
) produce glycoproteins in addition to eukaryotes, the glycopeptide bond has attained the broadest possible phylogenetic distribution.
It is the aim of this review to describe the great variety of glycopeptide linkages that have been reported to date as well as to indicate their distribution among well-defined glycoproteins. The large number of enzymes involved in the formation of sugarprotein bonds that have presently been characterized from various sources will also be surveyed and their affinity for certain domains of peptide chains evaluated. This information can be of value for the production of recombinant glycoproteins. Glycosidases that have been implicated in physiologically relevant scission of the sugaramino acid linkage will be briefly described, as will human diseases in which alterations in the attachment of carbohydrate to protein have been observed.
Nature and distribution of glycopeptide linkages of glycoproteins
At the present stage of our knowledge an impressive variety of carbohydratepeptide linkages have been described that are distributed among glycoproteins found in essentially all living organisms, ranging from eubacteria to eukaryotes. In the latter group they are distributed over a broad phylogenetic spectrum reaching from unicellular organisms, such as yeast and trypanosomes, to the highly differentiated tissues of the animal and plant kingdoms (Table I). Thirteen different monosaccharides and 8 amino acid types participate in these bonds so that at least 31 sugaramino acid combinations exist. If the known anomeric configurations of the glycosidic bonds are taken into account this number rises to a minimum of 37. With the additional consideration of the phosphoglycosyl linkages and the glycophosphatidylinositol (GPI) phosphoethanolamine bridge, a total of at least 41 linkages are found to occur (Table I).
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The report that amylogenin, which is believed to be a self-glycosylating protein from sweet corn, contains a Glc-ß-Arg linkage to the guanidino group of the Arg provides another example of an N-glycosyl bond (Singh et al., 1995).
O-glycosidic bonds
Linkages in which the sugar is attached to an amino acid containing a hydroxyl group occur in great variety of proteins, not only in regard to the partners in this linkage but also in different anomeric configurations (Table I). Every amino acid with a hydroxyl functional group (i.e., Ser, Thr, Tyr, Hyp [hydroxyproline], and Hyl [hydroxylysine]) has been implicated.
The GalNAc--Ser/Thr linkage has been considered a hallmark of mucins where it occurs in clusters. However, a wide variety of glycoproteins contain this linkage (Spiro, 1973
; Sadler, 1984
), such as fetuin, human gonadotropins, glycophorin, and antifreeze glycoproteins, which indicates that such O-linked oligosaccharides frequently also occur in other highly diverse molecules. Though at present it would appear that this linkage is limited to eukaryotes, its ß-anomer (GalNAc-ß-Ser/Thr) has been reported to occur in the S-layer of the archaebacterium Aneurinibacillus thermoaerophilus (Schäffer et al., 1999
).
GlcNAc-ß-Ser/Thr represents an increasingly important linkage that is widely dispersed among eukaryotes, from protozoa to higher mammals. It is distinctive in that it is found in nuclear and cytoskeletal proteins and indeed represents the first reported example of glycosylated proteins found outside of the secretory channels (Hart, 1997). In contrast to most other peptide-linked monosaccharides, the ß-linked GlcNAc-Ser/Thr does not become further substituted by other sugars, remaining a simple monosaccharide modification of the protein to which it is attached. Indeed this property permitted the use of radiolabeled UDP-Gal with purified GlcNAc-galactosyltransferase to demonstrate its presence in minute amounts (Holt et al., 1987
) and this continues to be used as an effective probe. Though the GlcNAc-ß-Ser/Thr bond appears to be confined to intracellular glycoproteins, the
-linkage of GlcNAc to Thr has been found in cell surface and secreted glycoproteins from Trypanosoma cruzi (Previato et al., 1998
) and Dictyostelium discoideum (Jung et al., 1998
).
Gal--Ser/Thr has been reported to be present in the cuticle collagens of the earthworm, Lumbricus terrestris (Muir and Lee, 1970
) and clamworm, Nereis virens (Spiro and Bhoyroo, 1980
), where it appears both unsubstituted and as di- and tri-
-linked galactose oligosaccharides. Because these collagens do not contain Hyl, the possibility of linkage to this amino acid, as occurs in vertebrate collagens, is excluded. Gal linked apparently only to Thr has also been found in vent worm cuticle collagen (Mann et al., 1996
). The Gal-
-Ser/Thr bond has also been observed in eubacteria, where it is present on the cellulosomes of Bacteroides cellulosolvens and Clostridium thermocellum (Gerwig et al., 1993
). In archaea the S-layer glycoproteins of H. halobium contain clusters of glucosylgalactose disaccharides linked solely to Thr by a bond with an as yet undetermined anomeric configuration (Mescher and Strominger, 1976
). Furthermore, it has been reported that single Gal residues
-linked to Ser are present in the cell wall of Phaseolus coccineus (O'Neill and Selvendran, 1980
) and other higher plants (Lamport et al., 1973
).
