From the Department of Pharmacology, University of Texas Southwestern Medical Center, Dallas, Texas 75390-9041
Glycosidically linked sugar polymers are well known as
nutritional and structural molecules, and it is now clear that they also have essential roles as carriers of biological information. The
constituent sugar residues contain multiple hydroxyl groups capable of
forming complex arrangements of hydrogen bonds. Sugars are often
modified with amino, N-acetyl, carboxyl, phosphate, and
sulfate groups, permitting more varied interactions than those achieved
with hydroxyls. Many different sugars occur in nature, and these can be
coupled in numerous ways through
Oligosaccharides as Information Carriers
or
glycosidic linkages of
their hydroxyls to form oligosaccharides (with relatively few sugars)
and polysaccharides (with many sugars) (1). For example, there are
eight different ways to couple the anomeric carbon (no. 1) of one
residue of glucose to the nonanomeric carbons (no. 2, 3, 4, or 6) of
another. Sugar polymers are also distinguished from other biological
polymers by facile formation of both linear and branched structures.
For example, the
1,4-linked mannose residue in asparagine
(N)-linked oligosaccharides is always linked to at least
three other sugars as indicated in Fig.
1. Oligosaccharides that carry
information are usually coupled to chemically distinct units termed
aglycones that themselves are not carbohydrates, but
typically are proteins or lipids, and whose biological properties can
be dramatically changed by the oligosaccharide.
View larger version (29K):
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Fig. 1.
Information encoded by
N-linked processing intermediates in the ER. The
structure of Glc3Man9GlcNAc2 linked
to asparagine and the residues removed by sequential glycosidase
reactions are shown. The information contents of
Glc3Man9GlcNAc2 (a) and
the products of each processing reaction (b-e) are
indicated. The A-isomer of Man8GlcNAc2 is
formed by Golgi endomannosidase cleavage of the linkage marked with an
asterisk. The B-isomer of
Man8GlcNAc2 results from reaction
(e).
The purpose of this minireview is to explore the roles of
oligosaccharides as carriers of intra- and intercellular information with emphasis on the relationships between oligosaccharide metabolism, quality control, and stress responses of the endoplasmic reticulum (ER).1
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Oligosaccharide-based Information in ER Protein Quality Control |
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The process of quality control for nascent proteins in the lumen of the ER is an excellent example of oligosaccharide-based information. Specifically, information-carrying N-linked oligosaccharides on newly synthesized ER glycoproteins are continuously altered during folding and assembly to reflect the status of the glycoproteins and to promote interaction(s) with appropriate components of the quality control machinery (2). Fig. 1 summarizes the five common N-linked intermediates that occur in the ER, the information they carry, and the enzymes that govern their formation. Additional details can be found in recent excellent reviews by Parodi (3) and Spiro (4).
Glc3Man9GlcNAc2-- This oligosaccharide is transferred cotranslationally by the multisubunit enzyme oligosaccharyltransferase from the lipid-linked oligosaccharide (LLO) Glc3Man9GlcNAc2-P-P-dolichol to sterically accessible asparaginyl residues in the context Asn-Xaa-Ser/Thr on nascent proteins in the ER lumen (5). Attachment of this oligosaccharide therefore signifies translocation of the polypeptide into the ER lumen but not necessarily completion of translation. Although the triglucosyl sequence of Glc3Man9GlcNAc2 is important for recognition by oligosaccharyltransferase (4), no specific function or informational content has been reported for Glc3Man9GlcNAc2 on glycoproteins, although its hydrophilic character promotes protein folding (see below).
Glc2Man9GlcNAc2-- With a half-time of less than 2 min (6) Glc3Man9GlcNAc2-protein is processed to Glc2Man9GlcNAc2 by a castanospermine (CSN)-sensitive enzyme, glucosidase I. No specific informational role has been reported for Glc2Man9GlcNAc2. Both Glc2Man9GlcNAc2 and Glc1Man9GlcNAc2 are substrates for glucosidase II, which is also inhibited by CSN.
Glc1Man9GlcNAc2--
The
presence of this oligosaccharide indicates that the protein to which it
is attached is ready to interact with a
lectin-chaperone,2 calnexin
(CNX) or calreticulin (CRT), to achieve the proper tertiary or
quaternary structure.
