key: cord-0786833-gu5mutt6
authors: Lehmann, F.; Tiralongo, E.; Tiralongo, J.
title: Sialic acid-specific lectins: occurrence, specificity and function
date: 2006-04-05
journal: Cell Mol Life Sci
DOI: 10.1007/s00018-005-5589-y
sha: 59fa6c7894293e3f8f30cef09038d8c156e7c998
doc_id: 786833
cord_uid: gu5mutt6

Sialic acids consist of a family of acidic ninecarbon sugars that are typically located at the terminal positions of a variety of glycoconjugates. Naturally occurring sialic acids show an immense diversity of structure, and this reflects their involvement in a variety of biologically important processes. One such process involves the direct participation of sialic acids in recognition events through specific interactions with lectins, a family of proteins that recognise and bind sugars. This review will present a detailed overview of our current knowledge regarding the occurrence, specificity and function of sialic acid-specific lectins, particularly those that occur in viruses, bacteria and non-vertebrate eukaryotes.

Sialic acids (Sia) are a family of nine-carbon a-keto acids ( Fig. 1) found predominantly at the non-reducing end of oligosaccharide chains on glycoproteins and glycolipids. Sia can occur free in nature, but are generally found glycosidically linked to either the 3-or 6-hydroxyl group of galactose (Gal) residues or to the 6-hydroxyl group of Nacetylglucosamine (GlcNAc) or N-acetylgalactosamine (GalNAc) residues. Sia can also exist as a2,8-linked homopolymers known as polysialic acid (Fig. 1) . The expression of Sia was previously thought to be unique to deuterostomes and pathogenic bacteria infecting these animals; however, more recent findings suggest that they may be more widely distributed and possibly quite ancient in their origin [1, 2] . Sia show remarkable structural diversity, with the family currently comprising over 50 naturally occurring members [1, 2] . The largest structural variations of naturally occurring Sia are at carbon 5, which can be substituted with either an acetamido, hydroxyacetamido or hydroxyl moiety to form 5-N-acetylneuraminic acid (Neu5Ac), 5-N-glycolylneuraminic acid (Neu5Gc) or deaminoneuraminic acids (KDN), respectively ( Fig. 1) [1]. Further structural diversity is generated primarily by a combination of the above-mentioned variations at C-5, with modifications of any of the hydroxyl groups located at C-4, C-7, C-8 and C-9. The diversity of Sia structure is reflected by its involvement in a variety of biological functions, many stemming from its unique physical and chemical properties, such as charge and size. For those interested in this aspect of Sia biology we recommend several excellent reviews [1-3]. Beside the more general functions attributed to its unique physiochemical properties, Sia can also mediate a variety of specific recognition processes [3] . For instance, as the terminal residues on many glycoconjugates, Sia can mask underlying structures, as observed for erythrocytes and other blood cells, as well as serum glycoproteins, where the In contrast to masking, Sia can also directly participate in a variety of recognition events (Fig. 2) , with this probably being its most important role. First noted in microorganisms, Sia are now recognized as being the most common ligand (or receptor) for pathogenic and non-pathogenic viruses, bacteria and protozoa. Obviously, if Sia only served as recognition sites for pathogens, the biosynthesis of such a complex monosaccharide would have been eliminated during evolution in higher animals. However, due to their exposed position on cell surfaces, Sia have evolved not only to shield cells from the environment, but also as recognition markers in multicellular organisms. Sugar-binding proteins (excluding antibodies and enzymes) are collectively called lectins, and there are numerous Sia-specific lectins in nature. This review will present a detailed overview of the occurrence, specificity and function of Sia-specific lectins, particular in viruses, bacteria and non-vertebrate eukaryotes. In all cases, where the crystal structures of Sia-specific lectins have been elucidated, these are cited within the Tables.

The adhesion of a virus particle to specific cell-surface molecules is the key interaction between the virus and its host, and as such is a critical step in the development of viral disease, as well as being a potential target for antiviral therapy. Attachment strategies employed by viruses involve multiple interactions between several viral and cellular molecules. Many viruses employ an adhesion-strengthening attachment strategy in which primary virus-cell interactions involve low-affinity adhesion of the virus to common cell surface molecules that are often carbohydrates in nature. This initial phase of attachment is then followed by higher-affinity interactions between the virus and a secondary receptor on permissive cells, an event that often triggers virus entry. Members of at least eight different virus families exploit sialoglycoconjugates for attachment. Some viruses bind preferentially to Sia attached via a particular glycosidic linkage, and this specificity may contribute to virus host range, tissue tropism and pathogenesis. In this section, we will discuss the role of viral Sia-specific lectins in host cell infection and pathogenesis, specifically Sia-lectins from influenza virus, paramyxovirus, reovirus and picornavirus. A comprehensive list of viral Sia-specific lectins thus far identified is presented in Table 1 .

Influenza belong to the family Orthomyxoviridae, which show a near obligatory dependence on the host cell surface Sia for infection. Whereas influenza B and C are purely human viruses, influenza A viruses circulate in a wide range of avian and mammalian hosts. Influenza A virus is probably the best-known and most-studied example in the field, and with the recent outbreaks of avian influenza in humans, probably the most likely to cause the next influenza pandemic. The surface of the influenza virus is decorated with two major antigenic glycoproteins, the receptor-destroying enzyme sialidase and the viral lectin haemagglutinin (HA The structural diversity of Sia is generated by a combination of variations at C-5 with modifications of any of the hydroxyl groups at C-4, C-7, C-8 and C-9. Sia is predominantly found glycosidically linked via a2,3-, a2,6or a2,8-linkages to underlying sugars as shown.

Cell. Mol. Life Sci. Vol. 63, 2006 Review Article 1333 ciliated cells of the human trachea. The avian influenza virus exclusively binds Siaa2,3Gal, thus limiting the host range to those species possessing these receptor structures (e.g. birds, horses and pigs). Recently, however, ciliated cells of the human trachea were found to contain a2,3-linked Neu5Ac and were able to replicate some avian influenza variants [6] . This finding provides a plausible mechanism accounting for the recent infections and fatalities associated with the H5N1 strain that were acquired only through direct contact with infected birds. The mechanism of H7N7 transmission discovered in the Netherlands is unknown. On the other hand, the H9N2 strain has acquired a preference for a2,6-linked Neu5Ac, therefore potentially being transmissible from human to human [7] . However, H9N2 has only caused mild symptoms in infected individuals, and no cases of human-to-human transmission have been reported. This indicates that an avian influenza virus with HA specificity similar to human strains, therefore allowing humanto-human transmission, is plausible.

The rise of a strain as fatal as H5N1, but potentially as transmissible as H9N2, will largely depend not only on the acquisition of HA human-like receptor specificity, but also on the maintenance of virulence characteristics. The most probable mechanism involves the participation of an intermediate host that can replicate both avian and human viruses, thus acting as a mixing vessel. Pigs represent one such adaptive host, since they possess both a2,3and a2,6-linkages and have been shown to bind avian and human influenza A viruses [8] . Interestingly, the HA specificity of the Spanish flu, a strain that resulted in 20 million deaths in 1918/19, possesses the binding site specificity of an avian HA [9, 10], but preferentially binds Neu5Aca2,6Gal [11] . The available crystal structure [9, 10], as well as recent binding studies [12] , strongly suggests that the exchange of Glu190 in the avian HA with Asp190 in Spanish flu HA leads to a subtle increase in binding pocket size that is then able to accommodate the binding of Neu5Aca2,6Gal structures. This shows that a minor alteration in the binding pocket of 

Human coronaviruses (CoV) cause respiratory tract illnesses such as the common cold and the recently identi- . Like influenza C, coronaviruses possess a HE. These viruses also express a spike protein (S) on their surface that has greater HA than HE activity and also binds Neu5,9Ac 2 [22] . This suggests that after initiating the infection by attachment to host cell surface Neu5,9Ac 2 , a secondary interaction of the S protein with a specific protein receptor is necessary for activation of the fusion process [23] . Interestingly, analysis of the murine hepatitis virus MHV-S and MHV-JHM strains with free Sia derivatives show that their HE specifically recognizes 4-O-acetyl Sia (Neu4,5Ac 2 ) and not Neu5,9Ac 2 . Since Neu4,5Ac 2 has not been found in mice, the nature of the substrates and/or secondary receptors for MHV-S in the natural host remains to be determined [24] . In contrast, avian infectious bronchitis virus (IBV) and the transmissible gastroenteritis virus (TGEV) do not possess genes encoding HE, and instead bind non-acetylated a2,3-linked Sia [25, 26] . This interaction is not only important for enhancing cell attachment and entry, but also increases the stability of the virus against detergent-like bile salts encountered in the gastrointestinal tract [27] . Furthermore, a role in overcoming the mucus barrier and intestinal peristalsis by binding of virions to Sia of mucin-type glycoproteins has been postulated [28] .

