Glycobiology Advance Access originally published online on July 21, 2005
Glycobiology 2005 15(12):53R-59R; doi:10.1093/glycob/cwj007
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© Published by Oxford University Press 2005.
REVIEW |
Roles for the galactose-/N-acetylgalactosamine-binding lectin of Entamoeba in parasite virulence and differentiation
Division of Infectious Diseases, University of Virginia Health System, MR4 Building, Room 2115, Charlottesville, VA 22908-1340
1 To whom correspondence should be addressed; e-mail: wap3g{at}virginia.edu
Accepted on June 30, 2005
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Abstract |
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Top
Abstract
IntroductionEntamoeba histolytica, an intestinal protozoan parasite, is a major cause of morbidity and mortality in developing countries. The pathology of the disease is caused by the colonization of the large intestine by the amoebic trophozoites and the invasion of the intestinal epithelium. Some of the trophozoites will eventually differentiate into the infectious cyst form, allowing them to be transmitted out of the bowel and into water supplies to be passed from person to person. Both the virulence of the organism and the differentiation process relies on a galactose-/N-acetylgalactosamine (GalNAc)-binding lectin that is expressed on the surface of trophozoites. The functional activity of this lectin has been shown to be involved in host cell binding, cytotoxicity, complement resistance, induction of encystation, and generation of the cyst wall. The role of the lectin in both differentiation and virulence suggests that it may be a pivotal molecule that determines the severity of the infection from a commensal state resulting from increased encystation to an invasive state. The lectin–glycan interactions that initiate these diverse processes are discussed with emphasis on comparing the binding of host ligands and the interactions involved in encystation.
Key words: amoebiasis / encystation / Entamoeba / lectin
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Introduction |
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Entamoeba histolytica, the causative agent of amoebiasis, is a leading cause of morbidity and mortality in developing countries. The life cycle consists of a transmissible cyst form, which is ingested by the host, and the mobile trophozoite form that emerges from the cyst in the small intestine of the host. The trophozoite then travels to the large intestine where it multiplies forming foci of dividing cells within the mucus layer (Figure 1). A subset of the population of cells then differentiates into the cyst form and is passed with the feces. The resident trophozoites within the intestine have the potential to penetrate the mucus layer through various means and come in contact with the cells of the epithelium. Colonic epithelial cells are killed and phagocytosed leading to the development of a flask-shaped ulcer as the amoeba travels laterally along the basal lamina. Portions of epithelium are sloughed off as neighboring flask-shaped ulcers converge. Eventually trophozoites are able to penetrate the basal lamina and enter the blood stream causing disseminated infection mostly manifesting as abscesses within the liver. Abscesses can also be found within the lungs and brain, although these types of extra intestinal pathologies are rare. These sites of infection are thought to be aberrant pathologies because of the lack of evidence for the encystation of the parasite within these niches.
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Throughout the lifecycle of the amoeba, lectin–glycoprotein interactions play a pivotal role in both the pathogenesis and the differentiation of the parasite. First, the parasite must contend with the mucus layer of the gut to maintain colonization of the colon. Second, the encystation process relies on a certain amount of exogenous multivalent carbohydrate ligands to proceed. Finally, the balance between binding of host mucins, bacteria, other trophozoites, and host cells may ultimately determine the course of the infection and may help to shed light on the factors responsible for the high variability of outcomes associated with Entamoeba infection.
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Glycoprotein–lectin interactions in pathogenesis |
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E. histolytica trophozoites express numerous cell surface and secreted molecules that assist with feeding and retention in the intestine and which also contribute to the virulence of the parasite. Adhesion of the trophozoites to colonic mucins, host cells, and bacteria occurs mainly through a galactose-binding lectin that is abundant on the surface of the cells. This adhesion is almost completely inhibited by ß-D-galactose (Gal), although some binding still occurs at high concentrations of Gal indicating that other molecules are also participating. Parasite–host interaction via this lectin is required for lysis of epithelial cells, as galactose inhibits overall virulence of the parasite in vitro. The lectin consists of a heavy subunit, a glycosylphosphatidylinositol (GPI)-anchored light subunit, and a CXXC domain-containing intermediate subunit that is also GPI anchored. Each lectin subunit is represented by multiple genes within the E. histolytica genome. Which of these different isoforms are used for certain functions has not been determined. The majority of the studies described either used biochemical methods to determine the involvement of the lectin or used a nomenclature numbering system that has since been changed with the sequencing of the genome. Therefore, it is likely that the specific affinities and downstream effects of the lectin complex may rely on the actual subunit isoforms involved.