Glc1Man9GlcNAc2-protein can be
formed by digestion of
Glc2Man9GlcNAc2-protein by
glucosidase II, with a half-time of ~5 min in vivo (6) or
by reglucosylation of Man9GlcNAc2-protein (see
below). Many glycoproteins require
Glc1Man9GlcNAc2-dependent interactions with CNX or CRT for efficient folding, assembly, and
export from the ER (3, 4, 7). CNX (8) and CRT (9) are clearly lectins,
and Glc1Man9GlcNAc2 can bind
directly whether it is free or linked to protein. Association
constants for CNX are in the range of 4-5 × 105
M1 (10).
Glc1Man(5-9)GlcNAc2, but not
Glc1Man4GlcNAc2, bind to CNX (11)
and CRT (9), and the three mannosyl residues that form the "arm" to
which glucose is attached also contribute to binding (11). Because only
oligosaccharides with a single
-1,3-linked glucosyl residue bind,
oligosaccharide ligands for these lectin-chaperones are referred to
collectively as monoglucosylated oligosaccharides.
In addition to their lectin activities, both CNX (12) and CRT (13) have efficient oligosaccharide-independent chaperone activities in vitro. There is abundant evidence that many glycoprotein folding intermediates first interact with CNX and CRT in a lectin-dependent manner, followed by formation of oligosaccharide-independent complexes (3, 8). It is probable that the chaperone activities of CNX and CRT contribute to glycoprotein folding in such complexes. Oligosaccharide-independent interactions with CNX and CRT would likely involve hydrophobic surfaces on glycoprotein folding intermediates. However, such hydrophobic interactions cannot be easily distinguished experimentally from irrelevant hydrophobic interactions that would also be anticipated with partially unfolded glycoproteins. Hence, the two-state mechanism has been difficult to prove (3). The situation has been complicated further by reports of some "lectin-only" and "lectin-independent" complexes of glycoprotein folding intermediates with CNX (3). It is possible that the mechanism used depends upon the specific glycoprotein in question. Resolution of this controversy may require the determination of three-dimensional structures of lectin-chaperone·glycoprotein complexes.
Glc1Man9GlcNAc2 is an excellent
substrate for the Golgi endomannosidase, which releases a
Glc1,3Man disaccharide to yield the A-isomer of
Man8GlcNAc2 (Fig. 1) (4). Because of the Golgi apparatus location of the endomannosidase (14), glycoproteins with
Glc1Man9GlcNAc2 that have escaped
further glycosidic processing, but have been properly folded and
exported from the ER, can be digested to enable Golgi-type processing
(4).
Man9GlcNAc2-- The presence of this oligosaccharide, formed by glucosidase II digestion of Glc1Man9GlcNAc2, indicates that the glycoprotein in question should be inspected for exposure of hydrophobic surfaces not present in the native glycoprotein. If such surfaces are found, the oligosaccharide is enzymatically reglucosylated to regenerate Glc1Man9GlcNAc2 for an additional round of binding to CNX/CRT. Reglucosylation is carried out by a single remarkable ER resident enzyme, UDP-glucose:unfolded glycoprotein glucosyltransferase (3). The existence of this enzyme was originally suggested by reports of direct transfer of glucose from UDP-glucose to glycoproteins (15, 16). The product, Glc1Man9GlcNAc2, is the same structural isomer as that achieved by glucosidase II processing of Glc2Man9GlcNAc2 (17). Although Man9GlcNAc2 oligosaccharides on improperly folded glycoproteins are good substrates, Man9GlcNAc2 on properly folded glycoproteins and free Man9GlcNAc2 oligosaccharides are poor substrates for the glucosyltransferase. Thus, the enzyme has a catalytic site for glucose transfer and a separate site that interacts with non-native surfaces on glycoprotein folding intermediates. For some misfolded glycoproteins, several rounds of reglucosylation-deglucosylation can occur (3).