Reoviruses belong to the family Reoviridae, which includes the orthoreoviruses, rotaviruses, Colorado tick fever and Bluetongue virus. Within the orthoreoviruses, most serotype 3 viruses bind cell surface Sia. Infections are initiated by the binding of the viral attachment protein, s1, to receptors on the host cell surface. The s1 protein consists of two distinct receptor-binding regions, a Sia-binding fibrous tail lectin domain and a junctional adhesion molecule-1 (JAM1)-binding globular head domain [29, 30] . The ability of the s1 lectin domain to utilize Sia as a viral coreceptor is dictated by a single amino acid, with the exchange of Leu204 to Pro204 converting a Sia negative binding (Sia -) phenotype to a Sia-positive binding (Sia + ) phenotype [30] . In the case of Sia + reovirus strains, initial binding is likely to be via multivalent virion-Sia interactions. By virtue of its rapid association rate, this interaction attaches the virion to the cell surface, enabling it to diffuse laterally until it interacts with the s1 head receptor molecule. This secondary interaction with JAM1 seems to be the only binding event available to Siastrains and may be necessary and sufficient for virus endocytosis [31] . Although serotype 1 reoviruses were initially thought not to bind Sia, recent studies have now shown that a2,3-linked Neu5Ac is involved in reovirus T1L binding to rabbit M cells and polarized Caco-2 BBe cells [32] . Rotaviruses, the leading cause of gastroenteritis in humans, possess an outermost layer composed of two proteins, VP4 and VP7. Treatment of the virus with trypsin results in the specific cleavage of VP4 into the polypeptides denoted as VP8* and VP5*. It is generally accepted that Neu5Ac is required by several animal rotavirus strains to attach to the cell surface. The infectivity of some of these strains is greatly diminished by the treatment of cells with sialidase; consequently, these strains are termed sialidase-sensitive. By contrast, many animal strains and most strains isolated from humans are sialidase-resistant [33] . This is believed to be due to the ability of these strains to bind gangliosides that possess internal Sia that are resistant to sialidase treatment [34] .

The gangliosides GM1 and GM3, and the Gal component of glycoprotein receptors, as well as integrins a2b1 and a4b1 all play a role in attachment and entry of rotaviruses into host cells, indicating that the rotavirus functional receptor is a complex of several cell components [35] . A recently proposed model suggests that the initial contact of a sialidase-sensitive virus strain with the cell surface is through the binding of the VP8* domain of VP4 to a ganglioside receptor which induces a conformational change in VP4, thus allowing the virus to interact with integrin a2b1 through VP5*. Following this second interaction, one to three additional interactions take place involving VP5* and VP7, integrins avb3 and axb2, and probably other proteins [36] .

Studies have now demonstrated that the rhesus rotavirus VP8* core specifically binds a-glycosidically linked Sia with a 10-fold lower affinity for Neu5Gc, requires no additional carbohydrate moieties for binding and does not distinguish 3′ from 6′ sialyllactose [37] . The broad specificity and low affinity of Sia binding by VP8* supports the suggestion that more specific interactions that occur after Sia binding are responsible for rotavirus host range and cell-type specificity.

The Picornaviridae comprise one of the largest and most important families of human and animal pathogens, including hepatitis A virus (HAV) and human rhinovirus (HRV). Among the Picornaviridae the use of Sia as a receptor has been described for encephalomyocarditis virus, human rhinovirus 87 (HRV87), Theiler's murine encephalomyelitis virus (TMEV), mengovirus and bovine enterovirus 261 [38] [39] [40] [41] . Moreover, the hepatitis A Cell. Mol. Life Sci. Vol. 63, 2006 Review Article 1337 virus (HAV) has recently been found to bind human red blood cells through an interaction with sialoglycoproteins [42] . Among the enteroviruses (EV), EV70 is the only human EV requiring cell surface Sia for attachment, with a strong preference for O-linked glycans containing terminal Siaa2,3-linked to galactose [43] . TMEV is unique among picornaviruses because of the existence of two naturally occurring neurovirulence groups with distinct disease phenotypes and highly similar amino acid sequences (>90%) and capsid structures [44] . While it is possible that members of the two TMEV neurovirulence groups use the same receptor protein, the attachment factors (co-receptors) clearly differ. While highneurovirulence strains bind the proteoglycan heparan sulfate, low-neurovirulence strains bind a2,3-linked Sia moieties on N-linked oligosaccharides [44] . Site-specific mutations together with crystallographic studies revealed four tightly clustered virus capsid amino acids, all within a positively charged area on the viral surface, with Sia contact through non-covalent hydrogen bonds being important for low-neurovirulence strain central nervous system persistence [45] .

As is the case with viral infections, adhesion of bacteria to host tissues represents an initial and essential step in pathogenesis. Bacterial surface components that mediate adherence are collectively called adhesins. Because cell surfaces are decorated with glycoconjugates, it is not surprising that an increasing number of carbohydratespecific bacterial adhesins have been discovered. Several Gram-negative and Gram-positive bacteria have been reported to use Sia-containing glycoconjugates on host cells as ligands (see Table 2 for full listing), although the identity of the specific bacterial lectin (or adhesin) remains uncertain in many cases. Often, these lectins are associated with multi-subunit fimbriae or pili, with the expression of specific lectins being responsible for the tissue tropism of infections.

Escherichia coli represents the head of the large bacterial family, Enterobacteriaceae, which are facultative anaerobic rods that live in the intestinal tract of healthy and diseased animals and humans. Pathogenic E. coli express several classes of fimbriae-associated lectins that mediate attachment through specific binding to different glycoconjugate receptors on a variety of human cells [46] . Strains shown to use sialoglycoconjugates as attachment sites express either S-fimbriae, K99-fimbriae, the F41 adhesin or one of the colonization factor antigens (CFA) [47] . S-fimbriae were found to preferentially bind to gangliosides carrying Neu5Gca2,3Gal and Neu5Aca2,8Neu5Ac structures, with the C-8 and C-9 hydroxyl groups on Sia being required for recognition [48] . The adhesion protein, SFaS, a minor component of the multi-subunit S-fimbriae, has been cloned and characterized [47] . Mutagenesis studies suggest that the amino acids Lys116 and Arg118 influence SfaS binding to Sia [49] . Notably, these amino acids are part of a stretch of conserved amino acids which are also found in other bacterial Sia-binding lectins such as CFAI and K99 adhesins of E. coli and the Vibrio cholerae toxin B subunit, as well as the E. coli toxin LTI-B [49] . The K99 fimbrial antigen is often found in enterotoxigenic E. coli isolated from calves, piglets and lambs suffering from diarrhoea. In contrast to S-fimbriae, where the adhesin SfaS is only a minor component, in K99fimbriae the Sia binding site is found in the major subunit. The presence of a hydrophobic region close to the binding site seems to enhance Sia binding affinity [50, 51] , which favours Neu5Gc over Neu5Ac. The specific recognition of Neu5GcLacCer by K99-fimbriated E. coli might contribute to host specificity, since humans and animals that lack Neu5Gc cannot be infected [52] . Often expressed simultaneously with K99 is F41, which binds glycophorin A with a clear selectivity for the M blood type [53] . Although the binding of F41 to glycophorin is clearly Sia-dependent, the polypeptide must also be involved since the M and N blood type determinant resides in the amino acid composition.