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The heavy subunit |
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The 170-kDa lectin subunit (hgl) gene family contains five members (Purdy et al., 1993
; Ramakrishnan et al., 1996). The 170-kDa heavy subunit is a type 1 transmembrane protein with a small intracellular domain and a carbohydrate recognition domain (CRD) contained in its extracellular domain (Dodson et al., 1999). No specific signaling pathways have been attributed to the heavy subunit, although it may harbor cryptic signaling domains that it shares in common with ß integrins. The cytoplasmic tail of the heavy subunit contains tyrosine, serine, and threonine residues, which could be phosphorylated. So far, however, there have been no descriptions of these additions to the cytoplasmic domain. Trophozoites expressing a truncated form of hgl containing only the transmembrane and intracellular domains led to a reduction in interaction with Caco cells and reduced liver pathology in the hamster model (Vines et al., 1998; Coudrier et al., 2005). These results are similar to those observed in trophozoites expressing a dominant negative myosin II protein, suggesting that the cytoplasmic domain interacts with the cytoskeleton and functions in invasion (Arhets et al., 1998; Coudrier et al., 2005; Tavares et al., 2005). Nonreceptor tyrosine kinases have not been shown to bind to the cytoplasmic tail. |
The light subunit |
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The 30-kDa light subunit (lgl) is covalently attached to the heavy subunit through disulfide linkages. The participation of lgl in lectin function is not known. Flag-tagged lgl that is expressed in trophozoites fails to bind to Gal-coated beads (Ramakrishnan et al., 2000
). The recombinant protein was not GPI modified and did not associate with hgl suggesting that it is unable to bind Gal as a monomer. Monoclonal antibodies generated to lgl do not inhibit the binding of ligands by the lectin. Also, antibodies against lgl that are able to bind to the denatured protein do not bind to whole fixed trophozoites. This could be because of the heavy subunit obscuring the epitopes on the light subunit not allowing the antibodies to bind. Interestingly, antisense inhibition of the 35-kDa light subunit causes decreased cytotoxicity although target cell binding, and phagocytosis are comparable with untransfected controls (Ankri et al., 1999). On the other hand, a dominant negative construct with an N-terminal truncation that was still able to associate with hgl caused a loss of cytotoxicity, cell binding, and phagocytosis (Katz et al., 2002). These studies suggest that lgl may play a larger role in lectin function possibly by recruiting other proteins such as the intermediate lectin subunit (Igl) or intracellular signaling molecules to sites of lectin binding. |
The intermediate subunit |
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The intermediate subunit was found with monoclonal antibodies that blocked adherence of trophozoites to erythrocytes. The protein consists of CXXC repeats and both C-terminal and N-terminal hydrophobic regions suggesting that it is a surface protein that is modified with a GPI anchor (Cheng et al., 2001
). Surface expression has been verified using confocal microscopy. The intermediate subunit is noncovalently associated with the hgl/lgl heterodimer. Other than the findings that the intermediate subunit is recognized by the immune system and that antibodies to the protein inhibit adherence, the function of the intermediate subunit in overall lectin function is not known. |
Host cell ligands |
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Possible carbohydrate ligands for the lectin have been studied either by utilizing direct binding of synthetic ligands to amoeba membranes or by measuring adherence and killing of target cells. A large number of natural and synthetic saccharides have been tested for their ability to block the hemagglutination reaction that is induced by the binding of red cells by amoebic trophozoites. The highest inhibition was achieved with a multivalent GalNAc39BSA molecule. Gal40BSA was also able to inhibit the hemagglutination but at a minimum inhibitory concentration of 30 times that of the N-acetylgalactosamine (GalNAc) conjugate. Possible in vivo ligands, including mucins and fetuins, exhibited the same levels of inhibition as Gal40BSA (Adler et al., 1995