Man9GlcNAc2 is also the preferred oligosaccharide on coagulation factors V and VIII (18) and a cathepsin Z-related protein (19) needed for interactions with ERGIC-53, a lectin that is a resident of the ER-Golgi intermediate compartment and is involved in trafficking of these glycoproteins. In both cases interactions with ERGIC-53 were hindered by treatments with CSN but not with the ER mannosidase I inhibitor deoxymannojirimycin.
Man8GlcNAc2--
The presence of
Man8GlcNAc2 on a misfolded glycoprotein
indicates that it should be degraded. The B-isomer of
Man8GlcNAc2 is generated by digestion of
Man9GlcNAc2 by a kifunensine- and deoxymannojirimycin-sensitive ER mannosidase I (Fig. 1). For most glycoproteins digestion by ER mannosidase I is the last step in glycan
processing before export to the Golgi apparatus and occurs at a time
when folding and assembly should be complete. Abundant biochemical
(Refs. 20 and 21, and references therein) and genetic (22) evidence
implicates Man8GlcNAc2 in the degradation of
many types of misfolded glycoproteins by cytoplasmic proteasomes, whereas properly folded glycoproteins bearing
Man8GlcNAc2 escape degradation. Two models have
been proposed, distinguished operationally by whether or not CNX
binding stabilizes the glycoprotein. As first shown with myosin
class I heavy chains (23) and subsequently with other systems (Refs. 20
and 21, and references therein), CNX binding stabilizes many misfolded
glycoproteins. It has been suggested that degradation might involve
interaction with a Man8GlcNAc2-specific lectin,
which remains to be identified. This model is supported by the finding
that misfolded carboxypeptidase Y bearing
Man9GlcNAc2, Man7GlcNAc2, or
Man6GlcNAc2 was more stable than with
Man8GlcNAc2 (22). Degradation of misfolded
variants of 1-antitrypsin (AT) in hepatoma
cells also requires formation of Man8GlcNAc2
(24). However,
1-AT variants are destabilized by
interaction with CNX. It has been proposed (24) that formation of
Man8GlcNAc2-
1-AT promotes CNX
binding and accelerates degradation of
1-AT because, after reglucosylation,
Glc1Man8GlcNAc2-
1-AT
is predicted to be more resistant to glucosidase II digestion than
Glc1Man9GlcNAc2-
1-AT. This model is based upon the observation that the relative activity of
glucosidase II toward free oligosaccharides is
Glc1Man9GlcNAc > Glc1Man8GlcNAc > Glc1Man7GlcNAc (25). In the same study
glucosidase II activity was found to be strongly influenced by the
attachment of substrate oligosaccharides to protein. Thus, it would be
interesting to extend these results with purified glucosidase II and
purified glycoproteins bearing known
Glc1ManxGlcNAc2 structural isomers. Recent studies have implicated Man7GlcNAc2, the
ER mannosidase II product of Man8GlcNAc2, in a
distinct mechanism involving nonproteasomal degradation of the
1-AT variant PI Z (26).
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Endoplasmic Reticulum Oligosaccharide Quality Control |
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The preceding section reviewed the role of N-linked
Glc3Man9GlcNAc2 in quality control
of nascent ER glycoproteins. Conversely, cells have several strategies
for maintaining the quantity of Glc3Man9GlcNAc2-P-P-dolichol, the
direct precursor of N-linked Glc3Man9GlcNAc2 (Fig.
2).
Glc3Man9GlcNAc2-P-P-dolichol
synthesis occurs in a stepwise manner from dolichol-P, requiring four
donor substrates in this order: UDP-GlcNAc (2 eq), GDP-mannose (5 eq), mannose-P-dolichol (MPD; 4 eq), and glucose-P-dolichol (GPD; 3 eq). MPD
and GPD are formed by transfer of mannose or glucose from GDP-mannose
or UDP-glucose, respectively, to dolichol-P. Each sugar residue in
Glc3Man9GlcNAc2-P-P-dolichol is
added by a separate transferase (5). This section will review
regulation of priming of dolichol-P by its conversion to
GlcNAc-P-P-dolichol, extension of LLO intermediates, and
transfer of
Glc3Man9GlcNAc2 from its
dolichol-P-P carrier to appropriate asparaginyl residues in
proteins.
|
Priming and Extension--
LLO synthesis is primed by
UDP-GlcNAc:dolichol-P GlcNAc-1-P transferase (GPT), which transfers
GlcNAc-1-P from UDP-GlcNAc to dolichol-P to yield
GlcNAc- P-P-dolichol (27). Tunicamycin (TN) is a selective inhibitor
of GPT (27), although high concentrations also inhibit protein
palmitoylation (28). Several forms of regulation of GPT have been
reported (27). Considerable information is available for the
stimulation of GPT in vitro by exogenously added MPD (29).