Of the CFA the most extensively studied are CFAI [54] , CFAII [55] and CFAIV [56] . Whereas CFAI is a single fimbrial antigen, CFAII and CFAIV are composed of antigenically distinct structures called coli surface antigens. Although very little is known about the receptors or binding structures for the different CFA, CFAI has been shown to bind to free Sia [57] , sialoglycoproteins [58] and GM2 [59] . Furthermore, purified CS2 antigen belonging to CFAII has been shown to be a Sia-dependent lectin inhibited specifically by sialyllactose [60] .

Helicobacter pylori (synonym of Campylobacter pylori) is a microaerophilic bacterium implicated in a variety of human gastric diseases, including antral gastritis, peptic ulcer and gastric cancer [61] . [64, 65] . Recently, a third a2,3-Sia-recognizing protein was identified from H. pylori [66] . Given that only inflamed healthy stomach tissue expresses high levels of Sia [67] , it would appear that interactions with Sia may be more important in longer-term survival and maintenance of a chronic state than in me- Review Article 1339 diating primary recognition events. A prominent feature of H. pylori-induced gastritis is infiltration of neutrophils into the gastric epithelium, leading to phagocytosis and an oxidative burst with production of reactive oxygen metabolites, which may provide the nutritional source for the bacterium [65] . Thus, initial attachment of H. pylori may be achieved through binding to receptors present in the normal gastric epithelium (e.g. Le b antigen and lactotetraosylceramide), whereas the Sia binding capacity of H. pylori mediates adhesion through lectins such as SabA to the epithelium in the already diseased stomach [64] .

Members of Pasteurellaceae are small rods that colonize the mucosal surface of the respiratory and genital tracts. Different members of the Pasteurellaceae group, such as Haemophilus influenzae, Actinobacillus actinomycetemcomitans and Pasteurella haemolytica have been found to possess Sia-specific lectins [68, 69] . The HMW1 and HMW2 proteins from H. influenzae are high-molecularweight adhesins that mediate binding to cultured epithelial cells. HMW1-mediated adherence studies revealed the involvement of a surface glycoprotein containing Nlinked oligosaccharide chains with terminal a2,3-linked Sia [70] . HMW1 binding to oropharyngeal epithelial cells and human erythrocytes was also inhibited by the gangliosides GM1, GM2 and GDla [71] . However, because GM1, GM2 and GDla are not involved in HMW1 attachment, a distinct receptor for HMW1 with a complementary function in the process of colonization has been suggested [70] . In addition, proteins P5 and P2, the most abundant major outer membrane proteins of H. influenzae, appear capable of interacting with mucin via Sia-containing oligosaccharides. Although this property may not impart long-term advantage on H. influenzae, in a normal host with intact mucociliary function it may facilitate the establishment of infection in conditions associated with an abnormality in mucus clearance, such as chronic bronchitis and cystic fibrosis [68] .

Streptococcus gordonii and other species of the viridans group, such as S. sanguis and S. oralis, comprise a prominent group of oral bacteria that occur primarily on the human tooth surface, and are well-known for their ability to colonize damaged heart valves, as well as being among the most frequently identified primary etiological agents of subacute bacterial endocarditis. Studies on the adhesion of viridans group streptococci to saliva-treated hydroxyapatite provided early evidence for bacterial recognition of Sia-containing salivary receptors [72] . Two Sia-binding adhesins have now been identified in different S. gordonii strains, designated GspB and Hsa. Both are members of a family of wall-anchored, serinerich repeat proteins that recognize a2,3-linked Sia [73, 74] . Hsa in particular binds to O-glycosylated mucintype glycoproteins, including salivary mucin MG2 and leukosialin (the major surface glycoprotein of human polymorphonuclear leukocytes). Moreover, Hsa as well as GspB seems to be involved in the aggregation of human platelets by S. gordonii through binding to platelet glycoproteins Iba and IIb, an interaction implicated in the pathogenesis of infective endocarditis [75, 76] .

Recently, the S. sanguis glycoprotein homologue of Hsa/ GspB was identified and named SrpA. Like its S. gordonii homologues, SrpA is involved in platelet aggregation, mediated by binding to GPIba in a Sia-dependent manner [77] . Furthermore, recent studies, together with the completion of various genome projects, have revealed Hsa/GspB homologues in other Gram-positive species [78, 79] .

In addition to adhesins, some bacterial pathogens express soluble lectins, which are typically toxins. This toxicity results from their ability to catalytically modify macromolecules that are required for essential cellular functions such as vesicular trafficking, cytoskeletal assembly, signalling or protein synthesis. To reach their targets, these proteins bind specific surface receptors before endocytosis and translocation across the internal membrane can occur. These toxins classically bind to oligosaccharide receptors on host cell surfaces, and many of them show high specificity toward Sia, generally located on gangliosides [80] . Many belong to the AB 5 family of toxins with an A-subunit carrying the catalytic domain of the toxin, while the B-subunit is responsible for binding the holotoxin to a receptor on the surface of the target cell, an obligatory step for the uptake of the enzymatic A-subunit. One of the best examples of a Sia-binding soluble lectin belonging to the AB 5 family is cholera toxin, produced by V. cholerae. The B-subunit exhibits specific binding to ganglioside GM1, delivering the A-subunit to the cytosol. This results in the overactivation of an intracellular signalling pathway in gastrointestinal epithelial cells, causing severe diarrhoea [81] .

Other notable examples of Siadependent toxins are those from Clostridium botulinum and Clostridium tetani, the causative agents of botulism and tetanus, respectively, which both recognize gangliosides [82] .

As we have shown, Sia-specific lectins play a key role in mediating adherence of pathogenic microorganisms to their respective hosts. The number of organisms belonging to the kingdom Protozoa recognized as medically significant is increasing, particularly in developing countries where, for instance, Plasmodium sp., the causative agent of malaria, is of particular concern. Even though at this stage only a few Sia-specific lectins expressed by protozoal pathogens have been reported, the number is increasing (see Table 3 ). Thus far protozoan Sia-specific lectins have been described in Leishmania sp., Tritrichomonas sp., Babesia sp. as well as Trypanosoma sp. and Plasmodium sp., with the latter being the most extensively studied.

Trypanosomes, such as Trypanosoma cruzi, the etiologic agent of Chagas disease, express a surface-bound protein, called trans-sialidase (TS), which enables the parasite to acquire Sia from mammalian host glycoconjugates. In T. cruzi, the TS family is encoded by approximately 140 genes [83] , many of which code for an inactive enzyme. Initial studies showed that an enzymatically inactive recombinant TS, which was able to agglutinate desialylated erythrocytes, possessed b-Gal binding activity [84] . More recent studies have shown that the inactive TS can also act as a Sia-recognizing lectin capable of stimulating CD4 + T cell activation in vitro and in vivo. The sialomucin CD43 was identified as a counter-receptor for TS on CD4 + T cells and tests revealed that the inactive TS displays a similar specificity to that described for active TS (specific for a2,3 linked Sia) [85] . The same group also showed that inactive TS from T. cruzi binds Sia and b-Gal residues in a sequential order mechanism, suggesting that binding of the sialyl residue induces a conformational switch that then permits interaction with b-Gal [86] . To our knowledge this is the first report of a lectin recognizing two distinct ligands by a sequential order mechanism and may have implications for the design of TS inhibitors.