). Assays developed using the inhibition of GalNAc39BSA binding to membranes allowed testing of synthetic monosaccharide derivatives as well as polyvalent ligands produced by linking multiple N-acylgalactosamines to polyamine backbones. The binding of GalNAc by the lectin was found to be dependent on the 4-OH, 5-OH, and 6-OH group as modification or deletion of these groups abrogated the inhibition of binding of GalNAc39BSA to membrane preparations. Similar Gal/GalNac lectins in mammals have 4-OH- and 5-OH-dependent binding, but modification of the 6-OH group does not affect binding affinity. In contrast, the amoebic lectin is more tolerable to modification of the N-acyl moiety than the mammalian lectin. GalNAc-terminated polyamine-linked saccharides were unable to inhibit binding to any appreciable degree (Yi et al., 1998). It has been suggested that the binding of GalNAc-terminated residues by the lectin relies on a certain spacing distance between residues for high-affinity binding. This makes it ideal for the high-affinity binding of lectins and host cells, where the interaction involves binding of distinct GalNAc-terminated residues on different carbohydrate chains. This is consistent with findings that protease-treated mucins were ineffective in blocking host cell binding by live trophozoites (Moncada et al., 2003).
Binding to host cells is dependent on the glycoproteins expressed on the target cell, although the amoeba has developed its own mechanisms to increase the binding capacity of the host cells. Analysis of possible target ligands on Chinese hamster ovary (CHO) cells was made possible by a number of glycosylation-deficient mutant cell lines. Cells lacking any terminal Gal, GalNAc, or N-acetylglucosamine (GlcNAc) on their N-and O-linked carbohydrate chains were resistant to rosetting and cytotoxic effects of trophozoite contact (Li et al., 1989) (Table I). Other cell types show differences in affinity of binding by the trophozoites depending on their differentiation state. When incubated with undifferentiated Caco cells, trophozoites are able to bind with high affinity in an allyl–lactose-dependent manner. After Caco cell differentiation, the binding of trophozoites is not inhibited by mM amounts of allyl-lactose (Li et al., 1994).
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Trophozoites also have the capability to modify host cell ligands, although actual the requirement of these capabilities for virulence has not been determined. Trophozoites have been shown to express a number of glycosidases including sialidase (Nok and Rivera, 2003), 
-glucosidase (Bravo-Torres et al., 2003, 2004), -mannosidase, ß N-acetylglucosaminidase, and ß N-acetylgalactosamidase (Connaris and Greenwell, 1997). The majority of these would be assumed to function as metabolic enzymes, although some may be important regulating the binding of trophozoites to intestinal mucins and host cells. CHO cells deficient in the addition of sialic acid residues on the terminal ends of N-linked carbohydrate chains exhibited increased sensitivity to lectin binding, suggesting that although trophozoites express a membrane bound sialidase, it may not be sufficient for exposing the maximal amount of GalNac and Gal residues on host cells (Li et al., 1988, 1989).
As the major constituent of the colonic mucus layer, intestinal mucins are a major factor influencing the outcome of E. histolytica infection. Mucin is a secreted glycoprotein containing 80% carbohydrate by mass as O-linked polysaccharide chains. This makes it a high affinity ligand for the lectin (KD = 8.2 x 10–11 M) and allows it to inhibit binding of trophozoites to host cells (Chadee et al., 1987, 1988, 1990; Moncada et al., 2003). Feeding trophozoites cause destruction of the mucins through the action of secreted glycosidases and cysteine proteases that are released upon binding of mucin side chains. Trophozoites also secrete a heat stable factor that causes increased mucin secretion from goblet cells in the gut (Chadee et al., 1991). It is possible to envision a model whereby goblet cells become depleted of mucin, and the overall integrity of the mucin layer is destroyed allowing access to the underlying epithelium.