Stimulation can be achieved with the physiological -isomer of MPD
but not with the
-isomer (30) or with GPD (31). GlcNAc-P-P-dolichol
was recently shown to stimulate MPD synthase in vitro (29).
The reciprocal stimulations of GPT and MPD synthase by their products
may help maintain a balance of LLO substrates; GlcNAc-P-P-dolichol is
needed for priming, and MPD is needed for extension. The intriguing
possibility remains that related regulatory relationships exist for GPD synthesis.
Priming is dependent upon the dolichol-P concentration because LLO synthesis in cultured cells is increased by supplementation with dolichol-P (27). The concentration of dolichol-P, also required for the MPD and GPD synthases and hence extension of LLO intermediates, is regulated in response to various biological stimuli associated with increased synthesis of N-linked glycoproteins by cis-isoprenyltransferase, the enzyme system catalyzing the chain elongation stage in de novo dolichol-P biosynthesis (32-34). cis-Isoprenyltransferase regulation is most likely at the level of mRNA synthesis, but direct transcriptional studies remain to be performed. LLO extension can also be controlled by the unfolded protein response (below) (35).
Oligosaccharide Transfer--
Oligosaccharide transfer from
Glc3Man9GlcNAc2-P-P-dolichol to
appropriate asparaginyl residues of nascent proteins is catalyzed by
the enzyme oligosaccharyltransferase (5). Even under conditions where
Glc3Man9GlcNAc2-P-P-dolichol
represents a minor fraction of the steady-state LLO pool, the
selectivity of oligosaccharyltransferase for
Glc3Man9GlcNAc2-P-P-dolichol
ensures that most nascent proteins will be modified with
Glc3Man9GlcNAc2. As an example of
the importance of oligosaccharyltransferase selectivity in quality
control, studies from the author's laboratory with primary human
dermal fibroblasts showed that if
Glc3Man9GlcNAc2-P-P-dolichol was
only 10% of the LLO pool, it still corresponded to essentially all of
the transferred oligosaccharide (35). However, lower percentages
resulted in transfer of incomplete oligosaccharide intermediates
that caused an unfolded protein response (see below). Mechanisms also
exist to eliminate excess
Glc3Man9GlcNAc2-P-P-dolichol (36,
37).
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Defective Synthesis or Processing of ER Information-carrying Oligosaccharides Triggers the Unfolded Protein Response (UPR) |
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Interference with protein folding, assembly, or misfolded protein
degradation in the ER triggers multiple aspects of the UPR (38-40).
The first UPR aspect to be established involves transcriptional activation of genes encoding ER lumen chaperones and enzymes involved in protein folding. Reports of transcriptional control now exist for
many genes, including those needed for ER maintenance and ER-associated
degradation (41, 42). UPR regulation of transcription occurs in
all eukaryotes examined so far. A novel ER-to-nucleus signaling pathway
in Saccharomyces cerevisiae has been elucidated, involving
the ER transmembrane kinase Ire1p/Ern1p. Corresponding pathways in
mammalian cells are more complex because at least two forms of Ire1p,
(43) and
(44), and the transcription factor ATF6 (45) are
involved. All three are synthesized as ER transmembrane proteins. There
is no evidence for proteolytic processing of Ire1p in S. cerevisiae. By comparison, activation of the UPR in mammalian
cells causes release of the cytoplasmic domains of the mammalian Ire1
proteins (46) and ATF6 (45) by "regulated intramembrane
proteolysis" (47). The released cytoplasmic domains then enter the
nucleus to facilitate transcription of mammalian UPR genes. The
cytoplasmic domain of ATF6, which clearly becomes a transcription
factor, is released by the site 1 and site 2 SREBP proteases (48),
raising the interesting possibility of a relationship between sterol
metabolism and the UPR. Mammalian cells with various presenilin-1
mutations have been reported to have impaired Ire1p function (46, 49),
suggesting a potential role for presenilin-1 in Ire1p cleavage,
although contradictory results have recently appeared (50). The
cytoplasmic domains of the Ire1 proteins are bifunctional
kinases-endonucleases that undergo autophosphorylation upon UPR
activation. In S. cerevisiae the Ire1p endonuclease activity
propagates the UPR by participating in splicing of the mRNA
encoding the transcription factor Hac1p (51). A similar chain of events
appears to occur in mammalian cells (46), although the endonuclease
substrate remains to be identified.