Although there are many intra-erythrocytic parasites, erythrocyte invasion has been most widely studied in Plasmodium species. Plasmodium species are the causative agents of malaria, a disease that afflicts millions Review Article 1341 worldwide, with P. falciparum responsible for the most severe form of human malaria. Parasite invasion is composed of an initial phase of random cell-cell contact, followed by reorientation and specific receptor-ligand interactions and subsequent entry into host erythrocytes [87] . Parasite proteins, which mediate interaction with erythrocyte receptors, whether Sia-dependent or -independent, belong to a family of erythrocyte-binding proteins (EBP). The erythrocyte-binding antigen-175 (EBA-175) [88, 89] and its paralogue, EBA-140 [90, 91] and EBA-181 [92] , are EBP of P. falciparum that belong to the Duffy binding-like protein family and require Sia on host receptors for binding and invasion. P. falciparum utilizes a number of receptors on the erythrocyte surface for merozoite invasion. The glycophorins (A, B and C), sialoglycoproteins present on the erythrocyte surface, serve as the major receptors for Sia-dependent invasion of erythrocytes [93] . Glycophorin A has been identified as the binding partner of EBA-175 [89] , whereas EBA-140 binds glycophorin C. Glycophorin B and the so-called receptor E can also bind P. falciparum in a sialidase-sensitive manner; however, the parasitic lectin responsible for binding in both cases remains to be identified [94] . The Sia-containing receptor for EBA-181 remains unidentified; however, it has been shown that it differs from the EBA-175 and EBA-140 receptors [92] . These studies and others [95, 96] , which specifically investigated EBA-175 binding to glycophorin A, show that the binding specificity of each parasitic binding protein is defined not only by the presence of Sia but also by the protein backbone. The recently published crystal structure of the erythrocyte binding domain of EBA-175, RII, complexed with a2,3-sialyllactose was found to be dimeric, displaying two prominent channels that contain four of the six observed glycan binding sites. Each monomer consists of two Duffy binding-like domains (F1 and F2), with F2 more prominently lining the channels and making the majority of the glycan contacts. Based on this structure a model, where RII dimerizes upon binding to glycophorin A on the erythrocyte surface during the invasion process, has been proposed [97] .

Sia-specific lectins have been isolated and characterized from the fruiting bodies of various mushroom species (see Table 4 and references therein). And even though some of these lectins may in the future prove useful tools for the analysis of Sia-containing glycoconjugates, their natural function, in many cases, is not clearly understood. However, the identification and isolation of Sia-specific lectins from pathogenic fungi, particularly airborne species that cause severe infections in immunocompromised individuals, has raised the possibility that the initial stages of infection, particularly fungal spore (conidia) binding to the lung epithelial cells, may be mediated through Sia (Table 4) .

The first human pathogenic fungal species thought to possess a Sia-specific lectin were Chrysosporium keratinophilum and Anixiopsis stercoraria (synonym of Aphanoascus fulvescens) [98] , which cause skin infections and onychomycosis in humans. Later, Sia-specific binding of dermatophytes to erythrocytes was observed. Dermato- phyte is the common name for a group comprising Microsporum, Trichophyton and Epidermophyton that causes skin disease (dermatophytosis) in animals, including humans. Species from all three genera were able to haemagglutinate rabbit erythrocytes; however, the haemagglutinating activity was greatest in the zoophilic (parasitic on animals) and anthropophilic (parasitic on man) dermatophytes, in comparison to geophilic (soil inhabiting) [99] . This indicates that those species that are primarily parasitic may express more Sia-specific lectin than those that normally inhabit the soil. The significance of Sia-specific lectins for the biology and pathogenicity of dermatophytes is at this stage difficult to ascertain; however, we may be able to draw some conclusions based on the importance of Sia recognition in the pathogenicity of other fungal species.

Histoplasma capsulatum is the causative agent of histoplasmosis, a severe pulmonary infection that is most commonly found in tropical areas. Early studies showed that a 50-kDa cell wall protein from H. capsulatum yeast was able to bind laminin with high affinity, a process thought to be important in the initial stages of infection [100] . Later, a specific lectin-like interaction between H. capsulatum yeast and macrophage-membrane proteins was identified [101] . This lectin-like binding was initially thought to be specific for b-Gal residues; however, more recent studies have shown binding to human erythrocytes may be mediated through Sia [102] . Treatment of erythrocytes with sialidase confirmed the importance of Sia; however, details regarding observed differences in 'attachment specificity' are not provided [103] .

In developed countries, Aspergillus fumigatus is now regarded as the most important airborne fungal human pathogen, causing aspergilloma, allergic bronchopulmonary aspergillosis and the usually fatal disease invasive aspergillosis in immunocompromised individuals [104] . In all cases infection begins with the inhalation of conidia, which adhere and germinate in the lung. The involvement of Sia in fungal biology has been most extensively studied in A. fumigatus, with several groups having investigated the Sia-dependent adhesion of A. fumigatus conidia to purified extracellular matrix protein (ECM) proteins [105, 106] . The participation of Sia in conidia-ECM adhesion was first proposed following the observation that conidial binding to laminin, fibrinogen and fibronectin could be inhibited by Neu5Ac and sialyllactose [107] . This led the authors to hypothesize the presence of a specific lectin on the conidial wall that binds Sia expressed on ECM proteins, a proposition later substantiated with the purification of a Sia-specific lectin from A. fumigatus [108] . To our knowledge this is the only Sia-specific lectin from a human pathogenic fungal species to be purified, thus providing an opportunity for the identification of similar lectins from other species, as well as providing the first clues as to the role of Sia in fungal pathogenicity. The ability of the purified A. fumigatus Sia-lectin to agglutinate erythrocytes was affected only by Neu5Ac and Sia-containing glycoproteins, including bovine mucin and fetuin, whereas Sia-containing colominic acid and human orosomucoid (a 1 -acid glycoprotein) were unable to inhibit haemagglutination activity. The major oligosaccharides present on human a 1 -acid glycoprotein are tri-and tetra-antennary N-glycans with terminal Neu5Aca2,3/ 6Galb1,4GlcNAc structures [109] . On the other hand, bovine mucin and fetuin contain a significant number of O-glycans with GlcNAcb1,3(Neu5Aca2,6)GalNAc-Ser/ Thr [110] and Neu5Aca2,3Galb1,3(Neu5Aca2,6)GalNA c-Ser/Thr [111] structures, respectively. Therefore, it appears that the Sia-specific lectin from A. fumigatus may recognize Neu5Aca2,6GalNAc structures preferentially over other Sia linkages.

Even though only a handful of Sia-specific lectins have been identified and isolated from plants (see Table 5 and references therein), their historical importance in investigating the expression and biology of Sia is unquestioned. The occurrence, specificity and application of Sia-specific plant lectins has been reviewed elsewhere [112] ; therefore, we will concentrate on the possible significance and function of these lectins in plant biology. A popular theory used to account for the presence of Siaspecific lectins in plants concerns their involvement in plant defence [113] . Some arguments in favour of this role include the fact that these lectins specifically bind Sia [114, 115] , a carbohydrate that plants themselves do not express. This may provide plants with a means of recognizing and combating sialylated pathogens. Further, the digestive tracts of animals capable of feeding on plants are covered with highly sialylated mucins, providing numerous ligands for Sia-specific lectins. Presumably, it is this binding of Sia-specific lectins from elderberry (Sambucus nigra) bark and wheat germ agglutinin that initiates the severe toxicity symptoms observed upon ingestion of plant lectins in higher organisms. The consequence of this is that elderberry, for example, is virtually never attacked in the wild [113] . Moreover, Sia-specific plant lectins, like other plant lectins, are predominantly localized in regions of the plant that are most susceptible to attack, and thus require an adequate protection strategy. For instance, the lectin from elderberry and the leguminous plant Maackia amurensis are found in the bark and seed, respectively [114, 115] . Peumans and van Damme have Cell. Mol. Life Sci. Vol. 63, 2006 Review Article 1343 suggested that this aspect of plant physiology has a direct influence on viability, arguing that 'a growing plant that is half eaten... may [still] survive and even produce viable offspring' [113] . All of the above hypotheses are based on the assertion that a family of plant lectins actually exists that specifically binds Sia. However, this view is not universally shared. The presence of Sia, is thought by some, to only provide an acidic group that enhances the interaction [116] . That is, the interaction with Sia-containing glycoconjugates is believed to be a purely coincidental one. Evidence supporting this assertion includes the observation that free Sia does not interact with 'putative' Sia-specific plant lectins, with Gal or lactose being the real binding partner [117] . The crystal structure of M. amurensis lectin complexed with sialoglycoconjugates shows that a Gal residue occupies the primary binding site [118] . A sulfate group at C3 of Gal instead of Sia was found to bind M. amurensis lectin, indicating that only a charged group is required rather than a complete Sia molecule [119] . However, this would mean that the presence of a Sia molecule, regardless of linkage, would elicit the same effect. This is clearly not the case (see Table 5 ). Finally, Sia-specific lectins appear not to be as widespread in plants as would be expected given their proposed importance in plant defence. In spite of these arguments it is nevertheless difficult to reconcile this view with the fact that these lectins show exquisite specificity for what in essence are the natural sialoglycoconjugates that they would encounter in nature. It is therefore reasonable to suggest that due to evolutionary pressure placed on these plants by sialylated pathogens and/or predators, they have developed extremely specific defence mechanisms.