The diverse effects of E. histolytica lectin interactions with host cells, bacteria, and mucins have been reviewed extensively (Mirelman et al., 1983; Mirelman, 1987; McCoy et al., 1994; Mann, 2002; Petri et al., 2002). Suffice it to say that the complexity of functions attributed to the lectin suggests that a further dissection of the lectin family is needed to determine whether different functions are dictated by the different isoforms of hgl, lgl, and Igl that make up the individual lectin complex.
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Glycoprotein–lectin interactions during encystation |
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Encystation of the parasite has been studied using a related amoeba Entamoeba invadens that causes infection in carnivorous reptiles. The developmental cycle of the two species is very similar, as they both differentiate into quadrinucleate mature cysts. The IP1 strain of E. invadens most commonly used exhibits a hyperactive encysting phenotype compared with other strains of E. invadens and readily encysts in vitro upon nutrient deprivation and hypo-osmotic shock (Vazquezdelara-Cisneros and Arroyo-Begovich, 1984
; Avron et al., 1986; Sanchez et al., 1994a). Although the genetic difference between E. invadens and E. histolytica is large, they are more closely related to each other than to the commensal Entamoeba coli. E. invadens, although it infects most reptiles, lives as a commensal in herbivores, whereas carnivores exhibit disease similar to the human infection with E. histolytica (Donaldson et al., 1975; Kojimoto et al., 2001). An important caveat to consider is that the sensing of extracellular ligands leading to signaling responses in the two species may be homologous but not necessarily identical as the amoeba evolved to sense either human or reptilian intestinal conditions. Normal flora within the gut and the mucin constituents are known to be affected by diet (Mai and Morris, 2004; Montagne et al., 2004), and therefore, care must be taken when drawing conclusions based on these studies as the constituents of the human gut and those of a reptile are likely highly variant.
E. invadens also contains a family of galactose-binding lectin subunits similar to those found in E. histolytica. Based on initial shotgun sequencing of the E. invadens genome (0.5X coverage), E. invadens contains 13 independent heavy subunit sequence reads and 3 light subunit reads (Wang et al., 2003). A number of CXXC repeat proteins were also described, but the number of these genes that may code for intermediate subunits is only speculation. The specificity of the E. invadens lectin is assumed to be limited to Gal, as GalNAc does not inhibit the aggregation reaction during encystation (Coppi and Eichinger, 1999).
When trophozoites are transferred from growth medium into encystation-induction medium consisting of 47% diluted growth medium lacking glucose, they form large multicellular aggregates. Five percent adult bovine serum is required for optimal aggregation and encystation. Within these aggregates, the cells begin to differentiate into the cyst form. Transcriptional changes occur whereby chitin synthase and chitinase are up-regulated along with numerous chitin-binding proteins. Other genes are also up-regulated including histone H2B and an unidentified transcript gene 122 (Sanchez et al., 1994b; Coppi and Eichinger, 1999). Lectin expression is down-regulated, as shown by northern blotting, and the lack of binding of anti-lectin antibodies to cysts (Frisardi et al., 2000). Under scanning electron microscopy, it has been shown that within the cellular aggregates chitin fibrils may even interweave between cells forming an extracellular matrix (Chavez-Munguia et al., 2003). The up-regulation of chitinase may then serve the purpose of remodeling this "extracellular matrix" to increase spread and make the excystation signaling process more efficient.
The encystation process can be regulated artificially with different concentrations and valencies of carbohydrate ligands. The initial clumping process is completely inhibited by Gal, implicating the galactose-binding lectin as the initiator of this interaction. The final stages of encystation are inhibited by GlcNAc. The cells are still able to form multicellular aggregates, but they do not go on to form mature detergent resistant cysts (Coppi and Eichinger, 1999). The inhibition of encystation by galactose is presumed to occur due to the inhibition of binding of the galactose-binding lectin on the cell surface. On the other hand, the inhibition of encystation because of the presence of GlcNAc is assumed to be more complicated. Two possible mechanisms for this inhibition have been proposed. Coppi and Eichinger (1999) suggest that end-product inhibition by GlcNac of the enzymes involved in UDP-GlcNac production of the cyst wall is similar to the effects observed in the fungus Blastocladiella emersonii (Selitrennikoff et al., 1976). A less complicated explanation is that GlcNac blocks the binding of chitin by the secreted chitin-binding proteins. This would not allow a preliminary matrix to form, and secreted cyst wall components would be lost into the supernatant.