Biochemical evidence exists for other UPR aspects in mammalian cells:
(i) inhibition of translation because of phosphorylation of eIF2 by
the transmembrane PKR-like ER-associated kinase "PERK" (52),
(ii) apoptosis involving CHOP (53) and ER-associated caspase-12
(54), and (iii) enhanced extension of dolichol-linked oligosaccharide
intermediates (35). Translational inhibition aids in resistance to ER
stress (55) by lowering the load of misfolded protein and by allowing
the selective expression of genes involved in amino acid metabolism
(56). PERK is also responsible for cell cycle arrest due to the UPR
(57). The mechanisms of activation for PERK and Ire1p by misfolded
proteins are similar (58). Under normal conditions the lumenal domains
of PERK and Ire1p interact dynamically with BiP. Misfolded proteins
that accumulate in the ER lumen form complexes with BiP, lowering the
amount of BiP available for interaction with Ire1p and PERK. In the
absence of bound BiP, the lumenal domains dimerize. Consequently, the cytoplasmic kinase domains are brought into proximity, allowing autophosphorylation and activation of downstream events.
All aspects of the UPR can be caused by interference with the synthesis
of N-linked oligosaccharides. (i) Inadvertent depletion of
glucose from culture medium, associated with deficient protein glycosylation, led to the discovery of stress induction of GRP78 (BiP)
and GRP94 as well as their designations as
glucose-regulated proteins (59,
60). (ii) TN, which blocks protein N-glycosylation by
inhibiting GPT, is a highly potent UPR inducer causing transcription of
BiP, phosphorylation of eIF2, inhibition of translation, and cell
death. The effect of the UPR on the dolichol pathway cannot be studied
with TN due to direct inhibition. Commercial TN preparations typically
contain mixtures of homologues that block N-glycosylation but paradoxically vary in their abilities to inhibit translation (61).
It remains to be determined whether these homologues also vary in other
aspects of UPR activation. (iii) CSN, an inhibitor of ER glucosidases I
and II, eliminates aspects of ER quality control requiring processing
of asparagine-linked
Glc3Man9GlcNAc2. CSN and
other glucosidase inhibitors are less potent UPR inducers than TN,
because their use does not cause inhibition of translation (62) or
cell death (63). This suggests that the N-linked
Glc3Man9GlcNAc2 oligosaccharide
itself contributes to glycoprotein folding and assembly, perhaps by
enhancing the hydrophilicity of folding intermediates. However, CSN
treatment does activate BiP transcription and the dolichol pathway
(35), confirming the importance of N-linked Glc0-2Man9GlcNAc2 in ER protein
quality control. (iv) A selection for S. cerevisiae mutants
with activated UPRs yielded cells with defects in genes required for
N-glycosylation (64).
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N-Linked Glycosylation as an Aspect of UPR |
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Screens for S. cerevisiae genes activated by the UPR
not only revealed genes encoding various ER chaperones and enzymes
involved in protein folding and assembly but also genes involved in
other functions associated with ER maintenance including the synthesis and processing of
Glc3Man9GlcNAc2-protein (Fig. 2)
(41). This evidence is supported by biochemical studies from the
author's laboratory (35). Activation of the UPR in primary cultures of adult dermal fibroblasts stimulated extension of LLO intermediates to
Glc3Man9GlcNAc2-P-P-dolichol and
increased the fraction of nascent ER proteins bearing
Glc3Man9GlcNAc2. The metabolic
step(s) in LLO synthesis activated by the UPR has yet to be identified.