Sia-specific lectins have a wide variety of functions in animals. Even though for many individual lectins a function is unknown, for the majority their principal role seems to relate to the proper function of the immune system. There are a variety of lectins reported to bind Sia with high specificity in different animal phyla. This strict specificity is of obvious importance, ensuring proper function and regulation of these lectins. However, animals must also cope with numerous pathogens that, as we have already discussed, bind to their hosts via Sia. Since many pathogens have evolved lectins that are highly specific for Sia type and linkage, their hosts have needed to counter with various modifications to avert pathogenic entry, all the while ensuring that the proper ligands for their endogenous lectins are preserved. This 'arms-race', a term used by Angata and Varki [2] , between host and pathogen not only explains the unusual structural complexity of Sia, but also the rapid evolution of some Sia-recognizing lectins, as is the case for the CD33-related siglecs [120] . This section will summarize the numerous Sia-binding proteins identified from invertebrate and vertebrate animals, their function and significance in animal biology.

Sia-specific lectins have been isolated and characterized from various invertebrates, including molluscs, arthropods, echinoderms and urochordates, with many species containing more than one such protein (see Table 6 and references therein). Even though some of these lectins have served as useful tools for the analysis of Sia-containing glycoconjugates, their natural function, in many cases, is unclear. In a similar way to that postulated in plants, it has been assumed that most of these lectins play some role in the defence mechanism against bacterial infections [121] . Invertebrates, without the benefit of an adaptive immune system, possess an immensely strong innate immune response to counteract the continuous challenge of infection. Innate immunity is mainly targeted toward antigens such as lipopolysaccharides commonly present on the In addition to their role in the immune system, invertebrate lectins have been reported to play an important role in sperm-egg binding, as shown for the species-specific Sia-binding protein [350-kDa sperm-binding protein (SBP)] found in sea urchins [123] .

In vertebrates a variety of Sia-dependent lectins are known to play an important role in cellular communication with many of them found in the immune system (see Table 7 for full listing). The first vertebrate Sia-binding protein reported was Complement Factor H, a soluble serum fac-tor that is part of the alternative pathway of complement, one of the earliest response components of the innate immune system [124] . Another important group of vertebrate Sia-binding proteins are the selectins, a family of C-type lectins that recognize sialyl Lewis x (sLe x ) and sialyl Lewis a (sLe a ) [125] . Together with other cell adhesion molecules, selectins mediate the adhesion and extravasation of leukocytes from the vascular bed into the surrounding tissue [126] . Furthermore, P-selectin has also been shown to be involved in tumour metastasis [127] . Siglecs are the largest family of sialic acid-recognizing lectins identified thus far with 11 members identified in the human genome. Each siglec has a distinct preference for specific Sia type and linkage (see Table 7 ). Apart from Siglec-4, all siglecs are expressed by cells of the immune system. However, the function/s of most members of the siglec family are only poorly understood, though their cell-type-specific expression suggests involvement in discrete cellular events. For further information we recommend that interested readers see recent comprehensive reviews from Varki and Angata [120] and Crocker [128] .

The immense structural diversity and wide distribution of Sia suggest that sialobiology has only scratched the surface regarding the identification of Sia-specific lectins in nature. This is particularly the case in the microbial world, where it seems probable that a vast array of Siaspecific lectins with unique specificities and functions exist that may not only prove useful tools for studying the biology of Sia, but may even represent novel targets for drug discovery. The biological roles of many of the Sia-specific lectins described still remain unknown; therefore, detailed investigations are necessary to further analyse the interaction of Sia-binding proteins with their counter-receptors, as well as to elucidate the resulting signals controlling their function. This will not only broaden our understanding of the role of Sia in biological systems but also its relevance in biomedical research. Of particular importance is the need for sialobiologists to better understand how Sia and Sia-specific lectins drive the constantly evolving 'armsrace' being waged between pathogenic microorganisms and their hosts.

In this review we have summarized the key features relating to the occurrence, specificity and function of the Sia-specific lectins currently known, specifically those identified and characterized from microorganisms and non-vertebrate eukaryotes. The challenge now for Sialobiologists is to not only continue identifying, but also analysing the function of novel Sia-specific lectins, thus adding to the growing list summarized herein. 

toroviral receptor-destroying enzymes

The S protein of bovine coronavirus is a hemagglutinin recognizing 9-O-acetylated sialic acid as a receptor determinant

Recognition of cellular receptors by bovine coronavirus

The hemagglutinin-esterase of mouse hepatitis virus strain S is a sialate-4-O-acetylesterase

Neuraminidase treatment of avian infectious bronchitis coronavirus reveals a hemagglutinating activity that is dependent on sialic acid-containing receptors on erythrocytes

Transmissible gastroenteritis coronavirus, but not the related porcine respiratory coronavirus, has a sialic acid (N-glycolylneuraminic acid) binding activity

Characterization of the sialic acid binding activity of transmissible gastroenteritis coronavirus by analysis of haemagglutination-deficient mutants

Binding of transmissible gastroenteritis coronavirus to brush border membrane sialoglycoproteins

Crystal structure of human junctional adhesion molecule 1: implications for reovirus binding

Utilization of sialic acid as a coreceptor enhances reovirus attachment by multistep adhesion strengthening

Reovirus binding to cell surface sialic acid potentiates virus-induced apoptosis

The viral sigma1 protein and glycoconjugates containing alpha2-3-linked sialic acid are involved in type 1 reovirus adherence to M cell apical surfaces

Human and most animal rotavirus strains do not require the presence of sialic acid on the cell surface for efficient infectivity

Glycosphingolipid binding specificities of rotavirus: identification of a sialic acid-binding epitope

Molecular biology of rotavirus cell entry

Multistep entry of rotavirus into cells: a Versaillesque dance

Specificity and affinity of sialic acid binding by the rhesus rotavirus VP8* core

Evidence for a direct role for sialic acid in the attachment of encephalomyocarditis virus to human erythrocytes

The major and minor group receptor families contain all but one human rhinovirus serotype

Biological properties of mengovirus: characterization of avirulent, hemagglutinationdefective mutants

Effect of neuraminidase pretreatment on the susceptibility of normal and transformed mammalian cells to bovine enterovirus 261

Capsid region involved in hepatitis A virus binding to glycophorin A of the erythrocyte membrane

Enterovirus 70 binds to different glycoconjugates containing alpha2,3-linked sialic acid on different cell lines

Theiler's virus persistence in the central nervous system of mice is associated with continuous viral replication and a difference in outcome of infection of infiltrating macrophages versus oligodendrocytes

Sialylation of the host receptor may modulate entry of demyelinating persistent Theiler's virus

Pilus and nonpilus bacterial adhesins: assembly and function in cell recognition

Cloning and characterization of the S fimbrial adhesin II complex of an Escherichia coli O18: K1 meningitis isolate