Studies showing the need for multivalent galactose-terminated ligands suggested a model whereby trophozoites would slowly degrade the surrounding mucin to the right valency of galactose residues through the action of secreted proteases and glycosidases. Once this effective ratio of cells and multivalent galactose-terminated residues are reached, the capping of the lectin would trigger an encystation signal. Because of the ubiquitous nature of Gal- and GalNac-terminated residues, a multitiered regulation of the encystation response is assumed to be necessary to facilitate the proper ratios of encysting cells to dividing cells. Research still needs to be done to determine what other molecules may interact with the lectin under the conditions observed in the local microenvironment of the encysting aggregate and compare these findings with the associated molecules when trophozoites come in contact with host cells.
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Lectin as an inducer of secretion |
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The binding of galactose-terminated molecules by the lectin does not appear to be only for the aggregation of cells. Within a serum free environment, the only aggregation that is observed is presumed to be either direct cell–cell interaction or due to residual serum components that were not washed off completely from the cell surface. Recent studies have shown that biogenic amines, including epinephrine, norepinephrine, serotonin, and histamine, induce encystation in a serum free environment (Coppi et al., 2002
). The restoration of encystation is completely inhibited by Gal. Epinephrine, norepinephrine (Coppi et al., 2002), dopamine, and serotonin (McGowan et al., 1983) are present in Entamoeba, although whether they are taken up from the external environment, or synthesized de novo, has not been elucidated. Transfer of trophozoites into media containing negligible glucose and 5% serum was shown to secrete epinephrine into the medium within a matter of minutes. All of these studies suggest a role of the lectin not only in clumping the cells together but also in the triggering of secretion and possibly priming of the receptors required to respond to these molecules.
The induced secretion of epinephrine is presumed to occur through calcium transients from either internal or external sources. Ethylene diamine tetraacetic acid, ethylene glycol-bis(ß-amino-ethyl ether)-N,N,N',N'-tetraacetic acid, calcium channel blockers, and inhibitors of calmodulin (Makioka et al., 2001) inhibit encystation and growth of E. invadens. A direct link between the binding of ligands by the lectin during encystation induction and the activation of calcium transients has not been found, but it is interesting to note that lectin binding to host cells either purified or in the context of cell–cell contact causes calcium transients in host cells, but not in contacting trophozoites (Ravdin et al., 1988). The differentiation between these two outcomes may allow for the dissection of two different pathways activated by different isoforms of the lectin subunits.
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Lectin as scaffolding protein |
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The lectin is also thought to orient other chitin-binding proteins within the nascent cyst wall. The most prominent protein within the cyst wall is a secreted chitin-binding protein called Jacob (Frisardi et al., 2000
). Jacob is a lectin containing five cysteine-rich chitin-binding domains. The protein also has predicted N- and O-linked glycosylation sites, some of which are glycosylated based on reactivity to other lectins and multiple migrating bands in two-dimensional gel analysis. These modifications are thought to allow the lectin to bind to Jacob as encysting cells release vesicles containing the protein. Secretory vesicles containing chitinase and calcoflor-positive material are also released by encysting cells (Ghosh et al., 1999; Chavez-Munguia et al., 2003). As these components are secreted onto the surface of the cell, a sequential binding of first Jacob and the lectin followed by binding of the GlcNac polymers would allow for a preliminary matrix of chitin fibers to form. Jacob would then act as a scaffolding cross-linking the nascent chitin fibrils and stabilizing the cyst wall similar to peritrophins in insect midguts (Elvin et al., 1996).