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Insights from Other Biological Systems: Stable and Transient Forms of Oligosaccharide Information |
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A survey of selected biological functions of oligosaccharides
reveals that oligosaccharides can carry information by either of two
modes, stable or transient. Oligosaccharides
carrying stable information are not altered in the course of
serving a biological role and are usually directly involved in the
function of the molecule or cell to which they are attached or from
which they originate. Examples include sialyl LewisX-like
glycans bound by selectins (65), sialylconjugates recognized by siglecs
(66), and sulfated GalNAc on glycoprotein hormones that interact with
specific clearance receptors (67). Chitin-like Nod factors
secreted by Rhizobia are recognized by specific receptors on
the root hairs of legumes to promote nodulation (68, 69). Recently,
Notch was shown to be modulated by its GlcNAc 1,3Fuc O-glycan, formed by the glycosyltransferase activity of
Fringe (70, 71).
In contrast, oligosaccharides that carry transient
information undergo structural changes during the course of biological activity and may not necessarily be involved in the ultimate biological functions of the molecules or cells that bear them. Therefore, the
critical modification might not be detected by biochemical analysis of
the mature glycoconjugate. The glucose residues on N-linked
oligosaccharides, which as noted by Spiro (4) are transient, are
definitive examples. Another example is the lysosomal sorting signal
mannose-6-P found on high mannose oligosaccharides of lysosomal
enzymes, which is dephosphorylated once the lysosome has been reached
(72). Monosaccharides can also carry information transiently.
O-GlcNAc on cytoplasmic and nuclear proteins can be removed
and replaced many times during the life of a protein (73).
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Summary and Perspectives |
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This article attempted to demonstrate how oligosaccharides can
carry biological information. The large variety of oligosaccharide structures that can be created by just a few glycosidically linked monosaccharides, and the potential for ionic as well as hydrogen bonds,
makes them highly suitable for this purpose. In particular, novel
oligosaccharides and oligosaccharide modifications are very likely to
carry essential information and should never be ignored. Because they
can perform so many functions, there is no way to predict how
oligosaccharides may be involved in any particular biological system
under study. For this reason, a fruitful area for future research will
be the development of new reagents and techniques that can identify
information-carrying oligosaccharides in action.
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ACKNOWLEDGEMENTS |
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I am especially grateful to Kazu Mori, Robert Spiro, Skip Waechter, Ann White, and David Williams, who provided excellent suggestions during the preparation of the article.
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FOOTNOTES |
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* This minireview will be reprinted in the 2001 Minireview Compendium, which will be available in December, 2001. Work in the author's laboratory is supported by National Institutes of Health Grant GM38545 and Welch Foundation Grant I-1168.
To whom correspondence should be addressed: Dept. of Pharmacology,
UT-Southwestern Medical Center, 5323 Harry Hines Blvd., Dallas, TX
75390-9041. Tel.: 214-648-2323; Fax: 214-648-8626; E-mail: mlehrm@
mednet.swmed.edu.
Published, JBC Papers in Press, January 26, 2001, DOI 10.1074/jbc.R100002200
2 The term "lectin-like chaperone" was originally introduced into the literature when the binding of CNX and CRT to glycoproteins was known to require specific oligosaccharide-dependent interactions, but the lectin activities for CNX and CRT remained to be demonstrated. Because the lectin activities of CNX and CRT have now been proven, the term "lectin-chaperone" will be used.
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ABBREVIATIONS |
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The abbreviations used are: ER, endoplasmic reticulum; AT, antitrypsin; CNX, calnexin; CRT, calreticulin; CSN, castanospermine; eIF, eukaryotic initiation factor; GPD, glucose-P-dolichol; GPT, GlcNAc-1-P transferase; GRP, glucose-regulated protein; LLO, lipid-linked oligosaccharide; MPD, mannose-P-dolichol; PERK, PKR-like ER kinase; TN, tunicamycin; UPR, unfolded protein response.
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