Specificity of S fimbriae on recombinant Escherichia coli: preferential binding to gangliosides expressing NeuGc alpha (2-3)Gal and NeuAc alpha (2-8)NeuAc

Functional analysis of the sialic acid-binding adhesin SfaS of pathogenic Escherichia coli by site-specific mutagenesis

Ganglioside epitope recognized by K99 fimbriae from enterotoxigenic Escherichia coli

Sialic acid and N-acetylgalactosamine specific bacterial lectins of enterotoxigenic Escherichia coli (ETEC)

Calf small intestine receptors for K99 fimbriated enterotoxigenic Escherichia coli

Involvement of the MN blood group antigen in shear-enhanced hemagglutination induced by the Escherichia coli F41 adhesin

Plasmid-controlled colonization factor associated with virulence in Escherichia coli enterotoxigenic for humans

Coli surface antigens 1 and 3 of colonization factor antigen II-positive enterotoxigenic Escherichia coli: morphology, purification and immune responses in humans

The possession of three novel coli surface antigens by enterotoxigenic Escherichia coli strains positive for the pu

Sialic acid-specific lectins tative colonization factor PCF8775

Purification and characterization of the CFA/I antigen of enterotoxigenic Escherichia coli

The binding of colonization factor antigens of enterotoxigenic Escherichia coli to intestinal cell membrane proteins

Colonization factor antigen on enterotoxigenic Escherichia coli is a sialicspecific lectin

Purification and characterization of CS2, a sialic acid-specific haemagglutinin of enterotoxigenic Escherichia coli

The disease spectrum of Helicobacter pylori: the immunopathogenesis of gastroduodenal ulcer and gastric cancer

Helicobacter pylori SabA adhesin in persistent infection and chronic inflammation

Carbohydrate binding specificity of the neutrophil-activating protein of Helicobacter pylori

Helicobacter pylori and complex gangliosides

The sialic acid binding SabA adhesin of Helicobacter pylori is essential for nonopsonic activation of human neutrophils

Identification of a new sialic acid-binding protein in Helicobacter pylori

Glycoconjugate distribution in the human fundic mucosa revealed by lectin-and glycoprotein-gold cytochemistry

Binding between outer membrane proteins of nontypeable Haemophilus influenzae and human nasopharyngeal mucin

Purification and characterization of an adhesin from Pasteurella haemolytica

The HMW1 adhesin of nontypeable Haemophilus influenzae recognizes sialylated glycoprotein receptors on cultured human epithelial cells

Blocking of fimbria-mediated adherence of Haemophilus influenzae by sialyl gangliosides

Specificity of salivary-bacterial interactions: II. Evidence for a lectin on Streptococcus sanguis with specificity for a NeuAcalpha2,3Ga1beta1,3Ga1NAc sequence

Identification and characterization of hsa, the gene encoding the sialic acid-binding adhesin of Streptococcus gordonii DL1

An accessory sec locus of Streptococcus gordonii is required for export of the surface protein GspB and for normal levels of binding to human platelets

Identification of platelet receptors for the Streptococcus gordonii DL1 sialic acid-binding adhesin

The Streptococcus gordonii surface proteins GspB and Hsa mediate binding to sialylated carbohydrate epitopes on the platelet membrane glycoprotein Ibalpha

A serine-rich glycoprotein of Streptococcus sanguis mediates adhesion to platelets via GPIb

The genome sequence of the probiotic intestinal bacterium Lactobacillus johnsonii NCC 533

Role of SraP, a serine-rich surface protein of Staphylococcus aureus, in binding to human platelets

Microbial recognition of target-cell glycoconjugates

Membrane traffic and the cellular uptake of cholera toxin

Different response of the knockout mice lacking b-series gangliosides against botulinum and tetanus toxins

The surface trans-sialidase family of Trypanosoma cruzi

Enzymically inactive members of the trans-sialidase family from Trypanosoma cruzi display beta-galactose binding activity

Transsialidase from Trypanosoma cruzi binds host T-lymphocytes in a lectin manner

Enzymatically inactive trans-sialidase from Trypanosoma cruzi binds sialyl and beta-galactopyranosyl residues in a sequential ordered mechanism

Studies on the role of red blood cell glycoproteins as receptors for invasion by Plasmodium falciparum merozoites

Binding of Plasmodium falciparum 175-kilodalton erythrocyte binding antigen and invasion of murine erythrocytes requires N-acetylneuraminic acid but not its O-acetylated form

A malaria invasion receptor, the 175-kilodalton erythrocyte binding antigen of Plasmodium falciparum recognizes the terminal Neu5Ac(alpha 2-3)Gal-sequences of glycophorin A

Glycophorin C is the receptor for the Plasmodium falciparum erythrocyte binding ligand PfEBP-2 (baebl)

Characterization of a Plasmodium falciparum erythrocyte-binding

A novel erythrocyte binding antigen-175 paralogue from Plasmodium falciparum defines a new trypsin-resistant receptor on human erythrocytes

Invasion of erythrocytes by malaria parasites: erythrocyte ligands and parasite receptors

Glycophorin B as an EBA-175 independent Plasmodium falciparum receptor of human erythrocytes

Evidence for two-stage binding by the 175-kD erythrocyte binding antigen of Plasmodium falciparum

Receptor and ligand domains for invasion of erythrocytes by Plasmodium falciparum

Structural basis for the EBA-175 erythrocyte invasion pathway of the malaria parasite Plasmodium falciparum

Detection of lectin from Chrysosporium keratinophilum (Frey) Carmichael and Anixiopsis stercoraria (Hansen) Hansen by inhibition of haemagglutination

Evidence for the lectin nature of some dermatophyte haemagglutinins

Murine laminin binds to Histoplasma capsulatum. A possible mechanism of dissemination

Interaction of murine macrophage-membrane proteins with components of the pathogenic fungus Histoplasma capsulatum

Histoplasma capsulatum yeast cells attach and agglutinate human erythrocytes

Pathogenesis II: fungal responses to host responses: interaction of host cells with fungi

The pathobiology of Aspergillus fumigatus

Adhesion of Aspergillus species to extracellular matrix proteins: evidence for involvement of negatively charged carbohydrates on the conidial surface

Binding of human fibronectin to Aspergillus fumigatus conidia

Sialic acid-dependent recognition of laminin and fibrinogen by Aspergillus fumigatus conidia

Purification and partial characterization of a 32-kilodalton sialic acid-specific lectin from Aspergillus fumigatus

Carbohydrate composition and immunomodulatory activity of different glycoforms of alpha1-acid glycoprotein

Structure determination of five sialylated trisaccharides with core types 1, 3 or 5 isolated from bovine submaxillary mucin

Structural determination of the O-linked sialyl oligosaccharides liberated from fetuin with endo-alpha-N-acetylgalactosaminidase-S by HPLC analysis and 600-MHz 1H-NMR spectroscopy

Sialic acid binding lectins

Lectins as plant defense proteins

Characterization of the carbohydrate binding specificity of the leukoagglutinating lectin from Maackia amurensis. Comparison with other sialic acid-specific lectins

The elderberry (Sambucus nigra L.) bark lectin recognizes the Neu5Ac

Gal/GalNAc sequence

Plant lectins: occurrence, biochemistry, functions and applications

The immobilized leukoagglutinin from the seeds of Maackia amurensis binds with high affinity to complex-type Asn-linked oligosaccharides containing terminal sialic acid-linked alpha-2,3 to penultimate galactose residues

An unusual carbohydrate binding site revealed by the structures of two Maackia amurensis lectins complexed with sialic acid-containing oligosaccharides

Enhanced 3-O-sulfation of galactose in Asn-linked glycans and Maackia amurensis lectin binding in a new Chinese hamster ovary cell line

Siglecs -the major subfamily of I-type lectins

Recent advances in the innate immunity of invertebrate animals

A cytolytic function for a sialic acid-binding lectin that is a member of the pentraxin family of proteins