The aggregation-induced secretion of epinephrine also suggests that the lectin may cause the secretion of general encystation-specific vesicles similar to those found in Giardia (Benchimol, 2004). The model for aggregation-induced encystation by mucin is shown in Figure 2. This would localize both encystation-signaling molecules and structural components of the cyst wall at lectin-induced focal adhesions. Trophozoites respond to epinephrine in a manner similar to the downstream effects of encystation induction (Frederick and Eichinger, 2004), and a subset of heterotrimeric G proteins are trafficked to cell–cell junctions when cells are grown in low glucose medium (J. Frederick, unpublished).
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The findings that the expression of lectin is down-regulated during encystation would suggest that large quantities of lectin molecules would need to be expressed on the cell during the induction of encystation to bind the Jacob protein, but after a preliminary matrix was formed, chitin-binding proteins would be tethered directly to the maturing cyst wall and the need for lectin–Jacob interaction would be diminished. This model would also be consistent with the requirement of aggregation for high efficiency encystation. Within an aggregate, the local concentration of these secreted molecules would be increased leading to more efficient chitin matrix construction.
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Endogenous targets for the lectin |
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The surface of the amoeba is also covered in a coating of lipophosphoglycans (LPGs) (Moody-Haupt et al., 2000
) that are assumed to be important for the protection of the cell from the actions of the parasites own virulence factors as well as protecting it from host immune mechanisms. The compositions of these LPGs are variable with respect to the virulent and avirulent E. histolytica. The majority of the carbohydrate modifications are chains with the general structure [Glc1-6]2-23Glcß1-6Gal. This would not make them suitable for lectin binding; however, the GPI anchor attached to these LPGs is modified with chains of -galactose. Antibodies to these LPGs have been shown to reduce the infection of human intestinal xenografts in mice (Zhang et al., 2002), and passive immunization of severe combined immunodeficient mice with LPG antibody protected them from developing liver abscesses (Marinets et al., 1997). Ghosh et al. (1999) suggest that these LPG molecules are not accessible to the lectin based on observations that trophozoites do not phagocytose and kill each other in a lectin-mediated fashion. E. histolytica trophozoites are able to bind and ingest E. invadens cysts presumably by binding Gal- and GalNAc-terminated glycoproteins, such as Jacob, that are present within the cyst wall. Another possible explanation for the protection of trophozoites from each other is that lectin binding of cell surface LPG is of low affinity because of the overwhelming amounts of glucose modification. Also, the signaling aspect of cell killing by the trophozoite cannot be realized because of the lack of downstream effector molecules that are present in target cells. Less virulent strains containing shorter chains of glycosylation have a higher amount of galactose relative to glucose. It is interesting to speculate that the less virulent strains may encyst more readily because of a higher likelihood of trophozoite aggregation based on LPG modification. A lack of characterization of LPG-like molecules on Entamoeba dispar, Entamoeba moshkovskii, and the different strains of E. invadens does not allow a correlation to be made between the composition of surface LPGs and encystation efficiency. As of yet, no evidence for a role of LPGs in encystation has been observed. |
Pathogenesis versus differentiation: Too much work for one molecule? |
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The number of functions assigned to the galactose-binding lectins of Entamoeba is extensive. One explanation for how a single protein complex mediates these vastly different outcomes relies on the findings that there are a number of different isoforms of the three subunits associated with lectin function. Similar to the heterodimers formed by the integrin proteins in mammalian cells, the family of lectin genes could potentially give rise to a number of functional lectins with varied specificity and signaling partners. The recent description of a family of transmembrane kinase molecules with a homologous domain structure to the intermediate subunit of the lectin (Beck et al., 2005
) may begin to shed light on the missing link between the different functions attributed to Gal and GalNac binding. |
Abbreviations |
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Gal, ß-D-galactose; GalNAc, N-acetylgalactosamine; Glc, D-glucose; GlcNAc, N-acetylglucosamine; GPI, glycosylphosphatidylinositol; hgl, 170-kDa lectin subunit; Igl, intermediate lectin subunit; lgl, 35-kDa lectin subunit; LPG, lipophosphoglycan
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