The well-studied mannoproteins of the yeast cell wall are known to contain the Man--Ser/Thr glycopeptide linkage (Herscovics and Orlean, 1993
). A Man-Ser/Thr carbohydratepeptide bond with an as yet unknown anomeric configuration has also been identified in the
-dystroglycans of peripheral nerve (Endo, 1999
) and in brain proteoglycans and glycoproteins (Finne et al., 1979
; Yuen et al., 1997
), as well as several proteins secreted by Flavobacterium meningosepticum (Plummer et al., 1995
). Furthermore, oligosaccharides
-linked to Thr by a Man residue have been found in the secreted 45-kDa glycoproteins of Mycobacterium tuberculosis (Dobos et al., 1996
). A unique GlcUA
1-6Man disaccharide linked to Thr with an as yet unspecified anomeric configuration has been found in the cuticle collagen of Nereis (Spiro and Bhoyroo, 1980
).
The Fuc--Ser/Thr and Glc-ß-Ser linkages can be considered together (Table I) because they appear to be primarily found in epidermal growth factor (EGF) domains (Harris and Spellman, 1993
) of mutimodular proteins such as coagulation and fibrinolytic factors. Proteins containing Fuc-
-Ser/Thr oligosaccharides include urokinase (Buko et al., 1991
), human coagulation factors VII (Bjoern et al., 1991
), IX (Nishimura et al., 1992a
), and XII (Harris et al., 1992
) and Notch1 (Moloney et al., 2000
). Fucose appears in the mature glycoproteins either alone or as the inner component of short oligosaccharides. The site of glucose attachment has so far been found to be limited to Ser, and in a number of instances this sugar residue is the attachment point of one or two Xyl residues (Harris and Spellman, 1993
). Coagulation factors VII and IX as well as human plasma protein Z (Nishimura et al., 1989
) have been shown to contain the Glc-ß-Ser bond, as has bovine thrombospondin (Nishimura et al., 1992b
).
The Pse--Ser/Thr and DiActrideoxyhexose-Ser/Thr linkages (see Table I for abbreviations) are unusual bonds that have recently been found in eubacteria. Pseudaminic acid, which occurs as multiple substituents in Campylobacter jejuni flagellin (Thibault et al., 2001
), is of particular interest because it represents the first report of an acidic monosaccharide directly linked to protein. The DiActrideoxyhexose-containing glycopeptide bond has been identified in the pili of Neisseria meningitides, where it is the linkage sugar of a digalactose-containing trisaccharide unit (Stimson et al., 1995
). FucNAc-ß-Ser/Thr represents another recently described eubacterial linkage which occurs in the pili of Pseudomonas aeruginosa 1244 (Castric et al., 2001
); the FucNAc attaches a trisaccharide containing xylose and a derivative of pseudaminic acid to the protein.
It has been known for some time that the attachment of the chondroitin sulfate and heparan sulfate glycosaminoglycan chains of mammalian proteoglycans is mediated by a Xyl-ß-Ser bond (Kjellén and Lindahl, 1991; Esko and Zhang, 1996
). This stands in contrast to corneal and skeletal keratan sulfate chains, which are linked to the protein by GlcNAc-ß-Asn and GalNAc-
-Ser/Thr linkages, respectively (Kjellén and Lindahl, 1991
).
Glc-Thr and GlcNAc-Thr are unusual glycopeptide bonds in that they are pathologically generated by the action of Clostridium toxins (vide infra) on the Rho family of low-molecular-mass GTPases (Busch and Aktories, 2000).
All vertebrate and invertebrate collagens including those of basement membranes, with the exception of the previously mentioned worm cuticle collagens, manifest the Gal-ß-Hyl glycopeptide linkages (Spiro, 1969, 1972a) along their peptide chains. The Hyl-linked saccharide can occur as unsubstituted Gal residues or in the form of Glc
1-2Gal disaccharides (Spiro, 1967
). Moreover, the collagenous regions of C1q complement (Shinkai and Yonemasu, 1979
) and the hepatic core specific lectin (Colley and Baenziger, 1987
) have been shown to contain Gal-ß-Hyl bonds. In contrast to the O-glycosidic linkages to Ser and Thr, which can be split by ß-elimination, the GalHyl bond is stable to even strong alkali treatment (Spiro, 1972b
).
Gal and Ara saccharides linked to Hyp are features of plant glycoproteins. The Gal-ß-Hyp glycopeptide bond has been found in wheat endosperm (Strahm et al., 1981), gum arabic from Acacia senegal (Qi et al., 1991
), and the cell wall of Chlamydomonas green algae (Miller et al., 1972
). Plant cell walls ranging the phylogenetic spectrum from land plants to green algae have been shown to contain the Ara-
-Hyp linkage (Yamagishi et al., 1976
), which is a the primary glycopeptide bond of arabinogalactans (Kieliszewski et al., 1995
); on the other hand the Ara-ß-Hyp combination has been reported to occur in potato lectin (Allen et al., 1978
).