Identification of the sea urchin 350-kDa sperm-binding protein as a new sialic acid-binding lectin that belongs to the heat shock protein 110 family: implication of its binding to gangliosides in sperm lipid rafts in fertilization

A novel sialic acid binding site on factor H mediates serum resistance of sialylated Neisseria gonorrhoeae

Selectin-carbohydrate interactions and the initiation of the inflammatory response

P-selectin deficiency attenuates tumor growth and metastasis

Siglecs in innate immunity

Sialic acid-specific lectins

Structure of the haemagglutinin membrane glycoprotein of influenza virus at 3 Å resolution

X-ray structures of H5 avian and H9 swine influenza virus hemagglutinins bound to avian and human receptor analogs

The 2.2 Å resolution crystal structure of influenza B neuraminidase and its complex with sialic acid

Structure of the haemagglutinin-esterase-fusion glycoprotein of influenza C virus

Structure of the haemagglutinin-neuraminidase from human parainfluenza virus type III

Structural studies of the parainfluenza virus 5 hemagglutinin-neuraminidase tetramer in complex with its receptor, sialyllactose

Purification and characterization of the hemagglutinin-neuraminidase of porcine rubulavirus LPMV

Membrane fusion of mumps virus with ghost erythrocytes and CV-1 cells

High-resolution structure of a polyomavirus VP1-oligosaccharide complex: implications for assembly and receptor binding

Sialyloligosaccharide receptors of binding variants of polyoma virus

Gangliosides are receptors for murine polyoma virus and SV40

Infection of glial cells by the human polyomavirus JC is mediated by an Nlinked glycoprotein containing terminal alpha(2-6)-linked sialic acids

An N-linked glycoprotein with alpha(2,3)-linked sialic acid is a receptor for BK virus

Structural and functional analysis of the surface protein of human coronavirus OC43

Hemagglutinating encephalomyelitis virus attaches to N-acetyl-9-O-acetylneuraminic acid-containing receptors on erythrocytes: comparison with bovine coronavirus and influenza C virus

Crystal structure of reovirus attachment protein sigma1 reveals evolutionary relationship to adenovirus fiber

Attachment and infection to MA104 cells of avian rotaviruses require the presence of sialic acid on the cell surface

Structure and function of a ganglioside receptor for porcine rotavirus

Crystallization and preliminary X-ray diffraction analysis of the sialic acid-binding domain (VP8*) of porcine rotavirus strain CRW-8

Initial interaction of rotavirus strains with N-acetylneuraminic (sialic) acid residues on the cell surface correlates with VP4 genotype, not species of origin

Group C rotavirus requires sialic acid for erythrocyte and cell receptor binding

Ganglioside GM(1a) on the cell surface is involved in the infection by human rotavirus KUN and MO strains

The rhesus rotavirus VP4 sialic acid binding domain has a galectin fold with a novel carbohydrate binding site

Identification of mutations in the rotavirus protein VP4 that alter sialic-acid-dependent infection

The site of bluetongue virus attachment to glycophorins from a number of animal erythrocytes

Crystal structure of species D adenovirus fiber knobs and their sialic acid binding sites

Adenovirus type 37 uses sialic acid as a cellular receptor

Initial interactions of subgenus D adenoviruses with A549 cellular receptors: sialic acid versus alpha(v) integrins

Sialic acid acts as a receptor for equine rhinitis A virus binding and infection

Mutations adjacent to the dimple of the canine parvovirus capsid structure affect sialic acid binding

Structure of adeno-associated virus serotype 5

Attachment of bovine parvovirus to O-linked alpha 2,3 neuraminic acid on glycophorin A

Structure of adeno-associated virus type 4

Adeno-associated virus serotype 4 (AAV4) and AAV5 both require sialic acid binding for hemagglutination and efficient transduction but differ in sialic acid linkage specificity

Regulation of susceptibility and cell surface receptor for the B-lymphotropic papovavirus by Nglycosylation

The role of sialic acid and Ca 2+ ions in rabies virus-infected foxes brain

Involvement of carbohydrates in vesicular stomatitis virus-cell early interaction

Attenuated murine cytomegalovirus binds to N-acetylglucosamine and shift to virulence may involve recognition of sialic acids

Cell membrane bound N-acetylneuraminic acid is involved in the infection of fibroblasts and phorbol-ester differentiated monocyte-like cells with human cytomegalovirus (HCMV)

The Vero cell receptor for the hepatitis B virus small S protein is a sialoglycoprotein

Glycoconjugate binding of gastric and enterohepatic Helicobacter spp

Attachment of nontypable Haemophilus influenzae to human pharyngeal epithelial cells mediated by a ganglioside receptor

Interaction of the salivary low-molecular-weight mucin (MG2) with Actinobacillus actinomycetemcomitans

Crystal structure of the OpcA integral membrane adhesin from Neisseria meningitidis

Recognition of saccharides by the OpcA, OpaD and outer membrane proteins from Neisseria meningitidis

Erythrocyte gangliosides act as receptors for Neisseria subflava: identification of the Sia-1 adhesin

Adherence of Brucella to human epithelial cells and macrophages is mediated by sialic acid residues

Pseudomonas aeruginosa binds to neoglycoconjugates bearing mucin carbohydrate determinants and predominantly to sialyl-Lewis x conjugates

In the immature mouse, Pseudomonas aeruginosa pili bind a 57-kd (alpha 2-6) sialylated corneal epithelial cell surface protein: a first step in infection

Role of Bordetella bronchiseptica sialic acid-binding hemagglutinin as a putative colonization factor

Glycoconjugates as components of receptors for Bordetella avium on the tracheal mucosa of turkeys

Attachment of Moraxella catarrhalis to pharyngeal epithelial cells is mediated by a glycosphingolipid receptor

Involvement of a sialic acid-binding lectin with hemagglutination and hydrophobicity of Flavobacterium psychrophilum

Treponema pallidum attachment to surface and matrix proteins of cultured rabbit epithelial cells

Binding of salivary glycoprotein-secretory immunoglobulin A complex to the surface protein antigen of Streptococcus mutans

Preparation of a sialic acid-binding protein from Streptococcus mitis KS32AR

Identification of N-acetylneuraminyl alpha 2 → 3 poly-N-acetyllactosamine glycans as the receptors of sialic acid-binding Streptococcus suis strains

Contribution of novel choline-binding proteins to adherence, colonization and immunogenicity of Streptococcus pneumoniae

Adhesion of viridans group streptococci to sialic acid-, galactose-and N-acetylgalactosamine-containing receptors

Adherence of Ureaplasma urealyticum to human epithelial cells

Interaction of Mycoplasma pneumoniae with erythrocyte glycolipids of I and i antigen types

Interaction of Mycoplasma gallisepticum with sialyl glycoproteins. Infect. Immun

The 1.25 Å resolution refinement of the cholera toxin B-pentamer: evidence of peptide backbone strain at the receptor-binding site

Studies on hemolytic action of a hemolysin produced by Vibrio mimicus. Microbiol. Immunol

Structural analysis of the catalytic and binding sites of Clostridium botulinum neurotoxin B

Gangliosides are the binding substances in neural cells for tetanus and botulinum toxins in mice

The crystal structure of tetanus toxin Hc fragment complexed with a synthetic GT1b analogue suggests crosslinking between ganglioside receptors and the toxin

Quantitative analysis of bacterial toxin affinity and specificity for glycolipid receptors by surface plasmon resonance

Interaction of Clostridium perfringens delta toxin with erythrocyte and liposome membranes and relation with the specific binding to the ganglioside GM2

Exploration of the GM1 receptor-binding site of heat-labile enterotoxin and cholera toxin by phenyl-ringcontaining galactose derivatives

Structure of a pertussis toxin-sugar complex as a model for receptor binding

Binding of pertussis toxin to lipid vesicles containing glycolipids

Sialic acid-specific lectins

The crystal structure and mode of action of trans-sialidase, a key enzyme in Trypanosoma cruzi pathogenesis