Recently a GlcNAc-Hyp bond has been characterized in cytoplasmic glycoprotein of Dictyostelium (Teng-umnuay et al., 1998). More specifically, this linkage was found to attach a pentasaccharide on the Skp1 component of the Skp1-cullin-F-box-protein complex (SCF), which is involved in the ubiquitination of various cell and other regulatory proteins.
Glycogenin, the protein primer for glycogen synthesis, has been shown to have the most internal sugar linked to protein by a Glc--Tyr bond in both muscle and liver (Smythe and Cohen, 1991
). On the other hand, Glc linked to Tyr by a ß-glycosidic linkage (Glc-ß-Tyr) has been found in the S-layer of eubacteria including Clostridium thermohydrosulfuricum (Messner et al., 1992
) and Thermoanaerobacterium thermosaccharolyticum D120-70 (Schäffer et al., 2000
). In another variant of the latter species (L111-69) a Gal-ß-Tyr linkage has been identified (Bock et al., 1994
).
C-mannosyl bonds
An entirely novel carbohydrateprotein linkage involving the attachment of an -mannosyl residue to C-2 of the Trp through a C-C bond, was described recently (de Beer et al., 1995
). Unlike the N- and O-glycosyl linkages, this glycopeptide bond does not involve an amino acid functional group. This linkage has been so far found in mammalian proteins including RNase2 (same as RNase Us) (de Beer et al., 1995
), interleukin-12 (Doucey et al., 1999
), and properdin (Hartmann and Hofsteenge, 2000
).
Phosphoglycosyl bonds
Attachment of sugar to protein via a phosphodiester bond represents another quite distinct type of glycopeptide linkage (Haynes, 1998) in which GlcNAc, Man, Xyl, and Fuc have been found to be involved (Table I). The GlcNAc-
-1-P-Ser linkage has been found in various proteins from Dictyostelium including proteinase-1 (Mehta et al., 1996
). Man-
-1-P-Ser has been observed in several major proteins of Leishmania species (Guha-Niyogi et al., 2001
), and Xyl-1-P-Ser has been found in T. cruzi (Haynes, 1998
). Furthermore, evidence for the presence of Fuc-ß-1-P-Ser in Dictyostelium has also been obtained (Srikrishna et al., 1998
).
Glypiated linkage
A major carbohydrateprotein connection is the GPI anchor. In this bond Man is linked to phosphoethanolamine, which in turn is attached to the terminal carboxyl group of the protein. This linkage is widely distributed among biologically important cell surface glycoproteins of eukaryotes, including the variant surface glycoproteins (VSGs) of trypanosomes and the Thy-1 antigen (Ferguson, 1999). Recently GPI-linked proteins have also been detected in the archaebacterium, Sulfolobus acidocaldarius (Kobayashi et al., 1997
).
Biosynthesis of glycopeptide linkages
At present the enzymes involved in the formation of at least 16 glycopeptide bonds have been identified and purified to various extents; moreover, a substantial number of these transferases have been cloned and in most instances the subcellular site of their action has been determined (Table II). With the exception of the GlcNAc-ß-Asn bond and the GPI anchor, the sugaramino acid linkage is formed by the direct enzymatic transfer of an activated monosaccharide or monosaccharide-1-phosphate to a specific amino acid residue in the polypeptide chain (Table II). Oligosaccharides are then generated by the sequential enzymatic attachment of sugars to the peptide-linked component. In the case of the Asn bond and the GPI anchor, a preassembled carbohydrate unit is added to the protein in the endoplasmic reticulum (ER), although by quite different mechanisms (vide infra). A strict amino acid consensus sequence has so far been established only for the GlcNAc-ß-Asn linkage, but distinct glycosylation motifs have been observed for a number of other glycopeptide bonds (Table III).
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In the formation of the N-glycosidic bonds of archaea, C55-60 dolichol monophosphate oligosaccharides have been implicated (Lechner and Wieland, 1989) and it has been suggested that in these primitive organisms N-glycosylation takes place on the outer surface of the cell membrane and that the Asn-X-Ser/Thr consensus sequence also is operative. Recently it has been reported that homologues of the highly conserved STT3 oligosaccharyltransferase subunit have been observed in archaea and also in the eubacterium Campylobacter jejuni 81-176 (Wacker et al., 2001
). However, gene replacement studies conducted on the Asn-bonds that occur in H. halobium (Table I) indicated that the Glc-ß-Asn bond in contrast to the GalNAc-ß-Asn does not have a strict requirement for the Asn-X-Ser/Thr consensus sequence; this led to the suggestion that distinct enzymes may be responsible for the formation of these two N-glycosidic bonds (Zeitler et al., 1998
).
O-glycosylation
The biosynthesis of the GalNAc--Ser/Thr bond has been extensively studied in eukaryotic cells, and it has become evident through the studies of a number of investigators that a family of at least nine GalNAc-transferases exists (Clausen and Bennett, 1996
; Ten Hagen et al., 2001
). Indeed, it has been suggested that these enzymes work in concert in a hierarchical manner to form the clustered Ser/Thr-linked oligosaccharides that frequently occur in the "mucin"-type of glycoprotein (Ten Hagen et al., 2001
). Several of these enzymes have been cloned and though it has become evident that they are distinct gene products and may be distributed on different chromosomes, they are generally homologous to each other (Clausen and Bennett, 1996
). Although these enzymes act on characteristic peptide regions (Table III), no specific consensus sequence has been identified despite numerous intensive investigations; this may very well be due to the multiplicity of the GalNAc-transferases. Because they are frequently assayed without prior separation, overlapping but distinct substrate specificities may therefore be masked. In general however, this linkage is found in clusters of Ser/Thr residues with a ß-turn near Pro and at a distance from charged amino acids. In vitro studies suggest that Thr is favored over Ser for
-GalNAc modification (Elhammer et al., 1993
). Immunoelectron microscopic studies (Roth et al., 1994
), in agreement with subcellular fractionation investigations (Hirschberg et al., 1998
), have indicated that
-GalNAc-transfer occurs in the cis-Golgi; however the multiple enzymes in this family make it possible that some act in a pre-Golgi or ER compartment, as had previously been suggested. Indeed it is not yet known if the entire GalNAc-transferase family occurs in every cell or species or if there is a selective distribution of the various enzyme isoforms.
Membrane GlcNAc-transferases that form the GlcNAc--Ser/Thr linkages have been characterized in Dictyostelium (Jung et al., 1998
) and T. cruzi (Previato et al., 1998
). These appear to be distinct from the enzyme that generates the GlcNAc-ß-Ser/Thr bond. Indeed it was reported that the optimal peptide for the cytosolic GlcNAc-transferase responsible for the formation of the GlcNAc-ß-Ser/Thr linkage is not a substrate for the latter enzyme (Previato et al., 1998
). It has been suggested that the GlcNAc-
-Ser/Thr linkage might have substituted for the
-GalNAc bond in more primitive eukaryotes before the epimerase that converts GlcNAc to GalNAc had evolved (Jung et al., 1998
). Studies on acceptor sites have indicated that the GlcNAc-transferase acts on clustered Thr residues near Pro and studies on Dictyostelium have indicated that these peptide sequences are similar to those reported for the addition of
-GalNAc residues in mammalian tissues (Jung et al., 1998
).
The GlcNAc-transferase responsible for the genesis of the GlcNAc-ß-Ser/Thr linkage was the first glycopeptide-forming enzyme to be localized outside of the channels of the secretory apparatus (Table II); it is widely distributed among eukaryotes and has a highly conserved primary sequence (Hart, 1997). This enzyme has been purified from rat liver cytosol (Haltiwanger et al., 1992
) and rabbit blood (Lubas et al., 1997
) and has been cloned from rat liver (Kreppel et al., 1997
) as well as C. elegans and human liver (Lubas et al., 1997
). This transferase has taken on importance not only because of the biologically relevant proteins on which it acts but also from the finding that the Ser/Thr residues it glycosylates appear to be identical to those that can undergo O-phosphorylation. This has suggested the possibility that there is a reciprocal relationship between these two peptide modifications in a potential regulatory cycle in which cytosolic ß-N-acetylglucosaminidase plays a key role (Comer and Hart, 2000
). Although no specific amino acid consensus sequence has as yet been found, some information relating to the polypeptide domains that it favors has been obtained (Table III) (Haltiwanger et al., 1997
).
The biosynthesis of the Man--Ser/Thr linkage has been studied most extensively in yeast (Herscovics and Orlean, 1993
; Strahl-Bolsinger et al., 1999
). It has been demonstrated that the formation of this glycopeptide bond takes place in the ER (Haselbeck and Tanner, 1983
) and moreover that the mannosyltransferase uses a dolichol-linked monosaccharide rather than a sugar nucleotide as the glycosyl donor (Table II). It has become apparent in recent years that seven genes for the protein O-mannosyltransferase (PMT1-7) with extensive shared homology are present in S. cerevisiae (Strahl-Bolsinger et al., 1999
) of which two have been cloned (Lussier et al., 1995
). The mannosylation of proteins from higher eukaryotes has not yet been defined, but a human homolog of the PMT1 transferase gene has recently been reported (Jurado et al., 1999
). Although a consensus sequence for O-mannosylation has not been established, glycosylation does take place in clustered Ser/Thr-rich domains with the latter amino acid serving as the better acceptor (Strahl-Bolsinger et al., 1999
) in cell-free studies (Table III).