Detection of lectin activity in Leishmania promastigotes and amastigotes

Purification and characterization of a sialic acid-specific lectin from Tritrichomonas mobilensis

Sialic acid-specific lectin from Tritrichomonas foetus

Some properties of sialic-acid binding systems in Tritrichomonas suis and Tritrichomonas foetus

A Plasmodium falciparum homologue of Plasmodium vivax reticulocyte binding protein (PvRBP1) defines a trypsin-resistant erythrocyte invasion pathway

Mapping regions containing binding residues within functional domains of Plasmodium vivax and Plasmodium knowlesi erythrocyte-binding proteins

Babesia divergens and Plasmodium falciparum use common receptors, glycophorins A and B, to invade the human red blood cell

Babesia bovis merozoites invade human, ovine, equine, porcine and caprine erythrocytes by a sialic acid-dependent mechanism followed by developmental arrest after a single round of cell fission

Babesia caballi and Babesia equi: implications of host sialic acids in erythrocyte infection

A sialic acid-binding lectin from the mushroom Hericium erinaceum

Purification and characterization of a Neu5Acalpha2-6Galbeta1-4Glc/GlcNAcspecific lectin from the fruiting body of the polypore mushroom Polyporus squamosus

Psathyrella velutina mushroom lectin exhibits high affinity toward sialoglycoproteins possessing terminal N-acetylneuraminic acid alpha 2,3-linked to penultimate galactose residues of trisialyl N-glycans. Comparison with other sialic acid-specific lectins

A sialic acid-specific lectin from the mushroom Paecilomyces japonica that exhibits hemagglutination activity and cytotoxicity

Structural basis of a fungal galectin from Agrocybe cylindracea for recognizing sialoconjugate

Isolation of a new heterodimeric lectin with mitogenic activity from fruiting bodies of the mushroom Agrocybe cylindracea

Recognition of fibronectin by Penicillium marneffei conidia via a sialic acid-dependent process and its relationship to the interaction between conidia and laminin

Purification and molecular characterization of a sialic acid specific lectin from the phytopathogenic fungus Macrophomina phaseolina

Strong affinity of Maackia amurensis hemagglutinin (MAH) for sialic acid-containing Ser/Thr-linked carbohydrate chains of N-terminal octapeptides from human glycophorin A

A comparative study of bark lectins from three elderberry (Sambucus) species

Purification and characterization of a Neu5Ac alpha 2 → 6Gal-beta1 → 4GlcNAc and HSO3(-) → 6Galbeta 1 → GlcNAc specific lectin in tuberous roots of Trichosanthes japonica

Mistletoe lectin I is a sialic acid-specific lectin with strict preference to gangliosides and glycoproteins with terminal Neu5Ac alpha 2-6Gal beta 1-4GlcNAc residues

Saracin: a lectin from Saraca indica seed integument recognizes complex carbohydrates

Structural basis for the unusual carbohydrate-binding specificity of jacalin towards galactose and mannose

Crystallographic refinement and structure analysis of the complex of wheat germ agglutinin with a bivalent sialoglycopeptide from glycophorin A

Identification of two binding sites for wheat-germ agglutinin on polylactosamine-type oligosaccharides

Sialic acid binding lectins from leaf of mulberry (Morus alba)

The prickly lettuce agglutinin. I. Isolation from leaves of the prickly lettuce plant (Lactuca scariole)

A heterogeneous sialic acid-binding lectin with affinity for bacterial LPS from horse mussel (Modiolus modiolus) hemolymph

A haemagglutinin in the tissue fluid of the Pacific oyster, Crassostrea gigas, with specificity for sialic acid residues in glycoproteins

Occurrence and characteristics of agglutination of Vibrio cholerae by serum from the eastern oyster

Factors in haemolymph of the mussel, Mytilus edulis L., of possible significance as defence mechanisms

Purification and partial characterization of a N-glycolyneuraminic acid specific lectin from the clam Anadara granosa (L)

Specificity of the sialic acid-binding lectin from the snail Cepaea hortensis

The specificity of the binding site of AchatininH, a sialic acid-binding lectin from Achatina fulica

N-glycolylneuraminic acid specific lectin from Pila globosa snail

Binding determinants of the sialic acid-specific lectin from the slug Limax flavus

Binding of alpha2-macroglobulin and limulin: regulation of the plasma haemolytic system of the American horseshoe crab

Functional and structural diversities of C-reactive proteins present in horseshoe crab hemolymph plasma

Isolation and characterization of a sialic acid-specific lectin from hemolymph of the Southeast asian horseshoe crab Tachypleus gigas

Binding studies of a sialic acid-specific lectin from the horseshoe crab Carcinoscorpius rotunda cauda with various sialoglycoproteins

The specificity of Centruroides sculpturatus Ewing (Arizona lethal scorpion) hemolymph agglutinins

Sialic acid-binding lectins in the 'whip scorpion' (Mastigoproctus giganteus) serum

A comparative study on the specificity of Androctonus australis (Saharan scorpion) and Limulus polyphemus (horseshoe crab) agglutinins

Serum lectins from the scorpion Vaejovis spinigerus Wood bind sialic acids

Purification of a sialic acid-specific lectin from the Indian scorpion Heterometrus granulomanus

Sialic acid binding lectins in the serum of American spiders of the genus Aphonopelma

Ultrastructural localization of a sialic acid-specific hemolymph lectin in the hemocytes and other tissues of the hard tick Ixodes ricinus (Acari; Chelicerata)

Isolation and characterization of Dorin M, a lectin from plasma of the soft tick Ornithodoros moubata

Tick lectins: structural and functional properties

Purification and characterization of a sialic acid specific lectin from the hemolymph of the freshwater crab Paratelphusa jacquemontii

Purification and characterization of an O-acetylsialic acid-specific lectin from a marine crab Cancer antennarius

Purification and characterization of N-glycolyneuraminic-acid-specific lectin from Scylla serrata

The lectin from the crustacean Liocarcinus depurator recognizes O-acetylsialic acids

Heterogeneity of lobster agglutinins. I. Purification and physiochemical characterization

Serological characterization of humoral lectins from the freshwater prawn Macrobrachium rosenbergii

Monodin, a new sialic acid specific lectin from black tiger prawn (Penaeus monodon)

Purification and characterization of a lectin from the white shrimp Litopenaeus setiferus (Crustacea decapoda) hemolymph

Characterization and partial purification of a lectin from the hemolymph of the white shrimp Litopenaeus schmitti

Carbohydrate binding specificity of immobilized Allomyrina dichotoma lectin II

Tunicate lectins: distribution and specificity

Insights into the molecular basis leukocyte tethering and rolling revealed by structures of P-and E-selectin bound to sLeX and PSGL-1

Crystal structure of the N-terminal domain of sialoadhesin in complex with 3′ sialyllactose at 1.85 Å resolution

High resolution crystal structures of Siglec-7. Insights into ligand specificity in the siglec family

Inhibition of the alternative pathway of human complement by structural analogues of sialic acid

Lectin activities of cytokines: functions and putative carbohydrate-recognition domains

Interleukin-2 binds to ganglioside GD1b

) I-type lectins

Sperm binding to oviductal epithelial cells in the rat: role of sialic acid residues on the epithelial surface and sialic acid-binding sites on the sperm surface

Carbohydrates mediate the adherence of hamster sperm to oviductal epithelium

Characterization of dystroglycan-laminin interaction in peripheral nerve

Mammalian fetuin-binding proteins sarcolectin, aprotinin and calcyclin display differences in their apparent carbohydrate specificity

Sialic acid-specific lectins

Differential expression of calcyclin and its accessible ligands in various types of cutaneous tumors

A sialic acid-binding lectin from ovine placenta: purification, specificity and interaction with actin

Ribonuclease-activity of sialic acid-binding lectin from Rana catesbeiana eggs

Modulation of sialic acid-binding proteins of rat uterus in response to changing hormonal milieu