Since the purification and characterization from Chinese hamster ovary cells of the transferase responsible for the formation of the Fuc--Ser/Thr linkage (Wang and Spellman, 1998
), it has been cloned from a human heart cDNA library (Wang et al., 2001
). Transcripts of this gene were observed to be expressed in all human tissues examined, and moreover homologs were found in mice, Drosophila, and C. elegans (Wang et al., 2001
). The enzyme was observed to be membrane associated and its type II transmembrane structure was believed to be consistent with a Golgi localization. O-fucosylation has been shown on EGF modules of various proteins and a consensus sequence has been identified (Table III) in which the glycosylation site is situated between the second and third conserved cysteine residues (Harris and Spellman, 1993
). A recent report on human platelet thrombospondin indicated that the Fuc-
-Ser/Thr linkages occur outside of the EGF module in a peptide sequence somewhat different from those in other proteins, suggesting that the consensus sequence may be broader than believed or more than one fucosyltransferase may exist (Hofsteenge et al., 2001
).
Although the enzymatic formation of the Glc-ß-Ser glycopeptide bond has not as yet been elucidated, it is apparent from structural studies conducted so far that this glucose modification, like fucosylation, is directed toward a consensus sequence on the EGF domain (Table III) and on the basis of studies on human factor IX it would appear that the glucose is attached to Ser located between the first and second conserved cysteine residues of the EGF motif (Harris and Spellman, 1993). More specifically, it has been shown that Ser-52 of human factor VII and Ser-53 of human factor IX as well as human and bovine protein Z are O-glucosylated (Nishimura et al., 1989
).
The initial step in proteoglycan biosynthesis is mediated by a glycosyltransferase that establishes the Xyl-ß-Ser bond. In rat liver the enzyme appears to be primarily Golgi-situated (Nuwayhid et al., 1986), whereas in chick chondrocytes it has been observed to be present in late ER and early Golgi compartments (Vertel et al., 1993
). This xylosyltransferase has been purified from rat chondrosarcoma (Schwartz and Dorfman, 1975
) and rat ear cartilage (Pfeil and Wenzel, 2000
). The enzyme has also been isolated from human choriocarcinoma cells (Kuhn et al., 2001
) and cloned from this source (Götting et al., 2000
). The amino acid sequences around the attachment sites have been documented and shown not to be invariable (Esko and Zhang, 1996
). However, in general they are represented by the motif shown in Table III where Ala can substitute for the more common Gly residue; furthermore, one or more acidic amino acids are found in close proximity to the glycopeptide bond.
The formation of the Glc-Thr and GlcNAc-Thr linkages represent events that are of a pathological nature (Table II). Both linkages are generated in the cytosol of Clostridium-infected mammalian cells through the action of the bacterial cytotoxins on the Rho family of small GTPases, including its Rac and Cdc42 members, resulting in an inhibition of their activity. Though C. difficile and C. sordelli toxins transfer Glc to Thr (Just et al., 1995), the toxin from C. novyi adds GlcNAc to this amino acid (Selzer et al., 1996
). The specific residues that are modified have been identified (Table III) and cloning of the C. difficile (Eichel-Streiber et al., 1992
) and C. novyi (Hofmann et al., 1995
) toxins has been achieved.
The transferase involved in the genesis of the Gal-Thr glycopeptide linkage of cuticle collagens has not as yet been identified but structural studies on the hydrothermal vent worm collagen (Mann et al., 1996) have indicated that the glycosylated Thr residues are found in the Gly-X-Thr positions (Table III). These substituted Thr constituents are believed to replace Hyp as the primary contributor to triple helix stabilization.
The galactosyltransferase responsible for the synthesis of the Gal-ß-Hyl was found to be widely distributed in the tissues of the rat, including kidney, cartilage, spleen and lung (Spiro and Spiro, 1971b). Its action is directed toward the collagen triplet (Table III) and requires that the
-amino group of the Hyl to be unsubstituted (Spiro and Spiro, 1971a
). Golgi localization of the enzyme was indicated by its association with light membrane fractions (Spiro and Spiro, 1971a
) and by in vivo studies on the hepatic core specific lectin that contains collagen-like domains in which glycosylated Hyl residues reside (Colley and Baenziger, 1987
). This intracellular site is in accord with the fact that a transporter for UDP-Gal is present in the Golgi apparatus and not in the ER (Hirschberg et al., 1998
).
The enzyme involved in the formation of the Ara--Hyp bond has not yet been characterized, but it has been determined that in higher plants repetitive Hyp-rich modules (Table III) are the site of arabinogalactan attachment (Kieliszewski et al., 1995
).
The cytoplasmic GlcNAc-transferase of Dictyostelium involved in the biogenesis of the GlcNAc-Hyp sugaramino acid connection has been purified (Teng-umnuay et al., 1999) and recently cloned (West et al., 2001
). Because this novel linkage has so far only been observed in the Skp1 component of the SCF complex, the assay of the glycosylation enzyme employed the Skp1 protein or its peptides. Attachment of the GlcNAc was shown to occur to a Hyp residue at amino acid position 143 and the enzyme works in conjunction with a series of other cytoplasmic glycosyltransferases to form a pentasaccharide carbohydrate unit (Teng-umnuay et al., 1998
). The cytoplasmic location of the GlcNAc-transferase suggested to these investigators that a bidirectional flow of the Skp1 protein through the ER membrane must occur because hydroxylation of Pro is believed to take place inside the vesicles (Teng-umnuay et al., 1998
).
It has been established that the Glc--Tyr linkage of mammalian glycogenin occurs on Tyr 194 of this protein and, moreover, that the formation of this bond quite uniquely is an autocatalytic cytosolic event (Alonso et al., 1994
) occurring between the two subunits of this primer protein (Lin et al., 1999
). The enzyme (i.e., glycogenin) has been cloned (Viskupic et al., 1992
) and it has been shown that although mutation of Tyr-194 to Phe or Thr results in the loss of the self-glucosylating activity, the glycogenin retains its capacity to transfer glucose to exogenous acceptors (Cao et al., 1995
). The recombinant monoglucosylated glycogenin can serve as an acceptor for mammalian glycogen synthase (Viskupic et al., 1992
); the Km for the latter enzyme is 1000-fold greater than for the glucosyltransferase that forms the glycopeptide bond (Pitcher et al., 1988
).
Phosphoglycosylation
The enzymatic attachment of a sugar to the polypeptide chain through a phosphodiester bridge, which has been termed phosphoglycosylation (Mehta et al., 1996), has been investigated in Dictyostelium and Leishmania (Table II). The GlcNAc-1-phosphotransferase was partially purified from Dictyostelium and localized to light membranes that are believed to represent the Golgi compartment (Merello et al., 1995
). Subsequent studies indicated that the enzyme recognizes Ser-containing peptides of various Dictyostelium proteins among which cysteine proteinases are the most prominent (Mehta et al., 1997
). Although no single specific motif was observed in the peptide acceptor, it was determined that the transfers occur in Ser-rich domains in which the flanking Ala residues preferentially influence phosphoglycosylation (Table III); Thr residues were not phosphoglycosylated by the enzyme.
Man-1-phosphotransferase has been characterized in Leishmania mexicana promastigotes and it is believed to be situated in the cis-Golgi compartment (Moss et al., 1999). The enzyme adds Man-
-1-phosphate to Ser residues in domains rich in this amino acid; it does not act on Thr and its action is promoted by flanking Asp and Glu residues.
C-mannosylation
The enzyme which links C-1 of mannose to the C-2 atom of the indole ring of Trp has been found to be present in a variety of cultured mammalian cells (Krieg et al., 1997) and has been studied in rat liver microsomes (Doucey et al., 1998
). Convincing evidence has been obtained that the glycosyl donor in this reaction is Dol-P-Man, and indeed it was reported that C-mannosylation is considerably reduced in Lec15 Chinese hamster ovary cells that are deficient in Dol-P-Man synthase activity (Doucey et al., 1998
). Furthermore, it was recently shown that C-mannosylation of Trp, along with all previously known classes of Dol-P-monosaccharide-dependent glycosyltransferase reactions, is regulated in hamster by the Lec35 gene, which is required for Dol-P-mannose utilization (Anand et al., 2001
). The dependence of the C-mannosylation on Dol-P-Man strongly suggests that it takes place in the ER, where all known Dol-P-Man-dependent reactions are localized (Anand et al., 2001
). The recognition signal for C-mannosylation has been assigned to a Trp-X-X-Trp sequence (Table III) in which the first Trp becomes glycosylated (Krieg et al., 1998
; Doucey et al., 1998
; Hartmann and Hofsteenge, 2000
); the Trp at position +3 is also important for the glycosylation to take place as the transfer activity was abolished when this amino acid was mutated to Ala and reduced to one-third when replaced by Phe (Krieg et al., 1998
). A survey of protein databases has indicated that the Trp-X-X-Trp consensus sequence is present in 336 mammalian proteins, suggesting the possibility that C-mannosylation may occur quite frequently in higher eukaryotes (Krieg et al., 1998
).
Glypiation
The process of adding GPI to proteins, which has been termed glypiation, is carried out by an ER-situated transamidase that cleaves the C-terminal peptide and concomitantly transfers the preassembled GPI anchor to the newly exposed carboxy-terminal amino acid residue to establish an amide bond between the latter and the ethanolamine moiety of the glycolipid (Kinoshita et al., 1997; Ferguson, 1999
). In contrast to the assembly of the oligosaccharide involved in formation of the N-glycosidic linkage to Asn, it is believed that GPI assembly takes place entirely on the cytoplasmic side of the ER and is presumably followed by its translocation to the lumenal side, where attachment to the protein takes place. The transamidase reaction has been observed in eukaryotes ranging from yeast to mammals and is believed to be carried out by a multiprotein complex that has as yet not been isolated in its intact form. The genes of two components (GPI8 and GAA1) have been cloned from yeast (Benghezal et al., 1996
; Hamburger et al., 1995
). Intensive studies have been carried out regarding the carboxy-terminal signal peptide that directs GPI attachment. It has been noted that this peptide, which has to be cleaved prior to binding of the GPI and consists of 1530 amino acids, has structural similarities to the NH2-terminal peptide that functions in general to direct nascent chains into the ER lumen (Micanovic et al., 1990
; Gerber et al., 1992
). The residue to which GPI becomes attached (termed
) has small side chains (e.g., Gly, Ala, Cys, Ser, Asn) as does the amino acid in the
+2 position (e.g., Gly, Ala). The latter site is followed by a short hydrophilic domain (57 residues) and this is followed by a hydrophobic region (1220 residues) that extends to the carboxy-terminus of the signal peptide. The
+1 position apparently can be filled by any amino acid except Pro or Trp.
Enzymatic cleavage of glycopeptide bonds
Although a number of endoglycosidases and glycosidases, usually of bacterial or plant origin, have been effectively employed to split N- and O-glycosidic bonds in structural investigations (Kobata, 1979; Maley et al., 1989
), brief mention will be made only of eukaryotic enzymes active at neutral pH that appear to play an important physiological role.
Cleavage of the GlcNAc-ß-Ser/Thr linkage has been shown to take place through the action of a specific cytosolically situated ß-N-acetylglucosaminidase, which has been purified from rat spleen cytosol (Dong and Hart, 1994) and recently cloned from human brain (Gao et al., 2001
). This enzyme is expressed in every human tissue examined and is believed to be a key component of the postulated regulatory cycle in which Ser/Thr residues on various nuclear and cytoplasmic proteins can be modified alternatively by O-GlcNAc or O-phosphate groups.
The finding that the release of polymannose oligosaccharides from their Asn linkage into the cytosol and ER lumen from newly synthesized glycoproteins occurs as part of the ER-associated quality control of misfolded or improperly oligomerized proteins (Moore and Spiro, 1994; Spiro and Spiro, 2001
) led to the finding that peptide-N-glycosidases that cleave the GlcNAc-ß-Asn bond occur in the cytosol and ER of liver and other eukaryotic tissues (Suzuki et al., 1997
, 1998; Weng and Spiro, 1997
).
Influence of enzymatic peptide glycosylation on human disease
It has become evident in recent years that defects in the attachment of carbohydrate to protein have been implicated in a number of human diseases. The congenital disorders of glycosylation represent a group of systemic diseases characterized most prominently by neurological and developmental deficiencies, and these have been well defined at a molecular level (Freeze and Westphal, 2001; Schachter, 2001
). At the present time six variants have been described that can be ascribed to specific enzymatic defects responsible for the impairment at different stages of dolichylpyrophosphate oligosaccharide assembly. Because the lipid-linked oligosaccharide is the glycosyl donor in the formation of the GlcNAc-ß-Asn linkage, this group of multisystem diseases ultimately represents a disorder of N-glycosylation.
As already indicated, the glycosylation by clostridial cytotoxins of a specific Thr residue on proteins that belong to the Rho family of mammalian GTPases is highly relevant to human disease (Busch and Aktories, 2000). Indeed, toxins produced by members of the Clostridium genus have been shown to be responsible for the causation of such pathological states as botulism, gas gangrene, antibiotic-associated diarrhea, and pseudomembranous colitis. Rho proteins act as molecular switches to control cellular processes, such as the organization of the actin cytoskeleton in eukaryotes, by cycling between the active GTP- and inactive GDP-bound states. The highly conserved Thr residue which is the substrate for the glycosylation by the toxins is involved in the nucleotide binding. It is believed that modification of this amino acid by addition of a GlcNAc or Glc residue results in a loss of effector binding by the Rho protein and inhibition of GTPase activity.
Although observations were made some time ago that formation of glucosamine from glucose was strongly favored over the production of glycogen in diabetic rats (Spiro, 1959, 1963), in more recent years this enhanced hexosamine flux has been the subject of intensive investigations that were to a large extent based on the description of the GlcNAc-ß-Ser/Thr carbohydrate unit by Hart and his collaborators (Hart, 1997
). Indeed the hexosamine flux hypothesis has been supported by the findings that high levels of GlcNAc brought about by infusion of this sugar (Hawkins et al., 1996
) or overexpression of the key enzyme for Glc to GlcNAc conversion, namely glutamine:fructose-6-phosphate amidotransferase (Hebert et al., 1996
), promotes the development of insulin resistance in rodents and cultured cells. The mechanism is believed to involve an increase in the presence of Ser/Thr-linked GlcNAc on important regulatory proteins through enhanced UDP-GlcNAc transfer by the GlcNAc:protein transferase (Tang et al., 2000
; Akimoto et al., 2001
). Presumably the resulting hyperglycemia would then lead to the microvascular complications, which are the hallmark of the uncontrolled diabetic condition (Spiro, 1976
). The observations that the level of GlcNAc transferase transcripts is particularly high in the ß-cells of islets of Langerhans and that the experimental diabetes agent, streptozotocin (a structural analog of GlcNAc) selectively inhibits the ß-N-acetylglucosaminidase activity in vitro (Hanover et al., 1999
) and elevates GlcNAc-ß-Ser/Thr levels in pancreas of diabetic rats (Akimoto et al., 2001
) has added to the intriguing puzzle relating to the generation of insulin-resistant diabetes.
Leukocyte adhesion deficiency II, a rare disorder characterized by recurrent infections and severe mental and growth retardation, has been attributed to a lack of GDP-Fuc formation due to impaired activity of GDP-mannose-4,6-dehydratase (Becker and Lowe, 1999). Recently a closely related disorder was described in a patient who manifested a decreased import of GDP-Fuc into the Golgi (Lübke et al., 1999
). Symptoms of the disease have been attributed to the absence of fucosylated selectin ligands (Phillips et al., 1995
). However, the realization that Fuc-
-Ser/Thr occurs on the EGF modules of the Notch1 receptor (Moloney et al., 2000
), either as an unsubstituted monosaccharide or an oligosaccharide species (Wang et al., 2001
) has opened the possibility that some of the developmental defects seen in leukocyte adhesion deficiency syndrome could be the result of impaired formation of the Fuc-
-Ser/Thr bond due to lack of the GDP-Fuc glycosyl donor.
Paroxysmal nocturnal hemoglobinuria is a disorder characterized by recurrent bouts of complement-mediated intravesicular hemolysis in which there is a defect in the biosynthesis of the GPI anchor of granulocytes and B lymphocytes (Tomita, 1999). Although it has been determined that the gene that is mutated in this condition is PIG-A, which is involved in the addition of GlcNAc to the inositol residue of the phosphatidylinositol (Takeda et al., 1993
), this disruption in the multistep GPI assembly ultimately results in an impairment of the en bloc attachment of the completed anchor to protein and therefore can be considered to bring about a defect in glypiation.
Concluding remarks
It is apparent from this review that a strikingly large number of diverse carbohydratepeptide linkages exist in nature and that many of these occur throughout the phylogenetic range, extending from the most primitive microorganisms to highly differentiated multicellular animals and plants. Clearly, the appearance of protein-linked oligosaccharides so early in evolution suggests that this co- or posttranslational event with its elaborate enzymatic machinery plays an essential biological role, because it takes place even in prokaryotic cells without secretory channels. At first consideration it appears surprising that such a high diversity of glycopeptide linkages has evolved. However, appreciation of the critical role that oligosaccharides play in the three-dimensional framework of proteins with diverse amino acid sequences makes glycopeptide bond multiplicity more understandable, since the formation of these crucial linkages determines to a large extent the nature of the final carbohydrate units that are subsequently formed by the numerous processing enzymes. A chronological survey of the description of new glycopeptide linkages suggests that this stream of discoveries will continue for some time into the future. Indeed, the finding in a variety of proteins of mannose linked by a C-C bond to the indole ring of Trp indicates that protein glycosylation does not even require an amino acid functional group and thereby expands the scope of future investigations into novel bonds. Although considerable attention has been given to glycopeptide linkages of eukaryotes, further exploration of archaea and eubacteria glycoproteins promises to yield much new information. The as-yet-incomplete study of the enzymes involved in the attachment of saccharides to protein suggests that in many instances, as exemplified by the multiple -GalNAc and
-Man:polypeptide transferases, a family of closely related enzymes may be involved in the formation of the same glycopeptide bond with each member of this group having specificity for different proteins or even different regions of the same polypeptide chain. Because glycosylation of proteins appears to be a highly directed process, up to now the difficulty in finding an invariant peptide consensus sequence for a number of sugaramino acid bonds may be due in part to a lack of resolution of all the members of such enzyme families. It is anticipated moreover that in future years there will be a major expansion in the elucidation of disease states in which attachment of saccharides to protein is altered through genetic or intracellular environmental factors.
Acknowledgments
Work from the authors laboratory was funded by grants DK17325 and DK17477 from the National Institutes of Health.
Abbreviatons
EGF, epidermal growth factor; ER, endoplasmic reticulum; GPI, glycophosphatidylinositol; Hyp, hydroxyproline; Hyl, hydroxylysine; PMT, protein O-mannosyltransferase; SCF, Skp1-cullin-F-box; VSG, variant surface glycoprotein; Dictyostelium when used in the text refers to the discoideum species.
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